bluuebunny/crossref_metadata_2025 huggingface dataset:
DESIGN, FABRICATION AND USE OF A NOVEL PENNING DISCHARGE SOURCE TO SYNTHESIZE CARBON AND CARBON NITRIDE FILMS
Authors: YANG B. Q. , FENG P. X.
Published: October 2008

The Penning discharge (PD) sputtering deposition technique was developed and used to synthesize carbon and carbon nitride films. This novel PD source, which was very different from traditional penning electrodes, was based on configurations of two hollow interpenetrating cylindrical electrodes. The discharge voltage, current, and spectral emissions of the plasma source had been characterized. In the pulsed gas beam plasma discharge, the intensity of spectral emission from discharge plasma supplied by the positive voltage was higher than that supported by using the negative voltage. In the static gas plasma discharge, the negative voltage discharge yielded a stable and concentrated plasma source, and the discharge current linearly increased with an increase of the discharge voltage. The phase change of the discharge following the variation of gas pressures was observed.

After characterization, the PD source was used in the sputtering deposition of both carbon and carbon nitride films. Microscope images of samples indicated that nanostructured films had been obtained. All samples were characterized by using Raman scattering spectroscopy.
STUDY OF COMPLEX ELECTROMAGNETIC FIELD USING HYBRID ISOPARAMETRIC FINITE ELEMENTS
Authors: LIU NIAN , XIE CHI
Published: October 2008

For complex electromagnetic fields in modern physics, a hybrid isoparametric finite element method (HIFEM) with high accuracy is introduced in the paper. The complex electromagnetic field in an electromagnetic device has been calculated successfully by the hybrid isoparametric finite element method (HIFEM) and the electromagnetic properties of the electromagnetic device under specific work conditions are evaluated. With the help of microcomputers, the electromagnetic simulation given in this paper is very useful in the analysis of operating properties under different work conditions and design of electromagnetic devices.
The Role of Gβγ Subunits in the Organization, Assembly, and Function of GPCR Signaling Complexes
Authors: Dupré Denis J. , Robitaille Mélanie , Rebois R. Victor , Hébert Terence E.
Published: October 2008

The role of Gβγ subunits in cellular signaling has become well established in the past 20 years. Not only do they regulate effectors once thought to be the sole targets of Gα subunits, but it has become clear that they also have a unique set of binding partners and regulate signaling pathways that are not always localized to the plasma membrane. However, this may be only the beginning of the story. Gβγ subunits interact with G protein–coupled receptors, Gα subunits, and several different effector molecules during assembly and trafficking of receptor-based signaling complexes and not simply in response to ligand stimulation at sites of receptor cellular activity. Gβγ assembly itself seems to be tightly regulated via the action of molecular chaperones and in turn may serve a similar role in the assembly of specific signaling complexes. We propose that specific Gβγ subunits have a broader role in controlling the architecture, assembly, and activity of cellular signaling pathways.
Progress in Genetic Studies of Pain and Analgesia
Authors: LaCroix-Fralish Michael L. , Mogil Jeffrey S.
Published: October 2008

Interindividual variability in pain sensitivity and the response to analgesic manipulations remains a considerable clinical challenge as well as an area of intense scientific investigation. Techniques in this field have matured rapidly so that much relevant data have emerged only in the past few years. Our increasing understanding of the genetic mediation of these biological phenomena have nonetheless revealed their surprising complexity. This review provides a comprehensive picture and critical analysis of the field and its prospects.
Lithium's Antisuicidal Efficacy: Elucidation of Neurobiological Targets Using Endophenotype Strategies
Authors: Kovacsics Colleen E. , Gottesman Irving I. , Gould Todd D.
Published: October 2008

Lithium used as a drug treatment for major mental disorders such as bipolar disorder and depression is effective in reducing the risk of both attempted and completed suicide. However, the mechanisms underlying lithium's antisuicidal actions are not yet known, limiting the development of novel lithium-mimetic compounds that may help reduce suicide risk with fewer undesirable side effects. Suicide is a complex behavior, complicated to study in humans, and impossible to fully reproduce in animal models. The endophenotype approach, by which quantitative measures of neurobiological function are used to assess and subclassify psychiatric illness, may present a path to new discoveries. Aggression and impulsivity are candidate endophenotypes strongly associated with suicide; we review the evidence supporting aggression and impulsivity as suicide endophenotypes, as well as the effects of lithium on these constructs in both humans and rodents. Examining the mechanisms that contribute to lithium's antiaggressive and antiimpulsive effects may assist in understanding how lithium acts to reduce the risk of suicide and in elucidating the neurobiological underpinnings of suicidal behavior.
Global and Site-Specific Quantitative Phosphoproteomics: Principles and Applications
Authors: Macek Boris , Mann Matthias , Olsen Jesper V.
Published: October 2008

Protein phosphorylation is a key posttranslational modification, which reversibly regulates almost all processes in the living cell. Deregulated signaling is a hallmark of cancer and other diseases, and protein kinases are prominent drug targets. Phosphorylation events are commonly probed in a targeted manner by phosphorylation-specific antibodies. In contrast, advances in proteomics technology, including phosphopeptide enrichment, high-accuracy mass spectrometry, and associated bioinformatics now make it possible to analyze entire phosphoproteomes. Quantitative methods can assess the relative change in phosphorylation for several thousand sites in a single experiment. Here we review enrichment strategies and methods for mass spectrometric fragmentation and analysis of phosphopeptides. We also describe different quantitative methods and their application to problems in cell signaling and drug target discovery. Emerging phosphoproteomics technologies are becoming more comprehensive, robust, and generically applicable to a wide range of questions, including areas outside traditional eukaryotic cell signaling such as Ser/Thr/Tyr signaling in bacteria.
Lipid Mediators in Health and Disease: Enzymes and Receptors as Therapeutic Targets for the Regulation of Immunity and Inflammation
Authors: Shimizu Takao
Published: October 2008

Prostaglandins, leukotrienes, platelet-activating factor, lysophosphatidic acid, sphingosine 1-phosphate, and endocannabinoids, collectively referred to as lipid mediators, play pivotal roles in immune regulation and self-defense, and in the maintenance of homeostasis in living systems. They are produced by multistep enzymatic pathways, which are initiated by the de-esterification of membrane phospholipids by phospholipase A2s or sphingo-myelinase. Lipid mediators exert their biological effects by binding to cognate receptors, which are members of the G protein–coupled receptor superfamily. The synthesis of the lipid mediators and subsequent induction of receptor activity is tightly regulated under normal physiological conditions, and enzyme and/or receptor dysfunction can lead to a variety of disease conditions. Thus, the manipulation of lipid mediator signaling, through either enzyme inhibitors or receptor antagonists and agonists, has great potential as a therapeutic approach to disease. In this review, I summarize our current state of knowledge of the synthesis of lipid mediators and the function of their cognate receptors, and discuss the effects of genetic or pharmacological ablation of enzyme or receptor function on various pathophysiological processes.
Targeting Proteins for Destruction by the Ubiquitin System: Implications for Human Pathobiology
Authors: Schwartz Alan L. , Ciechanover Aaron
Published: October 2008

Cellular proteins are in a dynamic state maintained by synthesis and degradation. The ubiquitin proteolytic pathway is responsible for the degradation of the bulk of cellular proteins including short-lived, regulatory, and misfolded/denatured proteins. Ubiquitin-mediated proteolysis involves covalent attachment of multiple ubiquitin molecules to the protein substrate and degradation of the targeted protein by the 26S proteasome. Recent understanding of the molecular mechanisms involved provides a framework to understand a wide variety of human pathophysiological states as well as therapeutic interventions. This review focuses on the response to hypoxia, inflammatory diseases, neurodegenerative diseases, and muscle-wasting disorders, as well as human papillomaviruses, cervical cancer and other malignancies.
Small-Molecule Inhibitors of the MDM2-p53 Protein-Protein Interaction to Reactivate p53 Function: A Novel Approach for Cancer Therapy
Authors: Shangary Sanjeev , Wang Shaomeng
Published: October 2008

Tumor suppressor p53 is an attractive cancer therapeutic target because it can be functionally activated to eradicate tumors. Direct gene alterations in p53 or interaction between p53 and MDM2 proteins are two alternative mechanisms for the inactivation of p53 function. Designing small molecules to block the MDM2-p53 interaction and reactivate the p53 function is a promising therapeutic strategy for the treatment of cancers retaining wild-type p53. This review will highlight recent advances in the design and development of small-molecule inhibitors of the MDM2-p53 interaction as new cancer therapies. A number of these small-molecule inhibitors, such as analogs of MI-219 and Nutlin-3, have progressed to advanced preclinical development or early phase cinical trials.
Regulatory mechanisms underlying agmatine homeostasis in humans
Authors: Haenisch Britta , von Kügelgen Ivar , Bönisch Heinz , Göthert Manfred , Sauerbruch Tilman , Schepke Michael , Marklein Günter , Höfling Katja , Schröder Detlev , Molderings Gerhard J.
Published: October 2008

Regulation of agmatine homeostasis has so far only been poorly defined. In the present study, three mechanisms regulating human agmatine homeostasis were investigated. 1) Enzymatic regulation: expression of arginine decarboxylase, diamine oxidase, and ornithine decarboxylase in human colon neoplastic tissue was, at the mRNA level, about 75% and 50% lower and 150% higher, respectively, than in the adjacent normal tissue; expression of agmatinase was unchanged. 2) Bacteria-derived agmatine: ten representative bacteria strains of the human intestinal microbiota considerably differed in agmatine production and its efflux into their surrounding fluid, suggesting that the composition of the intestinal microbiota influences the agmatine availability in the gut lumen for absorption. 3) Regulation of blood plasma agmatine concentration by the human liver: at low concentrations in portal venous blood plasma, agmatine either slightly increased or further decreased in blood plasma through liver passage. Above a threshold of 14 ng/ml agmatine in the portal venous blood plasma, substantial hepatic agmatine removal from blood occurred. Taken together, a perturbation of agmatine homeostasis has been proven to be involved in the regulation of malignant cell proliferation. The amount of agmatine available for absorption, which is an important physiological source of agmatine in the human organism, should differ considerably depending on the composition of the bacterial flora in the chyme since the various species of intestinal bacteria largely differ in their ability to form agmatine. Finally, evidence has been presented that the liver plays a crucial physiological role in the maintenance of agmatine homeostasis in the human organism.
Immune-mediated signaling in intestinal goblet cells via PI3-kinase- and AKT-dependent pathways
Authors: Wang Mei-Lun , Keilbaugh Sue A. , Cash-Mason Tanesha , He Xi C. , Li Linheng , Wu Gary D.
Published: October 2008

In the intestinal epithelium, activation of phosphatidylinositol 3-kinase (PI3-kinase)/AKT pathways, via growth factor-mediated signaling, has been shown to regulate cell proliferation and inhibit apoptosis. An immune-activated receptor critical for Th2 immune responses, IL-4Rα can also activate PI3-kinase via insulin receptor substrate (IRS)-dependent signaling. Here, using the intestinal goblet cell-specific gene RELMβ, we investigated the effect of PI3-kinase activation via Th2 immune responses on the goblet cell phenotype. IL-13 stimulation activated PI3-kinase and AKT signal transduction in LS174T cells. Not only did pharmacological inhibition of PI3-kinase and AKT1/2 inhibit RELMβ induction by IL-13, but AKT inhibition also significantly reduced constitutive basal expression of RELMβ, a response reproduced by the simultaneous pharmacological inhibition of both epidermal growth factor receptor and IGF-I receptor signaling. In vivo, the disruption of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), an inhibitor of PI3-kinase activation, led to the activation of RELMβ expression in the small intestine. Furthermore, induction of an intestinal Th2 immune response by infection with a small intestinal nematode parasite, Heligmosomoides polygyrus, led to enhanced epithelial cell proliferation, activation of AKT as demonstrated by the loss of Foxo1 nuclear localization, and robust induction of RELMβ expression in wild-type, but not IL-4Rα knockout, mice. These results demonstrate that Th2 immune responses can regulate goblet cell responses by activation of PI3-kinase and AKT pathways via IL-4Rα.
The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway
Authors: DeMorrow Sharon , Francis Heather , Gaudio Eugenio , Venter Julie , Franchitto Antonio , Kopriva Shelley , Onori Paolo , Mancinelli Romina , Frampton Gabriel , Coufal Monique , Mitchell Brett , Vaculin Bradley , Alpini Gianfranco
Published: October 2008

Cholangiocarcinomas are cancers that have poor prognosis and limited treatment options. The noncanonical Wnt pathway is mediated predominantly by Wnt 5a, which activates a Ca2+-dependent pathway involving protein kinase C, or a Ca2+-independent pathway involving the orphan receptor Ror2 and subsequent activation of Jun NH2-terminal kinase (JNK). This pathway is associated with growth-suppressing effects in numerous cell types. We have shown that anandamide decreases cholangiocarcinoma growth in vitro. Therefore, we determined the effects of anandamide on cholangiocarcinoma tumor growth in vivo using a xenograft model and evaluated the effects of anandamide on the noncanonical Wnt signaling pathways. Chronic administration of anandamide decreased tumor growth and was associated with increased Wnt 5a expression in vitro and in vivo. Treatment of cholangiocarcinoma cells with recombinant Wnt 5a decreased cell proliferation in vitro. Neither anandamide nor Wnt 5a affected intracellular calcium release, but both increased the JNK phosphorylation. Stable knockdown of Wnt 5a or Ror2 expression in cholangiocarcinoma cells abolished the effects of anandamide on cell proliferation and JNK activation. Modulation of the endocannabinoid system may be important in cholangiocarcinoma treatment. The antiproliferative actions of the noncanonical Wnt signaling pathway warrants further investigation to dissect the mechanism by which this may occur.
Increased tissue perfusion promotes capillary dysplasia in the ALK1-deficient mouse brain following VEGF stimulation
Authors: Hao Qi , Su Hua , Marchuk Douglas A. , Rola Radoslaw , Wang Yongqiang , Liu Weizhong , Young William L. , Yang Guo-Yuan
Published: October 2008

Loss-of-function activin receptor-like kinase 1 gene mutation (ALK1+/−) is associated with brain arteriovenous malformations (AVM) in hereditary hemorrhagic telangiectasia type 2. Other determinants of the lesional phenotype are unknown. In the present study, we investigated the influence of high vascular flow rates on ALK1+/− mice by manipulating cerebral blood flow (CBF) using vasodilators. Adult male ALK1+/− mice underwent adeno-associated viral-mediated vascular endothelial growth factor (AAVVEGF) or lacZ (AAVlacZ as a control) gene transfer into the brain. Two weeks after vector injection, hydralazine or nicardipine was infused intraventricularly for another 14 days. CBF was measured to evaluate relative tissue perfusion. We analyzed the number and morphology of capillaries. Results demonstrated that hydralazine or nicardipine infusion increased focal brain perfusion in all mice. It was noted that focal CBF increased most in AAVVEGF-injected ALK1+/− mice following hydralazine or nicardipine infusion (145 ± 23% or 150 ± 11%; P < 0.05). There were more detectable dilated and dysplastic capillaries (2.4 ± 0.3 or 2.0 ± 0.4 dysplasia index; P < 0.01) in the brains of ALK1+/− mice treated with AAVVEGF and hydralazine or nicardipine compared with the mice treated with them individually. We concluded that increased focal tissue perfusion and angiogenic factor VEGF stimulation could have a synergistic effect to promote capillary dysplasia in a genetic deficit animal model, which may have relevance to further studies of AVMs.
Differences in ischemia-reperfusion-induced endothelial changes in hearts perfused at constant flow and constant pressure
Authors: Singh Raja B. , Elimban Vijayan , Dhalla Naranjan S.
Published: October 2008

Isolated hearts subjected to ischemia-reperfusion (I/R) exhibit depressed cardiac performance and alterations in subcellular function. Since hearts perfused at constant flow (CF) and constant pressure (CP) show differences in their contractile response to I/R, this study was undertaken to examine mechanisms responsible for these I/R-induced alterations in CF-perfused and CP-perfused hearts. Rat hearts, perfused at CF (10 ml/min) or CP (80 mmHg), were subjected to I/R (30 min global ischemia followed by 60 min reperfusion), and changes in cardiac function as well as sarcolemmal (SL) Na+-K+-ATPase activity, sarcoplasmic reticulum (SR) Ca2+uptake, and endothelial function were monitored. The I/R-induced depressions in cardiac function, SL Na+-K+-ATPase, and SR Ca2+-uptake activities were greater in hearts perfused at CF than in hearts perfused at CP. In hearts perfused at CF, I/R-induced increase in calpain activity and decrease in nitric oxide (NO) synthase (endothelial NO synthase) protein content in the heart as well as decrease in NO concentration of the perfusate were greater than in hearts perfused at CP. These changes in contractile activity and biochemical parameters due to I/R in hearts perfused at CF were attenuated by treatment with l-arginine, a substrate for NO synthase, while those in hearts perfused at CP were augmented by treatment with NG-nitro-l-arginine methyl ester, an inhibitor of NO synthase. The results indicate that the I/R-induced differences in contractile responses and alterations in subcellular organelles between hearts perfused at CF and CP may partly be attributed to greater endothelial dysfunction in CF-perfused hearts than that in CP-perfused hearts.
Physical activity: does long-term, high-intensity exercise in horses result in tendon degeneration?
Authors: Birch Helen L. , Wilson Alan M. , Goodship Allen E.
Published: October 2008

This study explores the hypothesis that high-intensity exercise induces degenerative changes in the injury-prone equine superficial digital flexor tendon (SDFT), but not in the rarely injured common digital extensor tendon (CDET). The horse represents a large-animal model that is applicable to human tendon and ligament physiology and pathology. Twelve age-matched female horses undertook galloping exercise three times a week with trotting exercise on alternative days (high-intensity group, n = 6) or only walking exercise (low-intensity group, n = 6) for 18 mo. The SDFT, suspensory ligament, deep digital flexor tendon, and CDET were harvested from the forelimb. Tissue from the mid-metacarpal region of the right limb tendons was analyzed for water, DNA, sulfated glycosaminoglycan and collagen content, collagen type III-to-I ratios, collagen cross-links, and tissue fluorescence. Left limb tendons were mechanically tested to failure. The analyses showed matrix composition to have considerable diversity between the functionally different structures. In addition, the specific structures responded differently to the imposed exercise. High-intensity training resulted in a significant decrease in the GAG content in the SDFT, but no change in collagen content, despite a decrease in collagen fibril diameters. There were no signs of degeneration or change in mechanical properties of the SDFT. The CDET had a lower water content following high-intensity training and a higher elastic modulus. Long-term, high-intensity training in skeletally mature individuals results in changes that suggest accelerated aging in the injury-prone SDFT and adaptation in the CDET.
(Over)training effects on quantitative electromyography and muscle enzyme activities in standardbred horses
Authors: Wijnberg Inge D. , van Dam Klien G. , Graaf-Roelfsema Ellen de , Keizer Hans A. , van Ginneken Mireille M. E. , Barneveld Ab , Breda Eric van , van der Kolk Johannes H.
Published: October 2008

Too intensive training may lead to overreaching or overtraining. To study whether quantitative needle electromyography (QEMG) is more sensitive to detect training (mal)adaptation than muscle enzyme activities, 12 standardbred geldings trained for 32 wk in age-, breed-, and sex-matched fixed pairs. After a habituation and normal training (NT) phase ( phases 1 and 2, 4 and 18 wk, respectively), with increasing intensity and duration and frequency of training sessions, an intensified training (IT) group ( phase 3, 6 wk) and a control group (which continued training as in the last week of phase 2) were formed. Thereafter, all horses entered a reduced training phase ( phase 4, 4 wk). One hour before a standardized exercise test (SET; treadmill), QEMG analysis and biochemical enzyme activity were performed in muscle or in biopsies from vastus lateralis and pectoralis descendens muscle in order to identify causes of changes in exercise performance and eventual (mal)adaptation in skeletal muscle. NT resulted in a significant adaptation of QEMG parameters, whereas in muscle biopsies hexokinase activity was significantly decreased. Compared with NT controls, IT induced a stronger adaptation (e.g., higher amplitude, shorter duration, and fewer turns) in QEMG variables resembling potentially synchronization of individual motor unit fiber action potentials. Despite a 19% decrease in performance of the SET after IT, enzyme activities of 3-hydroxyacyl dehydrogenase and citrate synthase displayed similar increases in control and IT animals. We conclude that 1) QEMG analysis is a more sensitive tool to monitor training adaptation than muscle enzyme activities but does not discriminate between overreaching and normal training adaptations at this training level and 2) the decreased performance as noted in this study after IT originates most likely from a central (brain) rather than peripheral level.
Regulation of caspase-3 activity by insulin in skeletal muscle cells involves both PI3-kinase and MEK-1/2
Authors: Gao Yongmei , Ordas Ronald , Klein Janet D. , Price S. Russ
Published: October 2008

A hallmark of skeletal muscle atrophy is increased activities of several proteolytic systems, including caspase-3. We have previously shown that conditions involving insulin deficiency or insulin resistance increase both overall protein degradation and caspase-3-mediated actin cleavage. In the present experiments, we examined how insulin regulates caspase-3 activity in L6 myotubes. Reducing the serum concentration in the culture media from 2 to 0.5% overnight increased caspase-3 activity and actin cleavage. Addition of insulin to proteolytically active cells attenuated both responses within 4 h. Individually, inhibitors of either phosphatidylinositide 3-kinase (PI3K) or MEK1/2 partially blocked the insulin-induced reduction in caspase-3 activity; in combination, the inhibitors completely prevented insulin from attenuating caspase-3 activity. Insulin suppressed caspase-3 activity by a complex mechanism that included direct inhibition due to an increased interaction between caspase-3 and cellular inhibitor of apoptosis-1 and indirect inhibition via phosphorylation (i.e., inactivation) of the proapoptotic protein Bad, which participates in the intrinsic (i.e., mitochondrial) apoptosis activation cascade. Unlike other cell types, the phosphorylation of Bad Ser112 was mediated by the PI3K/Akt pathway rather than the MEK/ERK/ribosomal S6 protein kinase pathway. In summary, our findings indicate that insulin regulates caspase-3 activity by a multistep process that is unique to skeletal muscle, thus providing insights about the muscle-specific nature of the atrophy process.
Prostacyclin Prevents Murine Lung Cancer Independent of the Membrane Receptor by Activation of Peroxisomal Proliferator–Activated Receptor γ
Authors: Nemenoff Raphael , Meyer Amy M. , Hudish Tyler M. , Mozer Anthony B. , Snee Amy , Narumiya Shuh , Stearman Robert S. , Winn Robert A. , Weiser-Evans Mary , Geraci Mark W. , Keith Robert L.
Published: October 2008

Overexpression of prostacyclin synthase (PGIS) decreases lung tumor multiplicity in chemical- and cigarette-smoke–induced murine lung cancer models. Prostacyclin signals through a single G-protein–coupled receptor (IP), which signals through cyclic AMP. To determine the role of this receptor in lung cancer chemoprevention by prostacyclin, PGIS-overexpressing mice were crossed to mice that lack the IP receptor [IP(−/−)]. Carcinogen-induced lung tumor incidence was similar in IP(+/+), IP(+/−), and IP(−/−) mice, and overexpression of PGIS gave equal protection in all three groups, indicating that the protective effects of prostacyclin are not mediated through activation of IP. Because prostacyclin can activate members of the peroxisomal proliferator–activated receptor (PPAR) family of nuclear receptors, we examined the role of PPARγ in the protection of prostacyclin against lung tumorigenesis. Iloprost, a stable prostacyclin analogue, activated PPARγ in nontransformed bronchial epithelial cells and in a subset of human non–small-cell lung cancer cell lines. Iloprost-impregnated chow fed to wild-type mice resulted in elevated lung macrophages and decreased lung tumor formation. Transgenic animals with lung-specific PPARγ overexpression also developed fewer lung tumors. This reduction was not enhanced by administration of supplemental iloprost. These studies indicate that PPARγ is a critical target for prostacyclin-mediated lung cancer chemoprevention and may also have therapeutic activity.
Inflammation in Acute Kidney Injury
Authors: Kinsey Gilbert R. , Li Li , Okusa Mark D.
Published: October 2008

Ischemia-reperfusion injury (IRI) is one of the major causes of acute kidney injury (AKI) and evidence supporting the involvement of both innate and adaptive immunity in renal IRI has accumulated in recent years. In addition to leukocytes, kidney endothelial cells promote inflammation after IRI by increasing adhesion molecule expression and vascular permeability. Kidney tubular epithelial cells increase complement binding and upregulate toll-like receptors, both of which lead to cytokine/chemokine production in IRI. Activation of kidney resident dendritic cells, interferon-γ-producing neutrophils, infiltrating macrophages, CD4+ T cells, B cells and invariant natural killer T cells are all implicated in the pathogenesis of AKI. The complex interplay between innate and adaptive immunity in renal IRI is still not completely understood, but major advances have been made. This review summarizes these recent advances to further our understanding of the immune mechanisms of acute kidney injury.
Antioxidants
Authors: Koyner Jay L. , Sher Ali Roshan , Murray Patrick T.
Published: October 2008

Over the past several years, advances in our understanding of the pathogenesis of acute kidney injury (AKI) have demonstrated the role of oxidant stress and reactive oxygen metabolites (ROM) in the development of AKI in a variety of clinical settings. This review serves to define the pathways that lead to the generation of ROM following a variety of insults, as well as to review the current literature concerning the role of antioxidant therapy in the prevention and treatment of AKI in several clinical settings. Investigators have explored the potential therapeutic role of anti-oxidants in both experimental animal models and human studies of AKI in several clinical settings, including cardiac and aortic occlusive surgeries, sepsis, drug nephrotoxicity (cisplatin and gentamicin), as well as rhabdomyolysis. While the experimental animal studies have generally been more successful, taken together this literature supports the hypothesis that oxidant stress-induced production of ROM plays a major role in the pathogenesis of many forms of AKI, and continues to suggest the potential utility of antioxidant therapy in human AKI. Ongoing trials in concert with improved diagnostic techniques will hopefully lead to improved outcomes in the setting of AKI through the prophylactic or early therapeutic use of antioxidant therapy.
Cardiac Surgery-Associated Acute Kidney Injury: Putting Together the Pieces of the Puzzle
Authors: Shaw Andrew , Swaminathan Madhav , Stafford-Smith Mark
Published: October 2008

Background: Acute kidney injury (AKI) is a common problem in the context of cardiac surgery. There are both similarities and differences with AKI occurring in other clinical scenarios. In this paper, we discuss those aspects of AKI that are particular to cardiac surgery-associated AKI (CSA-AKI), with emphasis on recent advances in the field. Methods: We summarize the recent literature relating to CSA-AKI, focusing on epidemiology, pathophysiology, risk prediction and prevention. Results: The Acute Kidney Injury Network (AKIN) criteria for the diagnosis and severity of AKI are a useful framework within which future epidemiological studies of AKI may be considered. Percent change in serum creatinine remains a sensitive and clinically relevant continuous measure of declining kidney function. New biomarkers of diagnosis are currently being validated, while biomarkers of prognosis are lacking. Notably, intraoperative antifibrinolytic therapy effects invalidate ‘tubular proteinuria’ biomarkers. Better characterization of genetic predisposition to CSA-AKI may enhance risk prediction, since currently available clinical models lack precision, particularly for the important clinical endpoint of new renal replacement therapy. Conclusions: CSA-AKI remains a clinically relevant problem for 5–10% of cardiac surgery patients and is associated with adverse clinical outcomes. Small changes in serum creatinine are important and should not be ignored. The overall incidence of new dialysis after cardiac surgery remains low.
Radiocontrast-Induced Acute Kidney Injury
Authors: McCullough Peter A.
Published: October 2008

Many radiographic studies and procedures use iodinated contrast media and consequently pose the risk of contrast-induced acute kidney injury (AKI). This is an important complication, which accounts for a significant number of cases of hospital-acquired renal failure associated increased hospital length of stay and increased mortality. Sustained reductions in renal blood flow, hypoxic injury, direct cellular toxicity by the contrast media, and superimposed organ injury are all believed to play a role in this form of AKI. Avoidance of dehydration and multimodality prevention measures may reduce rates of this problem in patients at risk. Contrast-induced AKI is likely to remain a significant challenge for specialists in the future since the patient population is aging, chronic kidney disease and diabetes are coming more common, and use of iodinated contrast is growing.
Acute Kidney Injury: New Concepts
Authors: Moreau Richard , Lebrec Didier
Published: October 2008

Type 1 hepatorenal syndrome (HRS) is prerenal failure specific to decompensated cirrhosis. In patients with HRS, there is marked splanchnic/systemic vasodilation resulting in arterial hypotension, arterial baroreceptor unloading, overstimulation of the sympathetic nervous and renin-angiotensin systems. This reflex neurohumoral hyperactivity via endogenous vasoconstrictors/vasopressors such as angiotensin II and noradrenaline induces arterial vasoconstriction in different extrasplanchnic vascular beds (including preglomerular arteries in the kidneys). Decreased arterial pressure (i.e. low renal perfusion pressure) and preglomerular vasoconstriction are thought to play a major role in the decline of the glomerular filtration rate (GFR). Nonrandomized studies in patients with HRS have shown that the administration of a splanchnic vasoconstrictor (vasopressin analogue or α1-adrenoceptor agonist), usually combined with intravenous albumin, causes increases in arterial pressure, arterial baroreceptor uploading, decreased neurohumoral activity, decreased renal vascular resistance, and increased GFR. Randomized clinical trials have shown that treatment with a combination of the vasopressin analogue terlipressin and intravenous albumin improves renal function in patients with type 1 HRS. Vasopressor therapy with terlipressin plus intravenous albumin is the medical treatment of choice for type 1 HRS.
Injury and Inflammation from Resuscitation of the Preterm Infant
Authors: Jobe Alan H. , Hillman Noah , Polglase Graeme , Kramer Boris W. , Kallapur Suhas , Pillow Jane
Published: October 2008

We review information about how the preterm lung can be injured with the initiation of mechanical ventilation at birth. Although multiple variables such as pressure, tidal volume, positive end expiratory pressure, and the gas used for ventilation may contribute to the injury, the relative contribution of each is not known. Recent studies demonstrate that injury caused by initial high tidal volume is amplified by subsequent mechanical ventilation. A model for gas inflation of the fluid-filled lung may explain why even low tidal volumes may injure the preterm lung, and why the injury may initially occur to the small airways. Ventilation strategies that minimize injury need to be developed.
Long-Term Pharmacologic Neuroprotection after Birth Asphyxia: Where Do We Stand?
Authors: van Bel Frank , Groenendaal Floris
Published: October 2008

Perinatal hypoxia-ischemia or birth asphyxia is a serious complication with a high mortality and morbidity. For decades, neuroprotective options have been explored to reduce reperfusion and reoxygenation injury to the brain, which accounts for a substantial part of birth asphyxia-related brain damage. In this review, we focus on neuroprotective strategies with a long-term follow-up, reported in both experimental and clinical studies. Strategies related to modification of excitatory neurotransmitter production and action, reduction in free radical production and inflammation and neoneurogenesis will be briefly summarized. Since hypothermia has been proven to be beneficial for a selected group of asphyxiated neonates, we assume that a combination of this treatment option with a pharmacological means of neuroprotection will be the appropriate approach in the future. Finally, it is important to consider possible gender effects in view of the discussed pharmacological strategies.
Early Aggressive Nutrition for the Premature Infant
Authors: Parish Anjali , Bhatia Jatinder
Published: October 2008

Nutrition for sick newborn infants, both term and preterm, has been evolving since the first published report of use of total parenteral nutrition (TPN) in an infant. The more preterm infants have posed an even greater challenge, because optimal timing for use of enteral nutrition is an additional factor for completing their nutritional demands. Although benefiting the immune system among other physiological benefits, human milk has many nutritional gaps for the premature infant. The development of premature infant formulas and milk fortifiers has helped fill these gaps, but questions still exist about safety and efficacy of human milk versus formula. This article will focus on the use of TPN as well as early initiation of enteral feedings and the challenges this brings.
How Relevant Is Symptom Evaluation in NERD?
Authors: Stanghellini Vincenzo , Cogliandro Rosanna , Barbara Giovanni , Cremon Cesare , De Giorgio Roberto , Corinaldesi Roberto
Published: October 2008

Most patients presenting with esophageal and extraesophageal symptoms of gastroesophageal reflux disease (GERD) have negative endoscopic findings and are defined as being affected by non-erosive reflux disease (NERD). A correct recognition and analysis of symptoms in these patients is essential for an appropriate clinical management, as well as for scientific purposes. Symptoms alone do not capture all the clinical implications of NERD, but since their frequency and severity are strictly related to their influence on quality of life, they provide a sufficiently reliable picture of the disease. Most studies were carried out on patients with heartburn and regurgitation, and information about other clinical manifestations of NERD is extremely limited. Inclusion criteria and primary end-points of clinical trials are ill defined, particularly, when extraesophageal manifestations are considered. A new, validated instrument is now available to correctly measure all possible complains of GERD patients, including general well-being. This scale has been used also to identify the level of symptom frequency and severity that can be present in perfectly healthy, self-considering asymptomatic individuals, thus providing the first objective definition of ‘complete symptom relief’. Through instruments like this, our understanding of NERD and its management will certainly further improve in the years to come.
Is Conventional Endoscopic Identification of Non-Erosive Reflux Disease Adequate?
Authors: Falk Gary W.
Published: October 2008

Non-erosive reflux disease is defined as the presence of troublesome reflux-associated symptoms in the absence of mucosal breaks at endoscopy. Given the fact that the majority of patients with reflux symptoms will have a normal endoscopy, efforts are underway to determine if new endoscopic techniques can identify changes heretofore invisible at the time of standard white light endoscopy. However, for any new endoscopic technology to be useful, the grading system it uses must be accurate, reproducible, easy to remember and easy to interpret. These requirements represent a high bar indeed for any new approach to non-erosive reflux disease. Current techniques under investigation include high-resolution endoscopy, magnification endoscopy, chromoendoscopy, narrow-band imaging and confocal endomicroscopy. All of these new technologies can identify minimal abnormalities heretofore not seen with traditional white light endoscopy. All of these new techniques allow for more detailed imaging of the esophagus in gastroesophageal reflux disease patients which makes this field ripe for re-examination. The most exciting findings to date are with narrow-band imaging and confocal endomicroscopy. However, studies to date are small and require validation in larger numbers of patients by larger number of endoscopists. Furthermore, it is essential that we do not repeat the mistakes of the past as poor interobserver agreement has already been shown for minimal change esophagitis, albeit with more primitive technology.
A Critical Assessment of the Current Status of Non-Erosive Reflux Disease
Authors: Armstrong David
Published: October 2008

Non-erosive reflux disease (NERD) has assumed increasing prominence in studies of gastroesophageal reflux disease (GERD), but it remains a challenge to define NERD precisely and to define its place in the investigation and treatment of GERD. Most simply, NERD may be defined as GERD in an individual who has no evidence of erosions at endoscopy. Unfortunately, the characteristic symptoms of GERD – heartburn and regurgitation – are insufficient to identify all GERD patients and, hence, the diagnosis of NERD is hampered by the lack of clear criteria for the symptomatic diagnosis of GERD. The diagnosis of NERD is hampered further by limited interobserver agreement on the endoscopic diagnosis of erosive esophagitis and by the fact that endoscopy is often performed soon after patients have discontinued therapy. Improvements in endoscopic technology will increase the likelihood of identifying small erosions or other reflux-related lesions; however, this will increase the proportion of patients considered to have erosive esophagitis without defining precisely what constitutes NERD. It is important to recognize that NERD is but one manifestation of GERD and that it, like other manifestations of GERD, is associated with a marked diminution in patients’ quality of life. However, this recognition apart, there seems to be little practical benefit or understanding to be gained in clinical practice or clinical research from considering NERD as a distinct entity or from studying NERD patients in isolation. Advances in understanding the pathogenesis of GERD and its symptoms may be better served by categorizing GERD with respect to the spectrum of its histologic, functional, endoscopic and symptomatic manifestations rather than by studying NERD, a manifestation that is characterized solely by the absence of esophageal erosions.
Non-Erosive Reflux Disease – Some Clinical Case Scenarios
Authors: Heading Robert C.
Published: October 2008

The consensus meeting attempted to clarify concepts associated with the clinical entity often termed ‘NERD’ and to define it in a way that would permit physicians to communicate accurately amongst each other when they use the term, so that there may be a common understanding of the condition. In this paper, eight clinical case scenarios are presented that illustrate some points of potential uncertainty and ambiguity in the use of the term NERD and the clinical management of patients. They are discussed in relation to views reached by the consensus group.
The Prevalence of Attention Deficit Hyperactivity Symptoms in Schoolchildren in a Highly Consanguineous Community
Authors: Bener Abdulbari , Al Qahtani Razna , Teebi Ahmad S. , Bessisso Mohammed
Published: October 2008

Objective: The objective of the present study was to find the prevalence of attention deficit hyperactivity (ADH) symptoms in a sample of primary schoolchildren in Qatar and investigate the behaviour of the children with and without ADH symptoms in a highly consanguineous community. Subjects and Methods: A total of 2,500 primary school students, aged 6–12 years, were randomly selected from the government primary schools, and 1,869 students (947 boys and 922 girls) gave consent to participate in this study. An Arabic questionnaire was used to collect the sociodemographic variables and a standardized Arabic version of the Conners’ Teacher Rating Scale for ADH symptoms. Results: Of the 947 boys, 158 (16.7%; 95% confidence interval, CI, 14.4–19.2) and of the 922 girls, 50 (5.4%; 95% CI 4.1–7.1) scored above the cut-off (≧15) for ADH symptoms, thus giving an overall prevalence of 11.1% (95% CI 9.7–12.6). The children who had higher scores for ADH symptoms were in the age group of 6–9 years. Children who had higher scores for ADH symptoms had a poorer school performance than those with lower scores (p = 0.002). Two hundred (96.2%) children with ADH were disobedient, 126 (60.6%) noisy and hyperactive, 76 (36.5%) very cranky, 78 (37.5%) troublesome and 79 (37.9%) nervous. The logistic regression identified socio-economic condition, number of children, school performance and poor relationship between parents as the main contributors to ADH. Although the univariate analysis showed a significant relationship (p = 0.010) between ADH symptoms and consanguineous parents, logistic regression did not support this association (p = 0.075). This suggests that consanguinity has no impact on ADH children. Conclusion: The study revealed that ADH is a common problem among schoolchildren. The children with higher scores for ADH symptoms had a poorer school performance than those with lower scores. A significant difference exists between the behaviour of children with and without ADH.
Detrimental Effects of Variable Work Shifts on Quality of Sleep, General Health and Work Performance
Authors: Fido Abdullahi , Ghali Adel
Published: October 2008

Objectives: The aim of this study was to explore the detrimental effects of working a varying pattern of 8-hour shifts on quality of sleep, general health and work performance. Subjects and Methods: The Arabic version of the Pittsburgh Sleep Quality Index (PSQI)and 2 self-administered questionnaires were used to assess quality of sleep, work performance and general health in a sample of 200 males on a schedule of varying 8-hour shifts at the Kuwait Oil Company. A matched sample of an equal number of workers on a fixed daytime shift as a control group was enrolled in the study. Results: Compared with men working on a straight daytime shift schedule, those working on 8-hour variable shifts exhibited higher rates of heavy smoking (p < 0.003), coffee/tea consumption (p < 0.0001), constipation (p < 0.002), job stress (p < 0.0001) and poor sexual performance (p < 0.0001). Variable-shift workers reported persistent sleep disturbances in 3 dimensions of the global score of the PSQI (p < 0.0001). They also had significantly more complaints of fatigue (p < 0.005), poor level of work performance (p < 0.005) and loss of concentration (p < 0.005). Shift workers were significantly more prone to making errors and having accidents at work, and were more likely to report absence from work than the controls (p < 0.0001 and p < 0.005, respectively). Conclusion: These results suggest that the majority of workers on an 8-hour variable-shift schedule experienced various health problems, poor quality of sleep and an increased risk for errors and accidents at work as compared with those workers on a straight daytime shift schedule. There is a need to compare potential benefits of an alternative work shift schedule.
Microscopic Detection of Mixed Malarial Infections: Improvement by Saponin Hemolysis
Authors: Orjih Augustine U. , Cherian Preethi , AlFadhli Suad
Published: October 2008

Objective: The objective of the present study was to determine whether saponin hemolysis could improve microscopic detection of malaria parasites in human blood, since it has been previously reported that the technique has been used to enrich Plasmodium falciparum culture to ≧90% parasitemia. Material and Methods: Blood samples from suspected malaria cases were first examined in routine thick and thin smears under the microscope. The sample (1 ml) was then hemolyzed with 0.015% saponin in saline and centrifuged, the separated pellet was stained with Giemsa stain and examined microscopically, using PCR to confirm species identification. Results: With P. falciparum in vitro culture, the proportions of infected erythrocytes were approximately 0.7–2% before and 65–97% after saponin hemolysis, confirming published reports. In contrast, there was little or no increase in the proportions of intact infected erythrocytes after saponin hemolysis of clinical blood specimens. However, 20–600 hemolyzed parasites were detected per field under the microscope after saponin hemolysis of patients’ blood samples that contained only 1–15 parasites per field in conventional thick smears. In addition, more P. falciparum gametocytes were detected after saponin hemolysis. Conclusion: Saponin hemolysis concentrated the parasites in large volumes of blood into a small volume that could be smeared on a slide. This concentration method made it easy to detect malaria parasites and reduced the time needed for microscopy. In the present study, the method was comparable to PCR for the identification of P. vivax and P. falciparum mixed infections.