bluuebunny/crossref_metadata_2025 huggingface dataset:
Glycosyltransferases: Structures, Functions, and Mechanisms
Authors: Lairson L.L. , Henrissat B. , Davies G.J. , Withers S.G.
Published: February 2007

Glycosyltransferases catalyze glycosidic bond formation using sugar donors containing a nucleoside phosphate or a lipid phosphate leaving group. Only two structural folds, GT-A and GT-B, have been identified for the nucleotide sugar-dependent enzymes, but other folds are now appearing for the soluble domains of lipid phosphosugar-dependent glycosyl transferases. Structural and kinetic studies have provided new insights. Inverting glycosyltransferases utilize a direct displacement SN2-like mechanism involving an enzymatic base catalyst. Leaving group departure in GT-A fold enzymes is typically facilitated via a coordinated divalent cation, whereas GT-B fold enzymes instead use positively charged side chains and/or hydroxyls and helix dipoles. The mechanism of retaining glycosyltransferases is less clear. The expected two-step double-displacement mechanism is rendered less likely by the lack of conserved architecture in the region where a catalytic nucleophile would be expected. A mechanism involving a short-lived oxocarbenium ion intermediate now seems the most likely, with the leaving phosphate serving as the base.
Unsolved Mysteries in Membrane Traffic
Authors: Pfeffer Suzanne R.
Published: February 2007

Remarkable strides have been made over the past 20 years in elucidating the molecular basis of membrane trafficking ( 1 ). Indeed, a combination of biochemical and genetic approaches have determined the identity and function of many of the core constituents needed for protein secretion and endocytosis. But much remains to be learned. This review highlights underlying themes in membrane traffic to help us refocus and solve many remaining and newly emerging issues that are fundamental to mammalian cell biology and human physiology.
The Machines that Divide and Fuse Mitochondria
Authors: Hoppins Suzanne , Lackner Laura , Nunnari Jodi
Published: February 2007

Mitochondria are derived from eubacteria; however, in most eukaryotes, novel mechanisms for the propagation of this organelle and its genome have evolved. This review focuses on what is currently known about the novel molecular machines that divide and fuse mitochondria.
Why Do We Still Have a Maternally Inherited Mitochondrial DNA? Insights from Evolutionary Medicine
Authors: Wallace Douglas C.
Published: February 2007

The human cell is a symbiosis of two life forms, the nucleus-cytosol and the mitochondrion. The nucleus-cytosol emphasizes structure and its genes are Mendelian, whereas the mitochondrion specializes in energy and its mitochondrial DNA (mtDNA) genes are maternal. Mitochondria oxidize calories via oxidative phosphorylation (OXPHOS) to generate a mitochondrial inner membrane proton gradient (ΔP). ΔP then acts as a source of potential energy to produce ATP, generate heat, regulate reactive oxygen species (ROS), and control apoptosis, etc. Interspecific comparisons of mtDNAs have revealed that the mtDNA retains a core set of electron and proton carrier genes for the proton-translocating OXPHOS complexes I, III, IV, and V. Human mtDNA analysis has revealed these genes frequently contain region-specific adaptive polymorphisms. Therefore, the mtDNA with its energy controlling genes may have been retained to permit rapid adaptation to new environments.
Discovery of G Protein Signaling
Authors: Selinger Zvi
Published: February 2007

The mechanism of transmembrane signaling by the receptor-activated adenylyl cyclase was an enigma. It was suggested that hydrolysis of GTP is a turn-off mechanism that resets the active adenylyl cyclase to the inactive state. To test this hypothesis, we developed a specific GTPase assay and found that the catecholamine adrenergic agonists stimulated the hydrolysis of GTP. To resolve the question of how the hormone concurrently stimulates GTP hydrolysis and activates the adenylyl cyclase, we suggested the regulatory GTPase cycle. Thus, because the hormone facilitates the binding of GTP, which is subsequently hydrolyzed, the regulatory cycle results in a hormone-stimulated GTPase activity. This model also predicts that two mechanisms could account for stimulation of adenylyl cyclase activity—either by the familiar hormone stimulation of the activation reaction or by an inhibition of the turn-off reaction. Indeed, we showed that cholera toxin enhances adenylyl cyclase activity by inhibition of GTP hydrolysis. Finally, we also showed that the hormone-activated receptor stimulates adenylyl cyclase activity by facilitating the exchange of bound GDP for free GTP. Thus, we presented, for the first time, an explicit mechanism for receptor action.
Cooperation between GATA4 and TGF-β signaling regulates intestinal epithelial gene expression
Authors: Belaguli Narasimhaswamy S. , Zhang Mao , Rigi Mohammed , Aftab Muhammad , Berger David H.
Published: February 2007

Members of the transforming growth factor-β (TGF-β) family have been shown to play an important role in the regulation of gut epithelial gene expression. We have used the intestinal alkaline phosphatase (IAP) and intestinal fatty acid binding protein (IFABP) promoters to dissect the mechanisms by which TGF-β1 signaling regulates gut epithelial gene expression. TGF-β signaling alone was not sufficient for activation of IAP and IFABP promoters. However, TGF-β signaling cooperated with the gut epithelial transcription factor GATA4 to synergistically activate IAP and IFABP promoters. Coexpression of GATA4 along with the TGF-β1 signal transducing downstream effectors such as Smad2, 3, and 4 resulted in synergistic activation of both IAP and IFABP promoters. This synergistic activation was reduced by simultaneous expression of dominant-negative Smad4. −40 and −89 GATA binding sites in the IFABP promoter were required for the synergistic activation by Smad2, 3, and 4 and GATA4. GATA4 and Smad2, 3, and 4 physically associated with each other and this interaction was mediated through the MH2 domain of Smad2, 3, and 4 and the second zinc finger and the COOH-terminal basic domain of GATA4. The COOH-terminal activation domain and the Smad-interacting second zinc finger domain of GATA4 were required for the synergistic activation of the IFABP promoter. Naturally occurring oncogenic mutations within the GATA4-interacting MH2 domain of Smad2 reduced the coactivation of IFABP promoter by Smad2 and GATA4. Our results suggest that the TGF-β signaling regulates gut epithelial gene expression by targeting GATA4.
GPR93 activation by protein hydrolysate induces CCK transcription and secretion in STC-1 cells
Authors: Choi Sungwon , Lee Mike , Shiu Amy L. , Yo Sek Jin , Halldén Gunnel , Aponte Gregory W.
Published: February 2007

In the intestinal lumen, protein hydrolysate increases the transcription and release of cholecystokinin (CCK) from enteroendocrine cells of the duodenal-jejunal mucosa. Our recent discovery that a G protein-coupled receptor, GPR93, is activated by dietary protein hydrolysate causing induced intracellular calcium-mediated signaling events in intestinal epithelial cells raises a possibility that GPR93 might be involved in the protein hydrolysate induction of CCK expression and/or secretion. Using the enteroendocrine STC-1 cells as a model, the present study demonstrates that increasing expression of GPR93 amplifies the peptone induction of endogenous CCK mRNA levels. A similar increase in CCK transcription, indicated by the luciferase reporter activity driven by an 820-bp CCK promoter, is also observed in response to peptone at a dose as little as 6.25 mg/ml, but not to lysophosphatidic acid (LPA), an agonist of GPR93. We discovered that the upregulation of CCK transcription involves ERK1/2, PKA, and calmodulin-dependent protein kinase-mediated pathways. Additionally, GPR93 activation by peptone induces a response in CCK release at 15 min, which continues over a 2-h period. The cAMP level in STC-1 cells overexpressing GPR93 is induced at a greater extent by peptone than by LPA, suggesting a possible explanation of the different effects of peptone and LPA on CCK transcription and secretion. Our data indicate that GPR93 can contribute to the observed induction of CCK expression and secretion by peptone and provide evidence that G protein-coupled receptors can transduce dietary luminal signals.
Cloning and expression of cardiac Kir2.1 and Kir2.2 channels in thermally acclimated rainbow trout
Authors: Hassinen Minna , Paajanen Vesa , Haverinen Jaakko , Eronen Heli , Vornanen Matti
Published: February 2007

Potassium currents are plastic entities that modify electrical activity of the heart in various physiological conditions including chronic thermal stress. We examined the molecular basis of the inward rectifier K+ current ( IK1) in rainbow trout acclimated to cold (4°C, CA) and warm (18°C, WA) temperature. Inward rectifier K+ channel (Kir)2.1 and Kir2.2 transcripts were expressed in atrium and ventricle of the trout heart, Kir2.1 being the major component in both cardiac chambers. The relative expression of Kir2.2 was, however, higher ( P < 0.05) in atrium than ventricle. The density of ventricular IK1 was ∼25% larger ( P < 0.05) in WA than CA trout. Furthermore, the IK1 of the WA trout was 10 times more sensitive to Ba2+ (IC50 0.18 ± 0.42 μM) than the IK1 of the CA trout (1.17 ± 0.44 μM) ( P < 0.05), and opening kinetics of single Kir2 channels was slower in WA than CA trout ( P < 0.05). When expressed in COS-1 cells, the homomeric Kir2.2 channels demonstrated higher Ba2+ sensitivity (2.88 ± 0.42 μM) than Kir2.1 channels (24.99 ± 7.40 μM) ( P < 0.05). In light of the different Ba2+ sensitivities of rainbow trout (om)Kir2.1 and omKir2.2 channels, it is concluded that warm acclimation increases either number or activity of the omKir2.2 channels in trout ventricular myocytes. The functional changes in IK1 are independent of omKir2 transcript levels, which remained unaltered by thermal acclimation. Collectively, these findings suggest that thermal acclimation modifies functional properties and subunit composition of the trout Kir2 channels, which may be needed for regulation of cardiac excitability at variable temperatures.
Neuropeptide FF and neuropeptide VF inhibit GABAergic neurotransmission in parvocellular neurons of the rat hypothalamic paraventricular nucleus
Authors: Jhamandas Jack H. , Simonin Frédéric , Bourguignon Jean-Jacques , Harris Kim H.
Published: February 2007

Neuropeptide FF (NPFF) and neuropeptide VF (NPVF) are octapeptides belonging to the RFamide family of peptides that have been implicated in a wide variety of physiological functions in the brain, including central autonomic and neuroendocrine regulation. The effects of these peptides are mediated via NPFF1 and NPFF2 receptors that are abundantly expressed in the rat brain, including the hypothalamic paraventricular nucleus (PVN), an autonomic nucleus critical for the secretion of neurohormones and the regulation of sympathetic outflow. In this study, we examined, using whole cell patch-clamp recordings in the brain slice, the effects of NPFF and NPVF on inhibitory GABAergic synaptic input to parvocellular PVN neurons. Under voltage-clamp conditions, NPFF and NPVF reversibly and in a concentration-dependent manner reduced the evoked bicuculline-sensitive inhibitory postsynaptic currents (IPSCs) in parvocellular PVN neurons by 25 and 31%, respectively. RF9, a potent and selective NPFF receptor antagonist, blocked NPFF-induced reduction of IPSCs. Recordings of miniature IPSCs in these neurons following NPFF and NPVF applications showed a reduction in frequency but not amplitude, indicating a presynaptic locus of action for these peptides. Under current-clamp conditions, NPVF and NPFF caused depolarization (6–9 mV) of neurons that persisted in the presence of TTX but was abolished in the presence of bicuculline. Collectively, these data provide evidence for a disinhibitory role of NPFF and NPVF in the hypothalamic PVN via an attenuation of GABAergic inhibitory input to parvocellular neurons of this nucleus and explain the central autonomic effects of NPFF.
Novel functional interaction between Na+/H+exchanger 1 and tyrosine phosphatase SHP-2
Authors: Xue Jin , Zhou Dan , Yao Hang , Gavrialov Orit , McConnell Melanie J. , Gelb Bruce D. , Haddad Gabriel G.
Published: February 2007

Besides being a intracellular pH (pHi) regulator, Na+/H+exchanger (NHE)1 has recently been postulated as a membrane scaffold that assembles protein complexes and coordinates various signaling pathways. The aim of the present study was to uncover NHE1 interactive partners and study their functional implications. NHE1 interactive partners were screened in the mouse brain with a signal transduction AntibodyArray. Ten of 400 tested proteins appeared to be potentially associated with NHE1. These partners have been shown to be involved in either cell proliferative or apoptotic pathways. The interactions between NHE1 and Src homology 2 domain-containing protein tyrosine phosphatase (SHP-2), Bin1, and heat shock protein (HSP)70 were reciprocally confirmed by coimmunoprecipitation. Moreover, in vitro binding data have shown that NHE1 COOH terminus interacts directly with SHP-2. The functional significance of the association between NHE1 and SHP-2 was further investigated by measuring pHi, cell proliferation, and cell death with the fluorescent dye BCECF, [3H]thymidine incorporation, and medium lactate dehydrogenase activity, respectively. Our results revealed that cells with SHP-2 overexpression exhibited a higher steady-state pHiand a faster, NHE1-dependent pHirecovery rate from acid load in HEPES buffer. In addition, SHP-2 overexpression diminished the HOE-642-induced inhibition of cell proliferation and protected cells from hypoxic injury, especially in the presence of HOE-642. Together, our findings demonstrate that SHP-2 not only is physically associated with NHE1 but also modulates NHE1 functions such as pHiregulation, cell proliferation, and cell death under hypoxia.
Oxidative stress and disuse muscle atrophy
Authors: Powers Scott K. , Kavazis Andreas N. , McClung Joseph M.
Published: February 2007

Skeletal muscle inactivity is associated with a loss of muscle protein and reduced force-generating capacity. This disuse-induced muscle atrophy results from both increased proteolysis and decreased protein synthesis. Investigations of the cell signaling pathways that regulate disuse muscle atrophy have increased our understanding of this complex process. Emerging evidence implicates oxidative stress as a key regulator of cell signaling pathways, leading to increased proteolysis and muscle atrophy during periods of prolonged disuse. This review will discuss the role of reactive oxygen species in the regulation of inactivity-induced skeletal muscle atrophy. The specific objectives of this article are to provide an overview of muscle proteases, outline intracellular sources of reactive oxygen species, and summarize the evidence that connects oxidative stress to signaling pathways contributing to disuse muscle atrophy. Moreover, this review will also discuss the specific role that oxidative stress plays in signaling pathways responsible for muscle proteolysis and myonuclear apoptosis and highlight gaps in our knowledge of disuse muscle atrophy. By presenting unresolved issues and suggesting topics for future research, it is hoped that this review will serve as a stimulus for the expansion of knowledge in this exciting field.
Hypoxia-induced reactive oxygen species formation in skeletal muscle
Authors: Clanton Thomas L.
Published: February 2007

The existence of hypoxia-induced reactive oxygen species (ROS) production remains controversial. However, numerous observations with a variety of methods and in many cells and tissue types are supportive of this idea. Skeletal muscle appears to behave much like heart in that in the early stages of hypoxia there is a transient elevation in ROS, whereas in chronic exposure to very severe hypoxia there is evidence of ongoing oxidative stress. Important remaining questions that are addressed in this review include the following. Are there levels of Po2in skeletal muscle, typical of physiological or mildly pathophysiological conditions, that are low enough to induce significant ROS production? Does the ROS associated with muscle contractile activity reflect imbalances in oxygen uptake and demand that drive the cell to a more reduced state? What are the possible molecular mechanisms by which ROS may be elevated in hypoxic skeletal muscle? Is the production of ROS in hypoxia of physiological significance, both with respect to cell signaling pathways promoting cell function and with respect to damaging effects of long-term exposure? Discussion of these and other topics leads to general conclusions that hypoxia-induced ROS may be a normal physiological response to imbalance in oxygen supply and demand or environmental stress and may play a yet undefined role in normal response mechanisms to these stimuli. However, in chronic and extreme hypoxic exposure, muscles may fail to maintain a normal redox homeostasis, resulting in cell injury or dysfunction.
ADA*2 Allele of the Adenosine Deaminase Gene May Protect against Coronary Artery Disease
Authors: Safranow Krzysztof , Rzeuski Ryszard , Binczak-Kuleta Agnieszka , Czyzycka Edyta , Skowronek Janusz , Jakubowska Katarzyna , Wojtarowicz Andrzej , Loniewska Beata , Ciechanowicz Andrzej , Kornacewicz-Jach Zdzislawa , Chlubek Dariusz
Published: February 2007

Background/Aims: The common G22A polymorphism in the adenosine deaminase (ADA) gene leads to substitution Asp8Asn. The lower activity of the enzyme encoded by A22 (ADA*2) allele may increase tissue concentrations of adenosine, a potent cardioprotective agent. In a case-control study, we investigated the association between ADA polymorphism and coronary artery disease (CAD). Methods: A hundred and seventy-one CAD patients from the north-western part of Poland and 200 consecutive newborns from the same population were genotyped by PCR-RFLP. Results: Twenty-five ADA*1/*2 heterozygotes (12.5%) and 2 ADA*2/*2 homozygotes (1%) were found in the control group, while only 10 *1/*2 heterozygotes (5.9%) and no *2/*2 homozygotes were found in the CAD group. Frequencies of ADA*2 carriers (5.9% vs. 13.5%, p = 0.015) and ADA*2 allele (2.9% vs. 7.3%, p = 0.0083) were lower in CAD patients than in controls. Among CAD patients, a significantly lower proportion of *2 allele carriers was treated with diuretics and ACE inhibitors when compared to *1/*1 wild-type homozygotes. Conclusion: ADA*2 allele may decrease genetic susceptibility to CAD. ADA should be added to the list of candidate genes modifying the risk of cardiovascular diseases.
Detection of Mycobacterium leprae in Ocular Tissues by Histopathology and Real-Time Polymerase Chain Reaction
Authors: Shamsi Farrukh A. , Chaudhry Imtiaz A. , Moraes Milton O. , Martinez Alejandra N. , Riley Fenwick C.
Published: February 2007

Aim: To report detection of leprosy in ocular tissue by histopathology and its confirmation by genetic analysis. Methods: Excised tissue from a clinically-suspected ocular leprosy patient was processed and analyzed histopathologically. The DNA from the paraffin-embedded tissue was extracted, an 85 A-C intergenic region of Mycobacterium leprae was amplified using specific primers and analyzed by conventional as well as real-time polymerase chain reaction (RT-PCR). Results: With periodic acid-Schiff-hematoxylin (PAS-H) staining the specimen showed presence of a thin fibrinous layer of inflammatory cells. The majority of the tissue was fibrovascular with extensive infiltration by histiocytes having reticulated cytoplasm. Modified PAS-H and acid-fast staining (AFS) showed the presence of several acid-fast organisms within the cytoplasm of histiocytes and mast cells. Conventional PCR showed a 250-bp DNA from excised conjunctival tissue, which was in agreement with the positive controls for M. leprae. Through RT-PCR, it was calculated that the suspected tissue had 44.68 pg of M. leprae DNA, which is 8937.06 genome copies of M. leprae. Conclusions: Presence of inflammatory cells and AFS bacilli in tissue presented a typical picture of leprosy. M. leprae DNA can be detected using RT-PCR in ocular tissues when acid-fast bacteria are seen in histopathological sections. And when the diagnosis of leprosy is inconclusive and acid-fast bacteria are seen, RT-PCR for M. leprae DNA could be used as a rapid confirmatory test to identify the presence of M. leprae and, therefore, the diagnosis of leprosy.
Cooperative Inhibitory Effects of Budesonide and Formoterol on Eosinophil Superoxide Production Stimulated by Bronchial Epithelial Cell Conditioned Medium
Authors: Persdotter Sofia , Lindahl Maria , Malm-Erjefält Monika , von Wachenfeldt Karin , Korn Solange H. , Stevens Tim , Miller-Larsson Anna
Published: February 2007

Background: Improved asthma control by combinations of inhaled glucocorticosteroids (GCs) and long-acting β2-agonists (LABAs) includes a reduced frequency and severity of exacerbations. In view of the association of exacerbations with increased airway inflammation, the question has arisen as to whether LABAs are able to complement the known anti-inflammatory activity of GCs. To address this, we studied the effects of a LABA, formoterol (FORM), and a GC, budesonide (BUD), alone and in combination, on bronchial epithelial cell-mediated eosinophil superoxide production in vitro.Methods: We employed 2 experimental approaches. First, superoxide production by human eosinophils incubated with conditioned medium (CM) from human bronchial epithelial cells cultured for 24 h with vehicle, BUD, FORM or BUD + FORM was measured (Epi/Eos assay). Second, eosinophils were stimulated with vehicle-CM to which the drugs were added (Eos assay). Superoxide production was determined as the superoxide dismutase-inhibitable reduction of ferricytochrome C. Results: CM increased eosinophil superoxide generation (p < 0.01) and epithelial-derived granulocyte macrophage colony-stimulating factor was the mediator responsible. In both assays, FORM dose-dependently inhibited eosinophil superoxide similarly and in the same concentration range as BUD. The BUD + FORM combination was more effective than BUD alone, and it completely inhibited CM-induced superoxide production in the Epi/Eos assay, suggesting complementary effects of both drugs on bronchial epithelial cells and eosinophils. Conclusions: The cooperative, inhibitory effects of BUD and FORM on eosinophils and bronchial epithelial cells, in terms of their effects on eosinophil superoxide production, may represent a possible mechanism for the enhanced anti-inflammatory efficacy of BUD and FORM combination therapy of asthma.
Grapple® Allergy: The Grape or the Apple?
Authors: Otto Hans F. , Tankersley Michael S.
Published: February 2007

Background: Many foods can cause food allergies. Grapple® is just one of many new fruits recently introduced into grocery stores. Objective: To describe 2 unique patients with food allergies after consuming a unique food, a Grapple. Methods: Commercial skin prick testing, fresh fruit prick-prick and radioallergosorbent testing were used to characterize the food allergy reaction. Results: Clinical history and appropriate testing confirmed the Grapple food allergy. Conclusions: To our knowledge, these are the first 2 case reports of food allergy to a new fruit called Grapple. These cases illustrate the importance of consumer labeling laws and careful identification of component ingredients by food-allergic individuals.
Antagonism of IL-4 Signaling by a Phosphodiesterase-4 Inhibitor, Rolipram, in Human T Cells
Authors: Markova Tzvetanka Petrova , Niwa Atsuko , Yamanishi Hiromichi , Aragane Yoshinori , Higashino Hideaki
Published: February 2007

Background: Phosphodiesterase (PDE4) inhibitors prevent breakdown of cAMP and affect the increase in cellular levels of cAMP, which is known to regulate immune cell functions. Because IL-4 plays a causal role in the pathogenesis of allergic disorders, we were interested to study the modulatory mechanisms of a PDE4 inhibitor, rolipram, in IL-4-mediated signaling in T cells. Methods: Human peripheral T cells were stimulated with IL-4 in combination with rolipram, and RT-PCR was performed using primers specific for IL-5. To monitor activation of transcription factors, immunostaining was employed. Results: Rolipram or a cAMP-analogue, 8-Br-cAMP, significantly downregulated IL-4-induced expression of IL-5 mRNA. The rolipram-induced inhibition of IL-5 mRNA was mediated by activation of protein kinase A (PKA), because rolipram-downregulated mRNA expression of IL-5 was restored by PKA inhibitors. Immunostaining revealed that rolipram interfered with IL-4-induced nuclear translocation of activator protein (AP)-1 components. Conclusions: This is the first demonstration of suppression of IL-4 signaling by PDE4 inhibitors via prevention of nuclear translocation of AP-1.
Platinum Group Elements Enhance the Allergic Immune Response by Acting on Dendritic Cells
Authors: Paolucci Clara , Ponti Jessica , Fabbri Monica V. , Breda Daniela , Sabbioni Enrico , Burastero Samuele E.
Published: February 2007

Background: Atmospheric pollution may play a role in the immune response to allergens either directly or by entering the food chain. While particulate platinum group elements (PLGE) emitted by catalytic converters can be considered biologically inert, approximately 10% of these species accumulate in the environment as bioavailable soluble forms. Methods: We challenged in vitro human immature and mature monocyte-derived dendritic cells with subtoxic concentrations of soluble species of PLGE. Dendritic cells were studied both at baseline and following treatment with Na2PtCl6, Na2PdCl6 or Na3RhCl6. (NH4)6Mo7O24 was included as control. The following end-points were considered: expression of differentiation markers, effectiveness of allergen presentation and Th2 cytokine production by cocultured T lymphocytes, expression of IgE-type I receptor and efficiency of IgE-dependent endocytosis. Results: We found that treatment with PLGE (but not with the control metal) increased costimulatory molecule expression and antigen presentation, amplified IL-5 production by cocultured T lymphocytes, upregulated IgE-type I receptor membrane expression, and augmented IgE-type I receptor-mediated endocytosis. Conclusions: We conclude that PLGE have an adjuvant-like effect on dendritic cells that can favor and amplify the immune response to allergens.
Probiotics Have a Different Immunomodulatory Potential in vitro versus ex vivo upon Oral Administration in Children with Food Allergy
Authors: Flinterman A.E. , Knol E.F. , van Ieperen-van Dijk A.G. , Timmerman H.M. , Knulst A.C. , Bruijnzeel-Koomen C.A.F.M. , Pasmans S.G.M.A. , van Hoffen E.
Published: February 2007

Background: Previous studies suggest that administration of probiotics in vitro can stimulate regulatory and Th1 immune responses. We studied both the in vitro immunological effects of probiotics and the ex vivo immunological effects after oral administration of probiotics in children with food allergy, a Th2-mediated disease. Methods: Thirteen children were enrolled. Probiotics (n = 7) or placebo (n = 6) were orally administered during 3 months. At baseline and after 1 and 3 months, peripheral blood mononuclear cells were stimulated with crude peanut extract, anti-CD3, or anti-CD40 and IL-4 in the presence (in vitro response) or absence (ex vivo response) of probiotics. The proliferation and production of IFN-γ, IL-5, IL-13, IL-10, TNF-α, IL-6 and IgE were analyzed. Sensitization to peanut, cow’s milk and hen’s egg was determined before and after treatment. Results: The in vitro addition of probiotics to peripheral blood mononuclear cell cultures resulted in enhanced proliferation and production of IFN-γ, IL-10 and TNF-α. After oral treatment, proliferation in the presence of probiotics increased, whereas in vitro IgE production decreased in the probiotics group compared to baseline. The ex vivo production of IL-10, TNF-α and IL-6 tended to decrease. Th1 and Th2 cytokines were not altered. Sensitization remained unchanged. Conclusion: Probiotics enhanced the production of Th1 and regulatory cytokines in vitro. Oral administration of probiotics resulted in a slightly decreased ex vivo production of IL-10, TNF-α and IL-6. This indicates that probiotics have a different potential to modulate the immune response in vitro versus ex vivo.
Diagnosis of Dementia in Primary Care: A Representative Survey of Family Physicians and Neuropsychiatrists in Germany
Authors: Stoppe Gabriela , Haak Sebastian , Knoblauch Anita , Maeck Lienhard
Published: February 2007

Aim: To measure the diagnostic competence of family physicians (FP) and neuropsychiatrists (NP) for moderate dementia. Methods: Written case vignettes describing moderate dementia either of Alzheimer type or vascular type were randomized to a representative sample of 122 FP and 68 NP, corresponding to response rates of 71.8 and 67.3%, respectively. They served as the basis for a structured face-to-face interview. Results: NP and FP did not differ with regard to their diagnostic considerations, however, concerning diagnostic workup. Vascular dementia was much better recognized than dementia of Alzheimer type. Neuropsychological tests and brain imaging would be done by 14.8 and 32.8% of the FP in the case of vascular dementia. In Alzheimer dementia they would apply these methods in 24.6 and 19.7%, respectively. The corresponding numbers for NP were about 60% in both cases for testing and more than 80% for brain imaging. Conclusions: There is still a wide gap between guidelines and practice in primary care. The apparent overdiagnosis of vascular dementia may be one reason for the low drug treatment rates.
CSF Neurofilaments in Frontotemporal Dementia Compared with Early Onset Alzheimer’s Disease and Controls
Authors: Pijnenburg Yolande A.L. , Janssen John C. , Schoonenboom Niki S.M. , Petzold Axel , Mulder Cees , Stigbrand Torgny , Norgren Niklas , Heijst Hans , Hack C. Erik , Scheltens Philip , Teunissen Charlotte E.
Published: February 2007

Background: Frontotemporal dementia (FTD) is pathologically heterogeneous, sometimes revealing intraneuronal inclusions of neurofilaments. We therefore measured CSF neurofilament profiles in patients with FTD, patients with early onset Alzheimer’s disease (EAD) and healthy control subjects to explore the discriminative potential of CSF neurofilaments compared with the existing CSF biomarkers amyloid-β(1–42), tau and tau phosphorylated at threonine-181. Methods: CSF levels of light chain, heavy chain and hyperphosphorylated heavy chain neurofilaments (NfL, t-NfH and P-NfH) were compared between 17 subjects with FTD, 20 with EAD and 25 cognitively healthy controls. Results: A subgroup of FTD patients had remarkably high CSF levels of both NfL and NfH. The degree of NfH phosphorylation was increased in FTD compared to both other groups. The levels of CSF NfL were significantly higher in EAD compared to controls. Conclusion: Differences in CSF biomarker profiles might reflect differential involvement of neurofilaments and tau in FTD and EAD. The subgroup of FTD patients with high CSF neurofilament levels may have a different neuropathological substrate and future studies addressing this specific issue are needed.
US Multicenter Experience With the Wingspan Stent System for the Treatment of Intracranial Atheromatous Disease
Authors: Fiorella David , Levy Elad I. , Turk Aquilla S. , Albuquerque Felipe C. , Niemann David B. , Aagaard-Kienitz Beverly , Hanel Ricardo A. , Woo Henry , Rasmussen Peter A. , Hopkins L. Nelson , Masaryk Thomas J. , McDougall Cameron G.
Published: February 2007

Background and Purpose—

The current report details our initial periprocedural experience with Wingspan (Boston Scientific/Target), the first self-expanding stent system designed for the treatment of intracranial atheromatous disease.

Methods—

All patients undergoing angioplasty and stenting with the Gateway balloon–Wingspan stent system were prospectively tracked.

Results—

During a 9-month period, treatment with the stent system was attempted in 78 patients (average age, 63.6 years; 33 women) with 82 intracranial atheromatous lesions, of which 54 were ≥70% stenotic. Eighty-one of 82 lesions were successfully stented (98.8%) during the first treatment session. In 1 case, the stent could not be delivered across the lesion; the patient was treated solely with angioplasty and stented at a later date. Lesions treated involved the internal carotid (n=32; 8 petrous, 10 cavernous, 11 supraclinoid segment, 3 terminus), vertebral (n=14; V4 segment), basilar (n=14), and middle cerebral (n=22) arteries. Mean±SD pretreatment stenosis was 74.6±13.9%, improving to 43.5±18.1% after balloon angioplasty and to 27.2±16.7% after stent placement. Of the 82 lesions treated, there were 5 (6.1%) major periprocedural neurological complications, 4 of which ultimately led to patient death within 30 days of the procedure.

Conclusions—

Angioplasty and stenting for symptomatic intracranial atheromatous disease can be performed with the Gateway balloon–Wingspan stent system with a high rate of technical success and acceptable periprocedural morbidity. Our initial experience indicates that this procedure represents a viable treatment option for this patient population.
Determinants of Intracerebral Hemorrhage Growth
Authors: Broderick Joseph P. , Diringer Michael N. , Hill Michael D. , Brun Nikolai C. , Mayer Stephan A. , Steiner Thorsten , Skolnick Brett E. , Davis Stephen M.
Published: February 2007

Background and Purpose—

We report an exploratory analysis from a randomized study of recombinant activated factor VII (rFVIIa) in patients with intracerebral hemorrhage (ICH) examining potential factors associated with hemorrhage growth.

Methods—

We explored the relationship between 5 different measures of change in hemorrhage volume between baseline and 24-hour CTs (absolute and percent change in ICH volume, ICH growth—categoric [no growth if change <33% and <12.5 mL], absolute and percent change in ICH plus intraventricular hemorrhage [IVH] volume) and 31 demographic, clinical, imaging, historic, and baseline laboratory variables. Variables with a probability value of ≤0.10 were included in the final multivariable models.

Results—

Treatment with rFVIIa and a longer time-from-onset-to-baseline CT were related to a decrease in hemorrhage growth in all 5 models. ICH volume on baseline CT was consistently associated with ICH growth in the various models. Other variables significantly related to growth of ICH or ICH+IVH in at least 1 of the 5 models include serum glucose (increased levels associated with increased growth), body mass index (heavier people have less growth), prior use of antiplatelet agent (prior use associated with increased growth), serum cholesterol (higher level associated with less hemorrhage growth), and serum creatinine (higher level associated with more hemorrhage growth).

Conclusions—

Our exploratory analyses confirm that treatment with rFVIIa limits ICH growth in subjects with spontaneous ICH who met the criteria for this study. Most hematoma growth occurs early after onset of ICH. Larger hematomas on the baseline CT were associated with increased absolute ICH growth. The relationship of other factors to hemorrhage growth warrants further study.
Seasonal Dependence of the MJO–ENSO Relationship
Authors: Hendon Harry H. , Wheeler Matthew C. , Zhang Chidong
Published: February 2007

Observations of the development of recent El Niño events suggest a pivotal role for the Madden–Julian oscillation (MJO). Previous attempts to uncover a systematic relationship between MJO activity and the El Niño–Southern Oscillation (ENSO), however, have yielded conflicting results. In this study the MJO–ENSO relationship is stratified by season, and the focus is on MJO activity in the equatorial western Pacific. The results demonstrate that MJO activity in late boreal spring leads El Niño in the subsequent autumn–winter for the period 1979–2005. Spring is the season when MJO activity is least asymmetric with respect to the equator and displays the most sensitivity to SST variations at the eastern edge of the warm pool. Enhanced MJO activity in the western Pacific in spring is associated with an eastward-expanded warm pool and low-frequency westerly surface zonal wind anomalies. These sustained westerly anomalies in the western Pacific are hypothesized to project favorably onto a developing El Niño in spring.
Cloud Cover over the South Pole from Visual Observations, Satellite Retrievals, and Surface-Based Infrared Radiation Measurements
Authors: Town Michael S. , Walden Von P. , Warren Stephen G.
Published: February 2007

Estimates of cloud cover over the South Pole are presented from five different data sources: routine visual observations (1957–2004; Cvis), surface-based spectral infrared (IR) data (2001; CPAERI), surface-based broadband IR data (1994–2003; Cpyr), the Extended Advanced Very High Resolution Radiometer (AVHRR) Polar Pathfinder (APP-x) dataset (1994–99; CAPP-x), and the International Satellite Cloud Climatology Project (ISCCP) dataset (1994–2003; CISCCP). The seasonal cycle of cloud cover is found to range from 45%–50% during the short summer to a relatively constant 55%–65% during the winter. Relationships between Cpyr and 2-m temperature, 10-m wind speed and direction, and longwave radiation are investigated. It is shown that clouds warm the surface in all seasons, 0.5–1 K during summer and 3–4 K during winter. The annual longwave cloud radiative forcing is 18 W m−2 for downwelling radiation and 10 W m−2 for net radiation. The cloud cover datasets are intercompared during the time periods in which they overlap. The nighttime bias of Cvis is worse than previously suspected, by approximately −20%; CISCCP shows some skill during the polar day, while CAPP-x shows some skill at night. The polar cloud masks for the satellite data reviewed here are not yet accurate enough to reliably derive surface or cloud properties over the East Antarctic Plateau. The best surface-based source of cloud cover in terms of the combination of accuracy and length of record is determined to be Cpyr. The use of the Cpyr dataset for further tests of satellite retrievals and for tests of polar models is recommended.
Dynamics of the Extratropical Response to a Tropical Atlantic SST Anomaly
Authors: Li Shuanglin , Robinson Walter A. , Hoerling Martin P. , Weickmann Klaus M.
Published: February 2007

Previous atmospheric general circulation model (AGCM) experiments revealed that atmospheric responses to a tropical Atlantic sea surface temperature anomaly (SSTA) were asymmetric with respect to the sign of the SSTA. A positive SSTA produced a south–north dipole in geopotential heights, much like the North Atlantic Oscillation (NAO), while a negative SSTA yielded an eastward-propagating wave train, with the northern lobe of the NAO absent.

Here these height responses are decomposed into components that are symmetric or antisymmetric with respect to the sign of the SSTA. The symmetric, or notionally linear, component is a nearly south–north dipole projecting on the NAO, while the antisymmetric, or notionally nonlinear, component is a different dipole. Experiments with a diagnostic linear baroclinic model (LBM) suggest that both components are maintained primarily by transient-eddy forcing. Dynamical mechanisms for the formation of the two components are explored using the LBM and a nonlinear barotropic vorticity equation model (BVM). Transient-eddy feedback is sufficient to explain the linear response. The NAO-like linear response occurs when the initial heating induces transient-eddy forcing in the exit of the Atlantic jet. The structure of the background absolute vorticity in this region is such that this transient-eddy forcing induces a nearly north–south dipole in anomalous geopotential heights. When the nonlinear self-interaction of this transient-induced low-frequency perturbation is included in the BVM, the dipole axis tilts to the east or west, resulting in a response that is nonlinear about the sign of the forcing.
Climate Response to External Sources of Freshwater: North Atlantic versus the Southern Ocean
Authors: Stouffer Ronald J. , Seidov Dan , Haupt Bernd J.
Published: February 2007

The response of an atmosphere–ocean general circulation model (AOGCM) to perturbations of freshwater fluxes across the sea surface in the North Atlantic and Southern Ocean is investigated. The purpose of this study is to investigate aspects of the so-called bipolar seesaw where one hemisphere warms and the other cools and vice versa due to changes in the ocean meridional overturning. The experimental design is idealized where 1 Sv (1 Sv ≡ 106 m3 s−1) of freshwater is added to the ocean surface for 100 model years and then removed. In one case, the freshwater perturbation is located in the Atlantic Ocean from 50° to 70°N. In the second case, it is located south of 60°S in the Southern Ocean.

In the case where the North Atlantic surface waters are freshened, the Atlantic thermohaline circulation (THC) and associated northward oceanic heat transport weaken. In the Antarctic surface freshening case, the Atlantic THC is mainly unchanged with a slight weakening toward the end of the integration. This weakening is associated with the spreading of the fresh sea surface anomaly from the Southern Ocean into the rest of the World Ocean. There are two mechanisms that may be responsible for such weakening of the Atlantic THC. First is that the sea surface salinity (SSS) contrast between the North Atlantic and North Pacific is reduced. And, second, when freshwater from the Southern Ocean reaches the high latitudes of the North Atlantic Ocean, it hinders the sinking of the surface waters, leading to the weakening of the THC.

The spreading of the fresh SSS anomaly from the Southern Ocean into the surface waters worldwide was not seen in earlier experiments. Given the geography and climatology of the Southern Hemisphere where the climatological surface winds push the surface waters northward away from the Antarctic continent, it seems likely that the spreading of the fresh surface water anomaly could occur in the real world.

A remarkable symmetry between the two freshwater perturbation experiments in the surface air temperature (SAT) response can be seen. In both cases, the hemisphere with the freshwater perturbation cools, while the opposite hemisphere warms slightly. In the zonally averaged SAT figures, both the magnitude and the pattern of the anomalies look similar between the two cases. The oceanic response, on the other hand, is very different for the two freshwater cases, as noted above for the spreading of the SSS anomaly and the associated THC response.

If the differences between the atmospheric and oceanic responses apply to the real world, then the interpretation of paleodata may need to be revisited. To arrive at a correct interpretation, it matters whether or not the evidence is mainly of atmospheric or oceanic origin. Also, given the sensitivity of the results to the exact details of the freshwater perturbation locations, especially in the Southern Hemisphere, a more realistic scenario must be constructed to explore these questions.
The Influence of ENSO on the Generation of Decadal Variability in the North Pacific*
Authors: An Soon-Il , Kug Jong-Seong , Timmermann Axel , Kang In-Sik , Timm Oliver
Published: February 2007

This diagnostic study explores the generation of decadal variability in the North Pacific resulting from the asymmetry of the El Niño–Southern Oscillation phenomenon and the nonlinearity of the atmospheric tropical–extratropical teleconnection. Nonlinear regression analysis of the North Pacific sea surface temperatures and atmospheric fields with respect to the ENSO index reveals that the main teleconnection centers shift between El Niño and La Niña years. This asymmetry in the ENSO response, together with the skewed probabilistic distribution of ENSO itself, may contribute to the generation of the long-term decadal variability of sea surface temperatures in the extratropical North Pacific. It is argued that this hypothesis may explain the significant variance of the observed Pacific decadal oscillation in the extratropics.
Multi-Instrument Comparison of Top-of-Atmosphere Reflected Solar Radiation
Authors: Loeb Norman G. , Wielicki Bruce A. , Su Wenying , Loukachine Konstantin , Sun Wenbo , Wong Takmeng , Priestley Kory J. , Matthews Grant , Miller Walter F. , Davies R.
Published: February 2007

Observations from the Clouds and the Earth’s Radiant Energy System (CERES), Moderate Resolution Imaging Spectroradiometer (MODIS), Multiangle Imaging Spectroradiometer (MISR), and Sea-Viewing Wide-Field-of-View Sensor (SeaWiFS) between 2000 and 2005 are analyzed in order to determine if these data are meeting climate accuracy goals recently established by the climate community. The focus is primarily on top-of-atmosphere (TOA) reflected solar radiances and radiative fluxes. Direct comparisons of nadir radiances from CERES, MODIS, and MISR aboard the Terra satellite reveal that the measurements from these instruments exhibit a year-to-year relative stability of better than 1%, with no systematic change with time. By comparison, the climate requirement for the stability of visible radiometer measurements is 1% decade−1. When tropical ocean monthly anomalies in shortwave (SW) TOA radiative fluxes from CERES on Terra are compared with anomalies in Photosynthetically Active Radiation (PAR) from SeaWiFS—an instrument whose radiance stability is better than 0.07% during its first six years in orbit—the two are strongly anticorrelated. After scaling the SeaWiFS anomalies by a constant factor given by the slope of the regression line fit between CERES and SeaWiFS anomalies, the standard deviation in the difference between monthly anomalies from the two records is only 0.2 W m−2, and the difference in their trend lines is only 0.02 ± 0.3 W m−2 decade−1, approximately within the 0.3 W m−2 decade−1 stability requirement for climate accuracy. For both the Tropics and globe, CERES Terra SW TOA fluxes show no trend between March 2000 and June 2005. Significant differences are found between SW TOA flux trends from CERES Terra and CERES Aqua between August 2002 and March 2005. This discrepancy is due to uncertainties in the adjustment factors used to account for degradation of the CERES Aqua optics during hemispheric scan mode operations. Comparisons of SW TOA flux between CERES Terra and the International Satellite Cloud Climatology Project (ISCCP) radiative flux profile dataset (FD) RadFlux product show good agreement in monthly anomalies between January 2002 and December 2004, and poor agreement prior to this period. Commonly used statistical tools applied to the CERES Terra data reveal that in order to detect a statistically significant trend of magnitude 0.3 W m−2 decade−1 in global SW TOA flux, approximately 10 to 15 yr of data are needed. This assumes that CERES Terra instrument calibration remains highly stable, long-term climate variability remains constant, and the Terra spacecraft has enough fuel to last 15 yr.