bluuebunny/crossref_metadata_2025 huggingface dataset:
Cocaine- and amphetamine-regulated transcript is the neurotransmitter regulating the action of cholecystokinin and leptin on short-term satiety in rats
Authors: Heldsinger Andrea , Lu Yuanxu , Zhou Shi-Yi , Wu Xiaoyin , Grabauskas Gintautas , Song Il , Owyang Chung
Published: August 2012

Vagal CCK-A receptors (CCKARs) and leptin receptors (LRbs) interact synergistically to mediate short-term satiety. Cocaine- and amphetamine-regulated transcript (CART) peptide is expressed by vagal afferent neurons. We sought to demonstrate that this neurotransmitter regulates CCK and leptin actions on short-term satiety. We also examined the signal transduction pathways responsible for mediating the CART release from the nodose ganglia (NG). ELISA studies coupled with gene silencing of NG neurons by RNA interference elucidated intracellular signaling pathways responsible for CCK/leptin-stimulated CART release. Feeding studies followed by gene silencing of CART in NG established the role of CART in mediating short-term satiety. Immunohistochemistry was performed on rat NG neurons to confirm colocalization of CCKARs and LRbs; 63% of these neurons contained CART. Coadministration of CCK-8 and leptin caused a 2.2-fold increase in CART release that was inhibited by CCK-OPE, a low-affinity CCKAR antagonist. Transfection of cultured NG neurons with steroid receptor coactivator (SRC) or phosphatidylinositol 3-kinase (PI3K) small-interfering RNA (siRNA) or STAT3 lentiviral short hairpin RNA inhibited CCK/leptin-stimulated CART release. Silencing the expression of the EGR-1 gene inhibited the CCK/leptin-stimulated CART release but had no effect on CCK/leptin-stimulated neuronal firing. Electroporation of NG with CART siRNA inhibited CCK/leptin stimulated c-Fos expression in rat hypothalamus. Feeding studies following electroporation of the NG with CART or STAT3 siRNA abolished the effects of CCK/leptin on short-term satiety. We conclude that the synergistic interaction of low-affinity vagal CCKARs and LRbs mediates CART release from the NG, and CART is the principal neurotransmitter mediating short-term satiety. CART release from the NG involves interaction between CCK/SRC/PI3K cascades and leptin/JAK2/PI3K/STAT3 signaling pathways.
Pulmonary C-fiber activation attenuates respiratory-related tongue movements
Authors: Lee Kun-Ze , Fuller David D. , Hwang Ji-Chuu
Published: August 2012

The functional impact of pulmonary C-fiber activation on upper airway biomechanics has not been evaluated. Here, we tested the hypothesis that pulmonary C-fiber activation alters the respiratory-related control of tongue movements. The force produced by tongue movements was quantified in spontaneously breathing, anesthetized adult rats before and after stimulation of pulmonary C fibers via intrajugular delivery of capsaicin (0.625 and 1.25 μg/kg). Brief occlusion of the trachea was used to increase the respiratory drive to the tongue muscles, and hypoglossal (XII) nerve branches were selectively sectioned to denervate the protrusive and retrusive tongue musculature. Tracheal occlusion triggered inspiratory-related tongue retrusion in rats with XII nerves intact or following section of the medial XII nerve branch, which innervates the genioglossus muscle. Inspiratory-related tongue protrusion was only observed after section of the lateral XII branch, which innervates the primary tongue retrusor muscles. The tension produced by inspiratory-related tongue movement was significantly attenuated by capsaicin, but tongue movements remained retrusive, unless the medial XII branch was sectioned. Capsaicin also significantly delayed the onset of tongue movements such that tongue forces could not be detected until after onset of the inspiratory diaphragm activity. We conclude that altered neural drive to the tongue muscles following pulmonary C-fiber activation has a functionally significant effect on tongue movements. The diminished tongue force and delay in the onset of tongue movements following pulmonary C-fiber activation are potentially unfavorable for upper airway patency.
Aortic function quantified: the heart's essential cushion
Authors: Saouti Nabil , Marcus J. Tim , Noordegraaf Anton Vonk , Westerhof Nico
Published: August 2012

Arterial compliance is mainly determined by the elasticity of proximal large-conduit arteries of which the aorta is the largest contributor. Compliance forms an important part of the cardiac load and plays a role in organ (especially coronary) perfusion. To follow local changes in aortic compliance, as in aging, noninvasive determination of compliance distribution would be of great value. Our goal is to determine regional aortic compliance noninvasively in the human. In seven healthy individuals at six locations, aortic blood flow and systolic/diastolic area (ΔA) was measured with MRI. Simultaneously brachial pulse pressure (ΔP) was measured with standard cuff. With a transfer function we derived ΔP at the same aortic locations as the MRI measurements. Regional aortic compliance was calculated with two approaches, the pulse pressure method, and local area compliance (ΔA/ΔP) times segment length, called area compliance method. For comparison, pulse wave velocity (PWV) from local flows at two locations was determined, and compliance was derived from PWV. Both approaches show that compliance is largest in the proximal aorta and decreases toward the distal aorta. Similar results were found with PWV-derived compliance. Of total arterial compliance, ascending to distal arch ( segments 1–3) contributes 40% (of which 15% is in head and arms), descending aorta ( segments 4 and 5) 25%, and “hip, pelvic and leg arteries” 20%. Pulse pressure method includes compliance of side branches and is therefore larger than the area compliance method. Regional aortic compliance can be obtained noninvasively. Therefore, this technique allows following changes in local compliance with age and cardiovascular diseases.
Sustained postexercise increases in AS160 Thr642and Ser588phosphorylation in skeletal muscle without sustained increases in kinase phosphorylation
Authors: Schweitzer George G. , Arias Edward B. , Cartee Gregory D.
Published: August 2012

Prior exercise by rats can induce a sustained increase in muscle Akt substrate of 160 kDa (AS160) phosphorylation on Thr642(pAS160Thr642). Because phosphorylation of AS160 on both AS160Thr642and AS160Ser588is important for insulin-stimulated glucose transport (GT), we determined if exercise would also induce a sustained increase in pAS160Ser588concomitant with persistently elevated pAS160Thr642and GT. Given that the mechanisms for sustained postexercise (PEX) effects on pAS160 were uncertain, we also studied the four kinases known to phosphorylate AS160 (Akt, AMPK, RSK, and SGK1). In addition, because the serine/threonine phosphatase(s) that dephosphorylate muscle AS160 were previously unidentified, we assessed the ability of four serine/threonine phosphatases (PP1, PP2A, PP2B, and PP2C) to dephosphorylate AS160. We also evaluated exercise effects on posttranslational modifications (Tyr307and Leu309) that regulate PP2A. In isolated epitrochlearis muscles from rats, GT at 3hPEX with insulin significantly ( P < 0.05) exceeded SED controls. Muscles from 0hPEX vs. 0hSED and 3hPEX vs. 3hSED rats had greater pAS160Thr642and pAS160Ser588. AMPK was the only kinase with greater phosphorylation at 0hPEX vs. 0hSED, and none had greater phosphorylation at 3hPEX vs. 3hSED. Each phosphatase was able to dephosphorylate pAS160Thr642and pAS160Ser588in cell-free assays. Exercise did not alter posttranslational modifications of PP2A. Our results revealed: 1) pAMPK as a potential trigger for increased pAS160Thr642and pAS160Ser588at 0hPEX; 2) PP1, PP2A, PP2B, and PP2C were each able to dephosphorylate AS160; and 3) sustained PEX-induced elevations of pAS160Thr642and pAS160Ser588were attributable to mechanisms other than persistent phosphorylation of known AS160 kinases or altered posttranslational modifications of PP2A.
Divergent skeletal muscle respiratory capacities in rats artificially selected for high and low running ability: a role for Nor1?
Authors: Stephenson Erin J. , Stepto Nigel K. , Koch Lauren G. , Britton Steven L. , Hawley John A.
Published: August 2012

Inactivity-related diseases are becoming a huge burden on Western society. While there is a major environmental contribution to metabolic health, the intrinsic properties that predispose or protect against particular health traits are harder to define. We used rat models of inborn high running capacity (HCR) and low running capacity (LCR) to determine inherent differences in mitochondrial volume and function, hypothesizing that HCR rats would have greater skeletal muscle respiratory capacity due to an increase in mitochondrial number. Additionally, we sought to determine if there was a link between the expression of the orphan nuclear receptor neuron-derived orphan receptor (Nor)1, a regulator of oxidative metabolism, and inherent skeletal muscle respiratory capacity. LCR rats were 28% heavier ( P < 0.0001), and fasting serum insulin concentrations were 62% greater than in HCR rats ( P = 0.02). In contrast, HCR rats had better glucose tolerance and reduced adiposity. In the primarily oxidative soleus muscle, maximal respiratory capacity was 21% greater in HCR rats ( P = 0.001), for which the relative contribution of fat oxidation was 20% higher than in LCR rats ( P = 0.02). This was associated with increased citrate synthase (CS; 33%, P = 0.009) and β-hydroxyacyl-CoA (β-HAD; 33%, P = 0.0003) activities. In the primarily glycolytic extensor digitum longus muscle, CS activity was 29% greater ( P = 0.01) and β-HAD activity was 41% ( P = 0.0004) greater in HCR rats compared with LCR rats. Mitochondrial DNA copy numbers were also elevated in the extensor digitum longus muscles of HCR rats (35%, P = 0.049) and in soleus muscles (44%, P = 0.16). Additionally, HCR rats had increased protein expression of individual mitochondrial respiratory complexes, CS, and uncoupling protein 3 in both muscle types (all P < 0.05). In both muscles, Nor1 protein was greater in HCR rats compared with LCR rats ( P < 0.05). We propose that the differential expression of Nor1 may contribute to the differences in metabolic regulation between LCR and HCR phenotypes.
Subtle alterations in breathing and heart rate control in the 5-HT1Areceptor knockout mouse in early postnatal development
Authors: Barrett Karlene T. , Kinney Hannah C. , Li Aihua , Daubenspeck J. Andrew , Leiter James C. , Nattie Eugene E.
Published: August 2012

We hypothesized that absence of the 5-HT1Areceptor would negatively affect the development of cardiorespiratory control. In conscious wild type (WT) and 5-HT1Areceptor knockout (KO) mice, we measured resting ventilation (V̇e), oxygen consumption (V̇o2), heart rate (HR), breathing and HR variability, and the hypercapnic ventilatory response (HCVR) at postnatal day 5 (P5), day 15 (P15), and day 25 (P25). In KO mice compared with WT, we found a 17% decrease in body weight at only P5 ( P < 0.01) and no effect on V̇o2. V̇e was significantly ( P < 0.001) lower at P5 and P25, but there was no effect on the HCVR. Breathing variability (interbreath interval), measured by standard deviation, the root mean square of the standard deviation (RMSSD), and the product of the major (L) and minor axes (T) of the Poincaré first return plot, was 57% to 187% higher only at P5 ( P < 0.001). HR was 6–10% slower at P5 ( P < 0.001) but 7–9% faster at P25 ( P < 0.001). This correlated with changes in the spectral analysis of HR variability; the low frequency to high frequency ratio was 47% lower at P5 but 68% greater at P25. The RMSSD and (L × T) of HR variability were ∼2-fold greater at P5 only ( P < 0.001; P < 0.05). We conclude that 5-HT1AKO mice have a critical period of potential vulnerability at P5 when pups hypoventilate and have a slower respiratory frequency and HR with enhanced variability of both, suggesting abnormal maturation of cardiorespiratory control.
Unchanged [3H]ouabain binding site content but reduced Na+-K+ pump α2-protein abundance in skeletal muscle in older adults
Authors: McKenna Michael J. , Perry Ben D. , Serpiello Fabio R. , Caldow Marissa K. , Levinger Pazit , Cameron-Smith David , Levinger Itamar
Published: August 2012

Aging is associated with reduced muscle mass, weakness, and increased fatigability. In skeletal muscle, the Na+-K+ pump (NKA) is important in regulating Na+-K+ gradients, membrane excitability, and thus contractility, but the effects of aging on muscle NKA are unclear. We investigated whether aging is linked with reduced muscle NKA by contrasting muscle NKA isoform gene expression and protein abundance, and NKA total content in 17 Elderly (66.8 ± 6.4 yr, mean ± SD) and 16 Young adults (23.9 ± 2.2 yr). Participants underwent peak oxygen consumption assessment and a vastus lateralis muscle biopsy, which was analyzed for NKA α1-, α2-, α3-, β1-, β2-, and β3-isoform gene expression (real-time RT-PCR), protein abundance (immunoblotting), and NKA total content ([3H]ouabain binding sites). The Elderly had lower peak oxygen consumption (−36.7%, P = 0.000), strength (−36.3%, P = 0.001), NKA α2- (−24.4%, 11.9 ± 4.4 vs. 9.0 ± 2.7 arbitrary units, P = 0.049), and NKA β3-protein abundance (−23.0%, P = 0.041) than Young. The β3-mRNA was higher in Elderly compared with Young ( P = 0.011). No differences were observed between groups for other NKA isoform mRNA or protein abundance, or for [3H]ouabain binding site content. Thus skeletal muscle in elderly individuals was characterized by decreased NKA α2- and β3-protein abundance, but unchanged α1 abundance and [3H]ouabain binding. The latter was likely caused by reduced α2 abundance with aging, preventing an otherwise higher [3H]ouabain binding that might occur with a greater membrane density in smaller muscle fibers. Further study is required to verify reduced muscle NKA α2 with aging and possible contributions to impaired exercise capability and daily living activities.
The Essential Role of Giα2 in Prostate Cancer Cell Migration
Authors: Zhong Miao , Clarke Shineka , Vo BaoHan T. , Khan Shafiq A.
Published: August 2012

Cell- and receptor-specific regulation of cell migration by Gi/oα-proteins remains unknown in prostate cancer cells. In the present study, oxytocin (OXT) receptor was detected at the protein level in total cell lysates from C81 (an androgen-independent subline of LNCaP), DU145 and PC3 prostate cancer cells, but not in immortalized normal prostate luminal epithelial cells (RWPE1), and OXT-induced migration of PC3 cells. This effect of OXT has been shown to be mediated by Gi/oα-dependent signaling. Accordingly, OXT inhibited forskolin-induced luciferase activity in PC3 cells that were transfected with a luciferase reporter for cyclic AMP activity. Although mRNAs for all three Giα isoforms were present in PC3 cells, Giα2 was the most abundant isoform that was detected at the protein level. Pertussis toxin (PTx) inhibited the OXT-induced migration of PC3 cells. Ectopic expression of the PTx-resistant Giα2-C352G, but not wild-type Giα2, abolished this effect of PTx on OXT-induced cell migration. The Giα2-targeting siRNA was shown to specifically reduce Giα2 mRNA and protein in prostate cancer cells. The Giα2-targeting siRNA eliminated OXT-induced migration of PC3 cells. These data suggest that Giα2 plays an important role in the effects of OXT on PC3 cell migration. The Giα2-targeting siRNA also inhibited EGF-induced migration of PC3 and DU145 cells. Expression of the siRNA-resistant Giα2, but not wild type Giα2, restored the effects of EGF in PC3 cells transfected with the Giα2-targeting siRNA. In conclusion, Giα2 plays an essential role in OXT and EGF signaling to induce prostate cancer cell migration. Mol Cancer Res; 10(10); 1380–8. ©2012 AACR.
N-myc and Noncoding RNAs in Neuroblastoma
Authors: Buechner Jochen , Einvik Christer
Published: August 2012

Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Amplification and overexpression of the MYCN proto-oncogene occurs in approximately 20% of neuroblastomas and is associated with advanced stage disease, rapid tumor progression, and poor prognosis. MYCN encodes the transcriptional regulator N-myc, which has been shown to both up- and downregulate many target genes involved in cell cycle, DNA damage, differentiation, and apoptosis in neuroblastoma. During the last years, it has become clear that N-myc also modulates the expression of several classes of noncoding RNAs, in particular microRNAs. MicroRNAs are the most widely studied noncoding RNA molecules in neuroblastoma. They function as negative regulators of gene expression at the posttranscriptional level in diverse cellular processes. Aberrant regulation of miRNA expression has been implicated in the pathogenesis of neuroblastoma. While the N-myc protein is established as an important regulator of several miRNAs involved in neuroblastoma tumorigenesis, tumor suppressor miRNAs have also been documented to repress MYCN expression and inhibit cell proliferation of MYCN-amplified neuroblastoma cells. It is now becoming increasingly evident that N-myc also regulates the expression of long noncoding RNAs such as T-UCRs and ncRAN. This review summarizes the current knowledge about the interplay between N-myc and noncoding RNAs in neuroblastoma and how this contributes to neuroblastoma tumorigenesis. Mol Cancer Res; 10(10); 1243–53. ©2012 AACR.
Copper Modulates Zinc Metalloproteinase-Dependent Ectodomain Shedding of Key Signaling and Adhesion Proteins and Promotes the Invasion of Prostate Cancer Epithelial Cells
Authors: Parr-Sturgess Catherine A. , Tinker Claire L. , Hart Claire A. , Brown Michael D. , Clarke Noel W. , Parkin Edward T.
Published: August 2012

A disintegrin and metalloproteinases (ADAMs) and matrix metalloproteinases (MMPs) are zinc metalloproteinases (ZMPs) that catalyze the “ectodomain shedding” of a range of cell surface proteins including signaling and adhesion molecules. These “sheddases” are associated with the invasion and metastasis of a range of cancers. Increased serum and tumor tissue levels of copper are also observed in several cancers, although little is known about how the metal might promote disease progression at the molecular level. In the current study, we investigated whether copper might regulate the ectodomain shedding of two key cell surface proteins implicated in the invasion and metastasis of prostate cancer, the Notch ligand Jagged1 and the adhesion molecule E-cadherin, and whether the metal was able to influence the invasion of the prostate cancer epithelial cell line PC3. Physiological copper concentrations stimulated the ZMP-mediated proteolysis of Jagged1 and E-cadherin in cell culture models, whereas other divalent metals had no effect. Copper-mediated Jagged1 proteolysis was also observed following the pretreatment of cells with cycloheximide and in a cell-free membrane system, indicating a posttranslational mechanism of sheddase activation. Finally, the concentrations of copper that stimulated ZMP-mediated protein shedding also enhanced PC3 invasion; an effect that could be negated using a sheddase inhibitor or copper chelators. Collectively, these data implicate copper as an important factor in promoting prostate cancer cell invasion and indicate that the selective posttranslational activation of ZMP-mediated protein shedding might play a role in this process. Mol Cancer Res; 10(10); 1282–93. ©2012 AACR.
Corticosteroids plus Long-Acting Beta2-Agonists Prevent Double-Stranded RNA-Induced Upregulation of B7-H1 on Airway Epithelium
Authors: Kan-o K. , Matsumoto K. , Inoue H. , Fukuyama S. , Asai Y. , Watanabe W. , Kurokawa M. , Araya J. , Kuwano K. , Nakanishi Y.
Published: August 2012

Background: Airway viral infections provoke exacerbations of asthma and chronic obstructive pulmonary disease. B7-H1 is a costimulatory molecule that is implicated in an escape mechanism of viruses from host immune systems. This escape may be associated with the persistence of viral infection and lead to exacerbation of underlying diseases. We have shown that an analog of viral double-stranded RNA, polyinosinic-polycytidylic acid (poly IC), upregulated the expression of B7-H1 on airway epithelial cells, an effect which was corticosteroid-resistant. We investigated the effects of corticosteroids plus long-acting β2-agonists (LABAs; fluticasone/salmeterol or budesonide/formoterol) on the expression of B7-H1. Methods: BEAS-2B cells and primary airway epithelial cells were stimulated with poly IC or respiratory syncytial virus. The expression of B7-H1 was assessed by flow cytometry. Results: Poly IC upregulated the expression of B7-H1, which was suppressed by high-concentration corticosteroids but not by LABAs. The upregulation was suppressed by very low-concentration corticosteroids when used in combination with LABAs. Their combination also suppressed the virus-induced upregulation of B7-H1. Poly IC stimulation induced the nuclear translocation of nuclear factor ĸB (NF-ĸB). Inhibitors of NF-ĸB activation prevented the poly IC-induced upregulation of B7-H1. Low-concentration corticosteroids in combination with LABAs enhanced the de novo induction of IĸBα, the endogenous inhibitor of NF-ĸB activation. Conclusions: Fluticasone/salmeterol or budesonide/formoterol attenuate the virus-associated upregulation of B7-H1 on airway epithelial cells via suppression of NF-ĸB activation.
Increased Level of Antibodies Cross-Reacting with Ves v 5 and CRISP-2 in MAR-Positive Patients
Authors: Brunner-Agten S. , Pavlovic R. , Müller L. , Horn M.P. , Huber A.R. , Stadler B.M. , Vogel M.
Published: August 2012

Background: Anti-sperm antibodies (ASA) have been described to be involved in immunological infertility. A possible antigen for ASA is the human cysteine-rich secretory protein 2 (CRISP-2), a sperm surface protein important in sperm-oocyte interaction. Furthermore, anti-CRISP-2 antibodies were shown to decrease fertility rates in vitro. Recently, we have reported cross-reacting antibodies recognizing CRISP-2 and antigen 5 from yellow jacket venom (Ves v 5) in human serum. Methods: Here, we investigated anti-Ves v 5 and CRISP-2 antibodies in sera from two groups of donors: MAR+ and MAR– patients. Results: A higher incidence of allergy against hymenoptera venom was found in MAR+ patients. Interestingly, affinity-purified ASA from MAR+ patients’ sera reacted against both Ves v 5 and CRISP-2, leading to sperm immobilization. Immunofluorescence analysis showed that ASA bound to the sperm surface, including the head part where CRISP-2 is localized. Conclusion: Taken together, these results showed a higher incidence of antibodies cross-reacting with Ves v 5 and CRISP-2 in MAR+ patients. This leads to the hypothesis that MAR+ patients may have a higher risk to develop wasp allergy.
Specific IgG4 Production during House Dust Mite Immunotherapy among Age, Gender and Allergic Disease Populations
Authors: Lai Xuxin , Li Jing , Xiao Xiaoxiong , Liu Enmei , Zhang Chunqing , Wang Hongyu , Gjesing Birgitte , Zhong Nanshan , Spangfort Michael D.
Published: August 2012

Background: Specific IgG4 induced by allergen-specific immunotherapy (SIT) is an immunological marker related to the appearance of clinical tolerance. But specific IgG4 levels in different age, gender and allergic disease populations have not been fully investigated. Methods: This study involved 226 children and 109 adults with allergic rhinitis and/or asthma receiving a 156-week course of Dermatophagoides pteronyssinus (Der p) subcutaneous SIT. Symptom and medication scores, forced expiratory volume after 1 s (FEV1) and Der p-specific IgG4 levels at weeks 0, 5, 10, 25, 52, 104 and 156 were analyzed. Results: Rhinitis symptom and medication scores and FEV1 % predicted in children showed significantly greater improvement than in adults at week 104 and 156 (p < 0.05). Levels of Der p-specific IgG4 showed a significant increase after 10 weeks of subcutaneous SIT (p < 0.0001) and continued to increase during the 156-week SIT period. Before SIT, the initial Der p-specific IgG4 level was higher in children than adults (p = 0.0004). The increase ratio of Der p-specific IgG4 was higher in children than adults at 52 weeks (p < 0.001) and 104 weeks (p = 0.0156) of SIT, and was higher in rhinitis compared to asthma patients at 156 weeks of SIT (p = 0.0244). There was no difference between males and females at any time points. Conclusion: Children are more responsive to SIT, demonstrating clinical and FEV1 improvement and producing higher levels of allergen-specific IgG4 during a shorter SIT period compared to adults. Rhinitis patients show a higher increase in specific IgG4 compared to patients with asthma symptoms. The increase of Der p-specific IgG4 reflects a specific response of the immune system towards the SIT vaccine being administrated.
Anaphylactic versus Mild Reactions to Hazelnut and Apple in a Birch-Endemic Area: Different Sensitization Profiles?
Authors: Le T.M. , van Hoffen E. , Lebens A.F.M. , Bruijnzeel-Koomen C.A.F.M. , Knulst A.C.
Published: August 2012

Background: Hazelnut and apple are common causes of food allergy in Europe. In northern Europe, symptoms are usually mild and associated with cross-reactivity to the birch pollen allergen, Bet v 1. In the Mediterranean area, symptoms are more frequently severe and associated with sensitization to lipid transfer protein (LTP). This study compared patients with anaphylactic versus mild reactions to hazelnut and apple in The Netherlands, a birch-endemic area, with respect to sensitization to Bet v 1-homologues (i.e. PR10-proteins) and LTP. Methods: Twenty-one patients fulfilling the criteria for anaphylaxis and 21 with only mild symptoms (oral allergy) to hazelnut and/or apple were recruited. Specific immunoglobulin E to birch pollen, apple, hazelnut and PR10-proteins (rBet v 1, rPru p 1, rMal d 1 and rCor a 1) and recombinant LTP (rPru p 3 and rCor a 8) was measured by ImmunoCAP. Results: Both mild and anaphylactic apple-allergic patients were sensitized to PR10-proteins, whereas only 1/7 of the mild and none of the anaphylactic apple-allergic patients was sensitized to LTP. In contrast, anaphylactic hazelnut-allergic patients displayed no such clear sensitization pattern: some were sensitized to both PR10-proteins and hazelnut LTP (1/9), and others to only LTP (2/9) or to only PR10-proteins (4/9) or to neither PR10-proteins nor LTP (2/9). Conclusion: This study shows that in a birch-endemic area, the sensitization profile to PR10-proteins and LTP in anaphylactic patients may differ between different plant foods. In this patient group, anaphylaxis to hazelnut can be LTP-associated, whereas anaphylaxis to apple is not.
Is Medical Thoracoscopy Efficient in the Management of Multiloculated and Organized Thoracic Empyema?
Authors: Ravaglia Claudia , Gurioli Carlo , Tomassetti Sara , Casoni Gian Luca , Romagnoli Micaela , Gurioli Christian , Agnoletti Vanni , Poletti Venerino
Published: August 2012

Background: Pleural empyema can be subdivided into 3 stages: exudative, multiloculated, and organizing. In the absence of clear septation, antibiotics plus simple drainage of pleural fluid is often sufficient treatment, whereas clear septation often requires more invasive treatment. Objectives: The aim of this study was to report our experience and analyze the safety and efficacy of medical thoracoscopy in patients with multiloculated and organizing empyema. Methods: We performed a retrospective study reviewing the files of patients referred for empyema and treated by medical thoracoscopy at our department from July 2005 to February 2011. Results: A total of 41 patients with empyema were treated by medical thoracoscopy; empyema was free flowing in 9 patients (22%), multiloculated in 24 patients (58.5%), and organized in 8 patients (19.5%). Medical thoracoscopy was considered successful without further intervention in 35 of 41 patients (85.4%): all of the 9 patients with free-flowing fluid, 22 of the 24 patients with multiloculated empyema (91.7%), and only 4 of the 8 patients with organizing effusion (50%). Conclusions: Our study confirms that multiloculated pleural empyema could safely and successfully be treated with medical thoracoscopy while organizing empyema can be resistant to drainage with medical thoracoscopy, requiring video-assisted thoracic surgery or open surgical decortications; among this population, the presence of separate ‘pockets’ not in apparent communication with each other often leads to a surgical approach.
Enhanced Exhalation of Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 in Patients with COPD Exacerbation: A Prospective Study
Authors: Kwiatkowska S. , Noweta K. , Zieba M. , Nowak D. , Bialasiewicz P.
Published: August 2012

Background: Matrix metalloproteinase-9 (MMP-9) and its inhibitor tissue inhibitor of metalloproteinase-1 (TIMP-1) are involved in the pathogenesis of airway inflammation in patients with chronic obstructive pulmonary disease (COPD). However, no study so far has addressed their value as noninvasive biomarkers of airways inflammation. Objective: To evaluate MMP-9 and TIMP-1 concentrations in the exhaled breath condensate (EBC) of patients with stable COPD and also during the exacerbation episode. Methods: EBC and serum samples were collected in 17 stable-phase COPD patients who were current smokers as well as during their first exacerbation episode, and in 22 asymptomatic smokers. EBC and serum levels of MMP-9 and TIMP-1 were measured with ELISA kit. Results: Mean EBC MMP-9 and TIMP-1 levels were higher in patients with stable COPD than in asymptomatic smokers. Exacerbation of COPD increased 2-fold the exhalation of MMP-9 (18.5 ± 10.1 ng/ml vs. 8.9 ± 6.2 ng/ml, p = 0.01) and TIMP-1 (to 41.1 ± 20.4 ng/ml vs. 16.4 ± 6.8 ng/ml, p < 0.001). Both, MMP-9 and TIMP-1 in EBC correlated negatively with FEV1 (% predicted) at baseline (r = –0.78, p < 0.001 and r = –0.73, p < 0.001) and during the exacerbation episode (r = –0.57, p = 0.02 and r = –0.65, p = 0.005). Similar negative correlations were noted with FVC (% predicted), except for MMP-9 in EBC at exacerbation. Exhaled MMP-9 and TIMP-1 did not correlate with serum concentrations in COPD patients, either at baseline or during exacerbation. Conclusion: Exhaled MMP-9 and TIMP-1 increased during COPD exacerbation and was negatively correlated with spirometric variables, which suggests the usefulness of their measurement in EBC for the monitoring of airways inflammation. However, to better assess their diagnostic or prognostic value larger studies are necessary.
Temporary Endobronchial Embolization with Silicone Spigots for Moderate Hemoptysis: A Retrospective Study
Authors: Bylicki O. , Vandemoortele T. , Laroumagne S. , Astoul P. , Dutau H.
Published: August 2012

Background: The management of airway bleeding is generally performed in an emergency to prevent hypoxemia and lung flooding. When the bleeding arises from peripheral lesions that are not visible endoscopically, bronchoscopic options have limited curative intents. Endobronchial embolization using silicone spigots (EESS) is a novel approach. Objectives: We analyzed the efficacy and safety of EESS in a retrospective study. Methods: We retrospectively reviewed charts of patients referred to our center for moderate hemoptysis (MH) who underwent EESS. Successful management is defined as immediate bleeding cessation. Results: From December 2008 to January 2012, 9 patients were treated with EESS in our endoscopy unit. The MH originated from the left upper lobe in 4 cases, the right upper lobe in 3 cases and the right middle lobe and left lower lobe in 1 case each. Thirteen spigots were inserted. The success rate was 78%. Of the 9 patients, 7 were referred to interventional radiology for bronchial artery embolization, with a success rate of 86%, and 2 were referred for thoracic surgery. One patient had EESS as definitive treatment; the silicone spigots were bronchoscopically removed after a median of 4 days in 6 of the remaining 8 patients. Only 2 patients had hemoptysis recurrence after a median follow-up of 107 days (ranging from 13 to 1,017 days). None of the patients died from hemoptysis. Conclusion: EESS is an original, temporary technique that requires only a flexible bronchoscope and biopsy forceps for placement and removal. EESS ensures airway protection while waiting for definitive management.
Bronchoscopic Treatment of Emphysema: State of the Art
Authors: Gasparini Stefano , Zuccatosta Lina , Bonifazi Martina , Bolliger Chris T.
Published: August 2012

In recent years, different bronchoscopic techniques have been proposed for the treatment of emphysema, with the aim of obtaining the same clinical and functional advantages of lung volume reduction surgical techniques while reducing risks and costs. Such techniques can be classified into: methods employing devices that block the airways (e.g. spigots and unidirectional valves), methods that have a direct effect on the lung parenchyma (polymeric lung volume reduction, coils and thermal vapor ablation) and procedures that facilitate the expiration of trapped air from the emphysematous lung (airway bypass). This review aimed to evaluate the indications, outcomes and safety of the different techniques, based on the evidence from the available literature. Results obtained by these methods are encouraging, but they are still based mainly on studies with small groups of patients. However, several trials are ongoing and in the near future we will acquire more knowledge which should lead to a better optimization of these procedures. Meanwhile, the bronchoscopic treatment of emphysema cannot yet be considered a standard of care and patients should be treated in the context of clinical trials or controlled registries, with well-defined programs of evaluation and follow-up.
Impact of Long-Term Cinacalcet, Ibandronate or Teriparatide Therapy on Bone Mineral Density of Hemodialysis Patients: A Pilot Study
Authors: Mitsopoulos Efstathios , Ginikopoulou Eudoxia , Economidou Dominiki , Zanos Stavros , Pateinakis Panagiotis , Minasidis Elias , Memmos Dimitrios , Thodis Elias , Vargemezis Vassilis , Tsakiris Dimitrios
Published: August 2012

Background: Insufficient evidenced-based information is available for the treatment of osteoporosis in hemodialysis (HD) patients. Methods: In 102 HD patients, bone mineral density (BMD) was measured twice 16 ± 3 months apart. In the second BMD measurement 66 of them had a femoral neck (FN) T-score <–2.5. Of these 66 patients, 38 consented to a bone biopsy. Depending on both the bone biopsy findings and parathyroid hormone levels, patients were assigned to treatment groups. Eleven patients with osteitis fibrosa and iPTH >300 pg/ml received cinacalcet, 11 with osteitis fibrosa and iPTH <300 pg/ml received ibandronate, 9 with adynamic bone disease received teriparatide, and 7 with mild abnormalities received no treatment. A third BMD measurement was done after an average treatment period of 13–16 months. We compared the annual percent change of FN and lumbar spine (LS) BMD before and during treatment. Results: FN and LS BMD decreased significantly in the cinacalcet group, with an annual change of 3.6 and 3.4% before treatment to –4.2% (p = 0.04) and –7.7% (p = 0.02) during treatment, respectively. In the teriparatide group, FN and LS BMD increased, although not significantly, with an annual change of –5.4 and –2.6% before treatment to 2.7 and 4.9% during treatment, respectively. In both the ibandronate and the no treatment groups, BMD change rate remained negative during the whole study. Conclusions: Teriparatide administration improved BMD in HD patients with adynamic bone disease, although these results did not reach statistical significance. In HD patients with osteitis fibrosa, ibandronate did not improve BMD while cinacalcet reduced BMD.
Mortality in the TRACER and ATLAS ACS 2 Trials: Two More Reasons to Audit Vital Records in PLATO
Authors: Serebruany Victor L. , DiNicolantonio James J. , Can Mehmet Mustafa
Published: August 2012

Context: Extreme rates of vascular and all-cause mortality, especially in the clopidogrel arm of the PLATO (PLATelet Inhibition and Clinical Outcomes) trial, raise concerns of data accuracy and call for independent verification of vital records in the national death registries. Two recently completed acute coronary syndrome (ACS) trials, TRACER and ATLAS ACS 2 (Thrombin Receptor Antagonist for Clinical Event Reduction in ACS and Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with ACS-Thrombolysis in Myocardial Infarction), provide a valuable opportunity to match mortality numbers among 3 similar studies. Objective: To compare the rates of vascular and all-cause mortality in the PLATO, TRACER and ATLAS ACS 2 trials. Results: Despite a shorter mean follow-up (277 days) for the PLATO trial than for the TRACER (502 days) or ATLAS ACS 2 (393 days) trials, both vascular (5.1%) and all-cause (5.9%) mortality in PLATO were higher than in the TRACER (3.2 and 4.9%) or ATLAS ACS 2 (4.1 and 4.5%) control arms, respectively. Adjusting for follow-up duration, rates of vascular (0.0184/day), or all-cause (0.0213/day) mortality in PLATO differ importantly from daily death rates in TRACER (0.0063 and 0.0097) and ATLAS ACS 2 (0.0104 and 0.0115), suggesting that the risk of death in the control PLATO arm was approximately double that of the other trials. The mismatch is particularly striking considering that ATLAS ACS 2 enrolled more STEMI (ST-segment elevation in myocardial infarction) patients (50.9%) than PLATO (38.0%). Conclusions: Both overall and follow-up duration-adjusted mortality rates in PLATO far exceeded the risk of death observed in the two recent ACS trials. The background STEMI rates are not likely to be responsible for the PLATO mortality paradox. These data provide an additional reason to request an independent audit of the deceased PLATO clopidogrel cohort.
Botulinum Toxin A for the Treatment of Keloids
Authors: Gauglitz G.G. , Bureik D. , Dombrowski Y. , Pavicic T. , Ruzicka T. , Schauber J.
Published: August 2012

Introduction: Keloids are the result of excessive scar tissue formation. Besides their poor aesthetic appearance, keloids can be associated with severe clinical symptoms such as pain, itching, and rigidity. Unfortunately, most therapeutic approaches remain clinically unsatisfactory. Recently, injections with botulinum toxin A (BTA) were proposed for the treatment of established keloids in a clinical trial. In this study, we aimed to verify the effects of intralesional BTA for the treatment of therapy-resistant keloids using objective measurements. In addition, the underlying molecular mechanisms were investigated using cultured keloid-derived fibroblasts. Materials and Methods: Four patients received BTA (doses varying from 70 to 140 Speywood units per session) injected directly into their keloids every 2 months for up to 6 months. Differences in height and volume were evaluated clinically and measured with a 3-D optical profiling system. Keloid-derived fibroblasts were treated with different concentrations of BTA, and expression of collagen (COL)1A1, COL1A2, COL3A1, TGF-β1, TGF-β2, TGF-β3, fibronectin-1, laminin-β2, and α-SMA was determined by real-time quantitative PCR. MTT and BrdU assays were used to analyze the effects of BTA on fibroblast proliferation and metabolism. Results: Intralesional administration of BTA did not result in regression of keloid tissue. No differences in expression of ECM markers, collagen synthesis, or TGF-β could be observed after BTA treatment of keloid fibroblasts. In addition, cell proliferation and metabolism of keloid fibroblasts was not affected by BTA treatment. Conclusion: The suggested clinical efficiency of intralesional BTA for the therapy of existent keloids could not be confirmed in this study. Based on our data, the potential mechanisms of action of BTA on keloid-derived fibroblasts remain unclear.
25-Hydroxyvitamin D Levels and Risk of Ischemic Heart Disease, Myocardial Infarction, and Early Death
Authors: Brøndum-Jacobsen Peter , Benn Marianne , Jensen Gorm B. , Nordestgaard Børge G.
Published: August 2012

Objective—

We tested the hypothesis that reduced plasma 25-hydroxyvitamin D associates with increased risk of ischemic heart disease, myocardial infarction, and early death.

Methods and Results—

We measured baseline plasma 25-hydroxyvitamin D in 10 170 women and men from the Danish general population without vitamin D–fortified food. During 29 years of follow-up, 3100 persons developed ischemic heart disease, 1625 myocardial infarction, and 6747 died. Decreasing plasma 25-hydroxyvitamin D levels were associated with increasing risk of ischemic heart disease, myocardial infarction, and early death as a function of seasonally adjusted percentile categories (
P
for trend, 2×10
−4
–3×10
–53
). Comparing individuals with plasma 25-hydroxyvitamin D levels at the 1st to 4th percentile with individuals with levels at the 50th to 100th percentile, the multivariable adjusted risk was increased by 40% (95% CI, 14%–72%) for ischemic heart disease, by 64% (25%–114%) for myocardial infarction, by 57% (38%–78%) for early death, and by 81% (40%–135%) for fatal ischemic heart disease/myocardial infarction. In the meta-analyses of 18 and 17 studies, risk of ischemic heart disease and early death were increased by 39% (25%–54%) and 46% (31%–64%) for lowest versus highest quartile of 25-hydroxyvitamin D level.

Conclusion—

We observed increasing risk of ischemic heart disease, myocardial infarction, and early death with decreasing plasma 25-hydroxyvitamin D levels. These findings were substantiated in meta-analyses.
Feedback Regulation of Cholesterol Uptake by the LXR–IDOL–LDLR Axis
Authors: Zhang Li , Reue Karen , Fong Loren G. , Young Stephen G. , Tontonoz Peter
Published: August 2012

Inducible degrader of the low-density lipoprotein receptor (IDOL) is an E3 ubiquitin ligase that mediates the ubiquitination and degradation of the low-density lipoprotein receptor (LDLR). IDOL expression is controlled at the transcriptional level by the cholesterol-sensing nuclear receptor liver X receptor (LXR). In response to rising cellular sterol levels, activated LXR induces IDOL production, thereby limiting further uptake of exogenous cholesterol through the LDLR pathway. The LXR–IDOL–LDLR mechanism for feedback inhibition of cholesterol uptake is independent of and complementary to the sterol regulatory element–binding protein pathway. Since the initial description of the LXR–IDOL pathway, biochemical studies have helped to define the structural basis for both IDOL target recognition and LDLR ubiquitin transfer. Recent work has also suggested links between
IDOL
and human lipid metabolism.
A Prospective, Randomized Clinical Trial of Hemodynamic Support With Impella 2.5 Versus Intra-Aortic Balloon Pump in Patients Undergoing High-Risk Percutaneous Coronary Intervention
Authors: O'Neill William W. , Kleiman Neal S. , Moses Jeffrey , Henriques Jose P.S. , Dixon Simon , Massaro Joseph , Palacios Igor , Maini Brijeshwar , Mulukutla Suresh , Džavík Vladimír , Popma Jeffrey , Douglas Pamela S. , Ohman Magnus
Published: August 2012

Background—

Although coronary artery bypass grafting is generally preferred in symptomatic patients with severe, complex multivessel, or left main disease, some patients present with clinical features that make coronary artery bypass grafting clinically unattractive. Percutaneous coronary intervention with hemodynamic support may be feasible for these patients. Currently, there is no systematic comparative evaluation of hemodynamic support devices for this indication.

Methods and Results—

We randomly assigned 452 symptomatic patients with complex 3-vessel disease or unprotected left main coronary artery disease and severely depressed left ventricular function to intra-aortic balloon pump (IABP) (n=226) or Impella 2.5 (n=226) support during nonemergent high-risk percutaneous coronary intervention. The primary end point was the 30-day incidence of major adverse events. A 90-day follow-up was required, as well, by protocol. Impella 2.5 provided superior hemodynamic support in comparison with IABP, with maximal decrease in cardiac power output from baseline of −0.04±0.24 W in comparison with −0.14±0.27 W for IABP (
P
=0.001). The primary end point (30-day major adverse events) was not statistically different between groups: 35.1% for Impella 2.5 versus 40.1% for IABP,
P
=0.227 in the intent-to-treat population and 34.3% versus 42.2%,
P
=0.092 in the per protocol population. At 90 days, a strong trend toward decreased major adverse events was observed in Impella 2.5–supported patients in comparison with IABP: 40.6% versus 49.3%,
P
=0.066 in the intent-to-treat population and 40.0% versus 51.0%,
P
=0.023 in the per protocol population, respectively.

Conclusions—

The 30-day incidence of major adverse events was not different for patients with IABP or Impella 2.5 hemodynamic support. However, trends for improved outcomes were observed for Impella 2.5–supported patients at 90 days.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00562016.
Conditional Targeting of Tumor Necrosis Factor Receptor–Associated Factor 6 Reveals Opposing Functions of Toll-Like Receptor Signaling in Endothelial and Myeloid Cells in a Mouse Model of Atherosclerosis
Authors: Polykratis Apostolos , van Loo Geert , Xanthoulea Sofia , Hellmich Martin , Pasparakis Manolis
Published: August 2012

Background—

Previous studies implicated Toll-like receptor signaling as a critical pathogenic pathway in atherosclerosis, but the cell-specific mechanisms by which Toll-like receptors act to control atherosclerotic plaque development remain poorly understood.

Methods and Results—

To study the cell-specific role of tumor necrosis factor receptor–associated factor 6 (TRAF6) in atherosclerosis, we generated
ApoE
−/−
mice with endothelial cell– or myeloid cell–specific TRAF6 deficiency using Cre/LoxP-mediated gene targeting. Endothelial TRAF6 deficiency reduced atherosclerosis in female
ApoE
−/−
mice by inhibiting nuclear factor-κB–dependent proinflammatory gene expression and monocyte adhesion to endothelial cells. In contrast, myeloid cell–specific TRAF6 deficiency caused exacerbated atherosclerosis, with larger plaques containing more necrotic areas in both male and female
ApoE
−/−
mice. TRAF6-deficient macrophages showed impaired expression of the antiinflammatory and atheroprotective cytokine interleukin-10, elevated endoplasmic reticulum stress, increased sensitivity to oxidized low-density lipoprotein–induced apoptosis, and reduced capacity to clear apoptotic cells. Thus, the reduced antiinflammatory properties, coupled with increased sensitivity to apoptosis and impaired efferocytosis capacity of TRAF6-deficient macrophages, result in exacerbated atherosclerosis development in TRAF6
MYKO
/
ApoE
−/−
mice.

Conclusion—

Toll-like receptor–mediated TRAF6 signaling acts in endothelial cells to promote atherosclerosis but displays atheroprotective, antiinflammatory and prosurvival functions in myeloid cells.