bluuebunny/crossref_metadata_2025 huggingface dataset:
Nasal Inflammatory Mediator Release in Ragweed Allergic Rhinitis: Correlation with Cellular Influx into Nasal Secretions
Authors: Georgitis John W. , Stone Brian D. , Gottschlich Greg
Published: September 2009

Lipid-derived mediators are found in nasal secretions during the early and late phase of allergic responses. To explore this early response further, concentrations of inflammatory mediators were measured along with characterization of specific cell influx during dose-dependent ragweed challenges. Ten allergic rhinitis subjects underwent two unilateral nasal lavages using 3-fold concentrations of short ragweed antigen. Low doses of ragweed (0.016–0.114 units Amb a I) did not provoke cell influx (1 of 18 challenges), whereas moderate doses (0.432–1.3 units Amb a I) induced cell influxes in 7 of 18 and at high doses in 8 of 17 challenges (3.39–11.7 units Amb a I). The differential of the cellular influx was > 50% neutrophils in 7 challenges; > 50% eosinophils in 3, and a mixed pattern in 6. There was a significant association between the dose of antigen and the level of prostaglandin D2 (PGD2), leukotrienes (LTs) C4, D4 and E4. Challenges with an eosinophilic influx tended to be associated with higher concentrations of mediators than neutrophilic influxes. Similar to the immediate skin response, the early allergic response in the nose demonstrated a cell influx with release of PGD2, LTsC4, D4 and E4. Nasal cellular inflammation therefore can occur within minutes of allergen exposure.
Effect of Y-20811, a Long-Lasting Thromboxane A2 Synthetase Inhibitor, on Antigen-Induced Airway Hyperresponsiveness in Guinea Pigs
Authors: Kagoshima Masahiko , Tomomatsu Noriko , Aratani Hidekazu , Terasawa Michio
Published: September 2009

Effect of Y-20811 on airway hyperresponsiveness was studied in sensitized guinea pigs. Airway hyperresponsiveness to acetylcholine (ACh) reached maximum 7 h after antigen challenge in guinea pigs sensitized actively. Y-20811 (0.3–3 mg/kg) administered orally 3 h prior to challenge inhibited this airway hyperresponsiveness in a dose-dependent manner. Y-20811 (3 mg/kg) administered orally 4 h after antigen challenge also decreased the airway hyperresponsiveness. On the other hand, Y-20811 did not affect the bronchoconstriction induced by ACh, serotonin and histamine in nonsensitized guinea pigs. The number of eosinophils in bronchoalveolar lavage fluid in the guinea pig reached the peak 7 h after antigen challenge. Y-20811 had a tendency to decrease the number of total cells, macrophages and eosinophils in a dose-dependent manner. These results suggest that Y-20811 suppress the asthmatic mechanism which causes antigen-induced airway hyperresponsiveness.
Humoral Transplantation Antibodies Play a Role in Protracted Rejection of Murine Renal Allografts
Authors: Inoue K. , Niesen N. , Milgrom F. , Albini B.
Published: September 2009

Murine renal allografts were studied using (C57BL/6J × A/J)F1 mice as recipients and DBA/2 mice as donors. In this strain combination, protracted rejection was noted in that the circulation was maintained in the graft for over 10 weeks. In all grafts examined after 3 weeks, mononuclear cell infiltrates were noted; in addition, all grafts had immune deposits, apparently containing transplantation antibodies, in glomeruli, tubuli and vessels. These results stressed the role of humoral immunity in protracted renal allograft rejection.
Accelerated Response to Reinoculation in Experimental Allergic Encephalomyelitis: Clinical Study
Authors: Levine Seymour , Saltzman Arthur
Published: September 2009

An attack of experimental allergic encephalomyelitis is generally thought to confer resistance to a second attack. Nevertheless, some authors have produced second attacks, sometimes with an anamnestic shortening of the incubation period. In addition, second attacks of experimental allergic encephalomyelitis with accelerated onsets following reinoculation were found in every experiment when histopathologic rather than clinical criteria were employed. In the present work, we found that clinical signs with accelerated onset were also found in each experiment provided that the first attack was produced with the aid of Freund’s complete adjuvant and provided that the reinoculation stimulus was the highly potent combination of rat spinal cord and carbonyl iron. Whatever the potency of the reinoculation, and regardless of the occurrence of an accelerated onset, the eventual outcome was a decreased severity and mortality of the second attack of experimental allergic encephalomyelitis. The new data demonstrate that accelerated onset is not necessarily an indication of increased severity.
mRNA Variants Encoding Multiple Forms of the High-Affinity IgE Receptor Alpha Subunit in Transformed and Nontransformed Mast Cells
Authors: Robertson Michael W. , Mehl Virginia S. , Richards Mark L. , Liu Fu-Tong
Published: September 2009

Multiple mRNA species encoding several predicted forms of the high-affinity IgE receptor α sub-unit (FcεRI-α) have been previously characterized from rat basophilic leukemia cells. Using the polymerase chain reaction procedure, we have extended these findings to show that one FcεRI-α mRNA variant, characterized by a 163-bp deletion within the coding sequence, exists in normal rat connective tissue mast cells as well as in both transformed and non transformed murine mast cell lines. In addition, a partial murine FcεRI-α genomic clone, spanning the internal-deletion sequence, has been identified, and from analysis of this sequence a mechanism of alternative pre-mRNA splicing is proposed. Finally, mRNA variants have been translated in a cell-free system and the protein products partially characterized.
Studies of Dialyzates from Dermatophagoides farinae: Partial Purification and Haptenic Properties of Dialyzates from Dermatophagoides farinae
Authors: Tamura Hiroshi , Mochizuki Hiroyuki , Shigeta Makoto , Arakawa Hirokazu , Kuroume Takayoshi
Published: September 2009

Dialyzates from Dermatophagoides farinae were partially purified. Fractionation on HPLC and anion exchange chromatography revealed that the dialyzates consisted of 5 major fractions of glycoprotein whose apparent molecular sizes were 5.1, 4.1, 3.2, and less than 1.35 kD on HPLC. The apparent molecular size of two fractions was 5.3 and 2.9 kD on SDS-PAGE. They were basic glycoproteins which had a pi ranging from 7.46 to 8.71 on PAG-IEF. These fractions were allergenic in the RAST and ELISA inhibition tests but not in the skin prick test (SPT). Our results suggest that the dialyzates from D. farinae have haptenic properties. The dialyzates from D. faunae (low molecular weight) and its 5 fractions bound noncovalently to human serum albumin (HSA) at the free tyrosine residues of HSA. They proved to bind noncovalently to serum proteins and collagens. Once they bound to proteins, the conjugates became allergenic not only in the RAST and ELISA inhibition test but also in the SPT. Our results provide evidence that the dialyzates from D. farinae have haptenic properties.
Effects of N-Acetylcysteine on Histamine Release by Sodium Fluoride and Compound 48/80 from Isolated Rat Mast Cells
Authors: Hong X.J. , Francker A. , Diamant B.
Published: September 2009

N-acetylcysteine (NAC) enhances the release of histamine induced by the fluoride-calcium system but not by compound 48/80. After preincubation of the cells for 2 h at room temperature (RT) as well as at 37°C, NAC was found to enhance histamine release also when induced by compound 48/80. Both fluoride treatment and prolonged incubation at 37°C (but not at RT) for 2 h decreased the ATP content of the cells. NAC was found to counteract the fall in ATP caused by prolonged incubation of the cells at 37°C but not when induced by exposure to sodium fluoride. The results do not favor the concept that free radicals generated by fluoride treatment are responsible for the subsequent sensitivity of the cells to the secretory action of calcium. On the other hand, it cannot be excluded that free radicals generated during prolonged incubation of the cells at 37°C might be involved in the decrease of the sensitivity of the cells to the secretory action of the fluoride-calcium system and of compound 48/80. This is supported by the finding that the presence of NAC not only activated the secretory response but also counteracted the decrease of the cellular ATP content noted following preincubation of the cells for 2 h at 37°C.
Protective Effect of Loratadine on Specific Conjunctival Provocation Test
Authors: Ciprandi G. , Buscaglia S. , Pesce G.P. , Marchesi E. , Canonica G.W.
Published: September 2009

The protective effect of loratadine (anti-H1 antagonist) on clinical and cellular processes following the early phase of specific conjunctival provocation test was assessed in 20 patients affected by seasonal allergic rhinoconjunctivitis, in a double-blind, randomized, placebo-controlled, parallel-group study. Patients were randomly assigned to two treatment groups, each being given a single daily dose of loratadine 10 mg or placebo, for 7 days, out of pollen season. Pretreatment with Loratadine resulted in a significant higher allergen threshold dose than placebo (p <0.01). Patients treated with loratadine experienced a significant reduction (p <0.01) in conjunctival symptom severity as compared with placebo, following conjunctival challenge. Finally, the number of inflammatory cells was lower in the loratadine-treated patients compared to the placebo group (p <0.01). In conclusion, loratadine exerts a significant protective effect on the early phase cellular and clinical events of conjunctival reaction induced by allergen challenge in atopic patients.
Asthma in Tanta, Egypt: Serologic Analysis of Total and Specific IgE Antibody Levels and their Relationship to Parasite Infection
Authors: Alshishtawy Moeness M. , Abdella Aly M. , Gelber Lawrence E. , Chapman Martin D.
Published: September 2009

The relationship between asthma, IgE and parasite infection was compared in 68 randomly selected patients with asthma and 37 nonasthmatic controls living in Tanta, Egypt. Sera were assayed for total IgE and for IgE antibodies to inhaled allergens (mite, cat, cockroach, ryegrass, ragweed and 3 fungi) and to parasite antigens (Schistosoma mansoni and Brugia malayi). Parasite infection was determined by microscopic examination of stool specimens. Total IgE levels were significantly higher in patients with asthma (geometric mean 909 IU/ml), than in controls (geometric mean 145 IU/ml, p <0.001). The high IgE levels correlated with parasite infection and the presence of IgE antibodies to S. mansoni antigens, which were also elevated compared to controls. The prevalence of allergen-specific IgE antibodies among Egyptian asthmatics was low by comparison with ‘Western’ asthmatics, but nonetheless higher than among Egyptian controls. A radioallergosorbent test (RAST) values of >40 U/ml to any allergen was found in 19/68 (28%) sera from the asthma group, as compared to only 1/37 (3%) sera from controls (p <0.001). The highest RAST values were to dust mite (Dermatophagoides pteronyssinus and D. farinae)allergens, followed by rye grass and ragweed allergens. The results suggest that in this area of Egypt, several factors may influence the development of asthma, including nonspecific activation of IgE and/or inflammatory mechanisms by helminth parasites and sensitisation to environmental allergens.
Studies on Immunological Tolerance Induced in Mice by Kidney Allografts
Authors: Inoue K. , Niesen N. , Albini B. , Milgrom F.
Published: September 2009

(C57BL/6 × A/J)F1 murine recipients of DBA/2 kidney allografts developed tolerance to DBA/2 tissues, which was measured by observation of growth of a DBA/2 tumor. Eleven, 14 and 18 days after inoculation, the size of the tumor was considerably larger in kidney-grafted than in nongrafted animals. Still, the susceptibility of grafted animals to the tumor did not equal the susceptibility of the DBA/2 mice syngeneic with the tumor. Removal of the renal graft left the recipients with significant tolerance which, however, was weaker than that of the mice in which the kidney graft was left undisturbed. In parabiosis experiments, it was noted that the size of the DBA/2 tumor was equal in the partner which received the DBA/2 kidney graft and in the partner which was not grafted. These experiments rather clearly showed that the tolerance studied was of an ‘infectious’ type and that it was apparently transferred by some suppressing factor(s) present in the circulation.
Modulating the Functional Contributions of c-Myc to the Human Endothelial Cell Cyclic Strain Response
Authors: Hurley Nicole E. , Schildmeyer Lisa A. , Bosworth Kami A. , Sakurai Yumiko , Eskin Suzanne G. , Hurley Laurence H. , McIntire Larry V.
Published: September 2009

This study addresses whether pathological levels of cyclic strain activate the c-Myc promoter, leading to c-Myc transcription and downstream gene induction in human umbilical vein endothelial cells (HUVEC) or human aortic endothelial cells (HAEC). mRNA and protein expression of c-Myc under physiological (6–10%) and pathological cyclic strain conditions (20%) were studied. Both c-Myc mRNA and protein expression increased 2–3-fold in HUVEC cyclically strained at 20%. c-Myc protein increased 4-fold in HAEC. In HUVEC, expression of mRNA peaked at 1.5–2 h. Subsequently, the effect of modulating c-Myc on potential downstream gene targets was determined. A small molecular weight compound that binds to and stabilizes the silencer element in the c-Myc promoter attenuates cyclic strain-induced c-Myc transcription by about 50%. This compound also modulates c-Myc downstream gene targets that may be instrumental in induction of vascular disease. Cyclic strain-induced gene expression of vascular endothelial growth factor, proliferating cell nuclear antigen and heat shock protein 60 are attenuated by this compound. These results offer a possible mechanism and promising clinical treatment for vascular diseases initiated by increased cyclic strain.
Long-Term Prognosis of Patients with Large Subcortical Infarctions
Authors: Suto Yutaka , Nakayasu Hiroyuki , Maeda Masanobu , Kusumi Masayoshi , Kowa Hisanori , Awaki Etsuko , Saito Jun , Nakashima Kenji
Published: September 2009

Aim: We assessed the long-term prognosis of patients with large subcortical infarctions (LSCI). Methods: We defined LSCI as lesions ≥15 mm confined to deep penetrating arteries without a cardioembolic or atherothrombotic source. Patients with acute ischemic strokes were consecutively registered and followed for 751 ± 441 days. The clinical characteristics and long-term prognoses of patients with LSCI were compared to those of patients with lacunar (LACI), atherothrombotic (ATI) and cardioembolic infarctions (CEI). Results: At discharge from the hospital, the proportion of good outcomes (modified Rankin Scale ≤2) for patients with LSCI (52.1%) was similar to that for ATIs (47.2%), but worse than that for LACIs (73.2%). After a 3-year follow-up period, the mortality rates from LSCI, LACIs, ATIs and CEIs were 8.4, 8.2, 22.3 and 41.1%, respectively; the recurrence rates were 9.3, 14.1, 16.6 and 23.8%, respectively. Conclusions: The short-term prognosis of functional outcomes for LSCI was worse than that for LACIs, but similar to acute-phase ATI outcomes. The long-term prognosis after a LSCI is good, and recurrence tends to be lower than for LACIs.
From Stroboscope to Dream Machine: A History of Flicker-Induced Hallucinations
Authors: ter Meulen B.C. , Tavy D. , Jacobs B.C.
Published: September 2009

When early neurophysiologists, like William Grey Walter (1910–1977), started using intermittent photic driving in electroencephalography, they were struck by a wide range of visual hallucinations that were reported. In current neuroscience, the phenomenon is used mainly to model hallucinations that are related to altered neuronal activity between the thalamus and the visual cortex, such as the Charles Bonnet syndrome. However, during the psychedelic 1960s, Brion Gysin (1916–1986), a painter and a poet, became interested in the hallucinations and designed his own stroboscope or dream machine, as a means for spiritual enlightenment. This article traces back the history of flicker-induced hallucinations from the early use of stroboscopes in neurophysiology to the dream machine.
Blood Pressure Guidelines in Chronic Kidney Disease: A Critical Review
Authors: Thuraisingham R.C. , Yaqoob M.M.
Published: September 2009

The primary purpose of guidelines should be to improve patient care by providing an avenue for healthcare professionals to participate in the assessment of appropriate care, based on sound medical reasoning and robust scientific knowledge. Guidelines are usually meant to be evidence-based when they are derived from systemic reviews of the relevant literature. Nephrology as a medical subspeciality lags behind other clinical disciplines when it comes to availability of high-quality clinical studies with hard clinical outcomes. In the absence of robust clinical evidence, recommendations in renal guidelines are overwhelmingly opinion-based and reflect the experience of the various experts. Unfortunately, no guidelines are detailed enough to provide recommendations for individual patients with different types and severity of co-morbidities. We propose that guidelines should be viewed as desirables and should not replace a common sense clinical approach to patient care by an autonomously practicing competent clinician.
A Pilot, Randomized, Double-Blind, Cross-Over Study of High Cut-Off versus High-Flux Dialysis Membranes
Authors: Lee Darren , Haase Michael , Haase-Fielitz Anja , Paizis Kathy , Goehl Hermann , Bellomo Rinaldo
Published: September 2009

Background: High cut-off (HCO) membranes may increase β2-microglobulin (β2M) removal compared to standard high-flux membranes.Methods:Eight stable haemodialysis patients were enrolled in a prospective, randomized, double-blind, cross-over study and treated with HCO and high-flux membranes for 2 weeks each, between a 1-week washout period. Primary end point was serum β2M removal. Secondary end points included serum albumin concentrations, albumin and small solute clearances. Results: HCO membranes achieved significantly lower median post-dialysis β2M concentration (10.8 vs. 14.2 mg/l; p = 0.003) and greater β2M reduction ratio (62.3 vs. 51.0%; p < 0.002). Serum albumin decreased with HCO membranes (from 36 to 29.5 g/l; p = 0.018) but increased to 33.5 g/l after the washout period. Albumin clearance was significantly greater with HCO membranes (2.2 vs. 0.06 ml/min; p = 0.004). Urea reduction ratio was significantly lower with HCO membranes (64.8 vs. 71.5%; p < 0.001). Conclusion: β2M removal was superior with HCO membranes. Reduction in serum albumin and lower small solute clearance require further investigations.
Brain Size and Brain Organization of the Whale Shark, Rhincodon typus, Using Magnetic Resonance Imaging
Authors: Yopak Kara E. , Frank Lawrence R.
Published: September 2009

Very little is known about the brain organization of the suction filter feeder, Rhincodon typus, and how it compares to other orectolobiforms in light of its specialization as a plankton-feeder. Brain size and overall brain organization was assessed in two specimens of R. typus in relation to both phylogeny and ecology, using magnetic resonance imaging (MRI). In comparison to over 60 other chondrichthyan species, R. typus demonstrated a relatively small brain for its body size (expressed in terms of encephalization quotients and residuals), similar to the lamniforms Carcharodon carcharias, Cetorhinus maximus, and Carcharias taurus. R. typus possessed a relatively small telencephalon with some development of the dorsal pallium, which was suggestive of moderate social behavior, in addition to a relatively large diencephalon and a relatively reduced mesencephalon. The most notable characteristic of the brain of Rhincodon was a large and highly foliated cerebellum, one of the largest cerebellums within the chondrichthyan clade. Early development of the brain was qualitatively assessed using an in situ MRI scan of the brain and chondrocranium of a neonate specimen of R. typus. There was evidence that folding of the cerebellar corpus appeared in early development, although the depth and number of folds might vary ontogenetically in this species. Hierarchical cluster analysis and multidimensional scaling ordinations showed evidence of convergent evolution with the basking shark, Cetorhinus maximus, another large-bodied filter feeding elasmobranch, supporting the claim that organization of the brain is more similar in species with analogous but independently evolved lifestyles than those that share taxonomic classification.
Antioxidants Reverse Age-Related Collateral Growth Impairment
Authors: Miller Steven J. , Coppinger Brian J. , Zhou Xiaosun , Unthank Joseph L.
Published: September 2009

Aging is a major risk factor for the development of cardiovascular diseases, including arterial occlusive disease. Oxidant stress increases with age, and may be a significant factor contributing to vascular dysfunction and disease. We have shown that aging and hypertension impair collateral growth, the natural compensatory response to arterial occlusive disease, and that antioxidants restore collateral growth in young hypertensive rats. The aim of this study was to test the hypothesis that oxidant stress mediates collateral growth impairment in nondiseased, aged rats. Ileal arteries were induced to become collaterals via ligation of adjacent arteries. Growth was assessed at 7 days by repeated in vivo measurements and comparison to same-animal control arteries. Collateral diameter enlargement did not occur in aged rats, but luminal expansion was stimulated by pretreatment with tempol. Co-administration of L-NAME with tempol prevented tempol-mediated collateral development. Expression of p22phox mRNA was increased in aged versus young rat arteries, suggesting NAD(P)H oxidase as a source of reactive oxygen species. Treatment with apocynin increased collateral growth capacity, whether administered prior to, or 7 days following, arterial ligation. The results suggest that antioxidant treatment may be useful in promoting collateral growth to compensate for age-related arterial occlusive disease.
Interactive Role of Protein Phosphatase 2A and Protein Kinase Cα in the Stretch-Induced Triphosphorylation of Myosin Light Chain in Canine Cerebral Artery
Authors: Obara Kazuo , Mitate Ayako , Nozawa Kayo , Watanabe Makiko , Ito Yoshihiko , Nakayama Koichi
Published: September 2009

The interactive role of protein kinase C (PKC) isoforms and protein phosphatase 2A (PP2A) in the mechanisms underlying the gradual reduction in stretch-induced contraction through triphosphorylation of 20-kDa myosin light chain (MLC20) was investigated in the canine basilar artery. In the presence of 5 mM tetraethylammonium, stretching at a rate of 1 mm/s from the initial length (Li) to 1.5 Li produced a contraction. Maintaining the stretched state for 15 min (15-min stretch) produced triphosphorylation of MLC20 at Ser-19, Thr-18 and Thr-9, and a gradual reduction in the contraction, both of which were reversed by Gö6976 (1 µM), an inhibitor of conventional PKC. The 15-min stretch increased PKCα activity whereas it decreased PP2A activity, both of which were blocked by Y-27632, an inhibitor of rho kinase. Okadaic acid (OA; 1 µM), a PP2A inhibitor, also produced triphosphorylation of MLC20 at the same amino acid residues and activated PKCα, which was inhibited by Gö6976. Stretching and OA increased phosphorylation of 17-kDa PKC-potentiated inhibitory phosphoprotein (CPI-17), and this phosphorylation was inhibited by Gö6976. The present results suggest that activation of PKCα mediated by an inhibitor of PP2A is involved in the stretch-induced triphosphorylation of MLC20, and that this triphosphorylation counteracts the stretch-induced contraction.
Differential Microvasculature Dysfunction in Living Kidney Donor Transplant Recipients: Nondialyzed versus Dialyzed Chronic Kidney Disease Patients
Authors: Chung Ada W.Y. , Yang H.H. Clarice , Sigrist Mhairi K. , Chum Elliott , Booth Anthony D. , Gourlay William A. , Levin Adeera
Published: September 2009

We hypothesized that there was differential vasomotor dysfunction in the microcirculation between nondialyzed and dialyzed chronic kidney disease (CKD) patients. During live donor kidney transplantation procedures, skin arterioles (SkA; internal diameter = 120 ± 5 µm) from donors (n = 27) and recipients (nondialysis = 15; dialysis = 20) were dissected from the abdominal wall at the incision site. In vivo aortic pulse wave velocity (PWV) was also measured. In the in vitro isometric force measurement, nondialyzed SkA exhibited comparable contraction to donor SkA, whereas dialyzed SkA had 60 and 40–50% increase in contraction in response to depolarization and agonist (that is, phenylephrine, serotonin and endothelin-1) stimulation, respectively. The acetylcholine-induced relaxation in the nondialyzed SkA was decreased by 50% compared with dialyzed SkA. However, pre-incubation with superoxide dismutase greatly enhanced the relaxation response in the nondialyzed, but not in the dialyzed SkA and donor SkA. Pre-incubation with NG-nitro-L-arginine methyl ester (L-NAME) elevated the resting tension and left-shifted the concentration response curve of phenylephrine-stimulated contraction in the donor-SkA. L-NAME only increased the resting tension in the nondialyzed vessel. In vitro stiffness positively correlated with PWV (R2 = 0.302, p = 0.001), and dialyzed SkA was 60% stiffer than nondialyzed and donor SkA. The acetylcholine relaxation was negatively correlated with PWV in donors and recipients (R2 = 0.282, p = 0.01). In conclusion, we have uniquely demonstrated differential microvasculature dysfunction between nondialyzed and dialyzed CKD patients.
Effects of L-Arginine on 7-Nitroindazole-Induced Reference and Working Memory Performance of Rats
Authors: Akar Füruzan Yildiz , Celikyurt Ipek Komsuoglu , Ulak Guner , Mutlu Oguz
Published: September 2009

Background/Aims: This study was performed in order to elucidate the effects of 7-nitroindazole (7-NI) and L-arginine on cognitive functions of rats in a three-panel runway task. Methods: 7-NI (2.5, 5, 10 mg/kg) and L-arginine (200 mg/kg) were injected intraperitoneally into male Wistar rats 30 min before the test. Results: 7-NI (5, 10 mg/kg) significantly increased the number of errors (pushes made on the 2 incorrect panels of the panel gate at 4 choice points) and prolonged the latency of reference memory in the three-panel runway task. The negative effects of 7-NI on reference memory was counteracted by L-arginine, a substrate for nitric oxide synthase. While having no effect on the number of working memory errors in working memory trials, 7-NI prolonged the latency from the 2nd to the 6th trial at the 5- and 10-mg/kg doses. Concurrent administration with L-arginine counteracted the 7-NI-induced prolongation of latency from the 2nd to the 6th trial. Conclusion: 7-NI impaired reference memory but not working memory in the three-panel runway test. Moreover, nitric oxide played an essential role in the development of reference memory and the negative effects of 7-NI on memory were counteracted by L-arginine.
Imatinib in Gastrointestinal Stromal Tumor: Does Treatment Duration Matter?
Authors: Adenis Antoine , Penel Nicolas , Blay Jean-Yves
Published: September 2009

Whereas 10 years ago no effective systemic therapy was available for gastrointestinal stromal tumors, the introduction of imatinib into clinical practice has dramatically improved the outcome of advanced disease, through favorable impact on disease-free survival for some patients with a localized and resectable tumor. This reviewprovides a clinical perspective on the available data, evidence- or expert-based, for calculating the optimal treatment duration with imatinib.
Melanoma Promotion after Photodynamic Therapy of a Suspected Bowen’s Disease Lesion
Authors: Schreml Stephan , Gantner Susanne , Steinbauer Julia , Babilas Philipp , Landthaler Michael , Szeimies Rolf-Markus
Published: September 2009

We report on a 61-year-old male patient who developed a melanoma at the site of a suspected Bowen’s lesion on the right cheek. This lesion had evolved for years and had been treated using photodynamic therapy (PDT) in an outpatient facility. Only a couple of months after a single PDT treatment, a melanoma was histologically diagnosed. After excision, multiple metastases were found. The therapeutic strategy comprised re-excision, neck dissection and lateral parotidectomy – due to a metastasis – as well as subsequent α-interferon injections. The possible role of PDT in the promotion of melanoma is discussed.
Effects of Head Circumference and Metabolic Syndrome on Cognitive Decline
Authors: Lee Kang Soo , Eom Jin-Sup , Cheong Hae-Kwan , Oh Byoung Hoon , Hong Chang Hyung
Published: September 2009

Background: Brain volume progressively decreases with an increase in atrophy, and the brain becomes more susceptible to degenerative brain diseases such as Alzheimer’s disease. Metabolic syndrome has also been associated with an increased risk of cognitive decline in the elderly. Aims: In this study, we aimed to examine the effects of head circumference and metabolic syndrome on cognitive decline. Methods: This study was part of a longitudinal study conducted on Koreans aged 60 years or older. We analyzed a final sample of 596 Korean participants with complete baseline and 2-year follow-up data. The cognitive function of the subjects was assessed using the Korean version of the Mini Mental State Examination (MMSE). Head circumference was measured from the glabella to the occipital protuberance using a measuring tape. Metabolic syndrome was defined according to the NCEP-ATP III standards. Central obesity was assessed on the basis of waist-circumference values, in accordance with the World Health Organization Western Pacific Region report on Asians. We used a longitudinal factorial design in which the MMSE score was the dependent variable, and head circumference and metabolic syndrome were considered as factors. Results: After adjusting the results for age, gender, education, height, weight, baseline MMSE, and number of follow-up years, we observed that smaller head circumference and the presence of metabolic syndrome were independently associated with rapid cognitive decline. Conclusion: All these findings suggest that smaller head circumference and the presence of metabolic syndrome have additive effects on cognitive decline.
Effect of Ageing on Isometric Strength through Joint Range at Knee and Hip Joints in Three Age Groups of Older Adults
Authors: Samuel Dinesh , Rowe Philip J.
Published: September 2009

Background: Strength of lower extremity muscles is an important determinant of mobility-based functional activities. Loss of strength with age produces functional limitation in activities of daily living such as rising from a chair or stair negotiation. However, there is limited information on the effect of age-related changes on the torque-producing ability of muscles through their ranges of joint motion. Objective: To investigate the effect of ageing on the torque-producing ability of lower extremity muscles in a large sample of older adults in three age groups. Methods: Eighty-two volunteers participated in this study and were divided into six groups according to their chronological age (60s, 70s and 80s and above) and gender (male, female). Isometric muscle strength was measured at the knee and hip joints at three positions through the joint range using a custom-built strain gauge torque dynamometer and a purpose built plinth. Results: The peak torque of major muscle groups of the knee and hip joints decreased with increasing age at all the three joint positions at which strength was tested. The 80-year-olds had 20% lower strength compared to the 60-year-olds. Age-related decrease in muscle strength was significant when comparing 80-year-olds with the 60-year-olds (p < 0.05). Strength loss was noted to be higher at the inner (muscle is shortened from mid-position) and outer (muscle is lengthened from mid-position) ranges of muscle action when compared with the mid-range position (mid-position). Gender-based differences were significant for all the strength tests (p < 0.05). Conclusions: Strength decreased with increasing age at all the positions within joint range of motion for knee and hip joints. However, the percentage loss of muscle strength was different at different positions in the joint range. Our findings suggest that muscle strength was more preserved in the middle range of muscle function compared to the inner and outer range of muscle action. In older people, lower extremity muscles might be required to produce higher moments in joint positions that are not within the optimum mid-position for muscle action.
The Role of KRAS Mutations in Predicting the Efficacy of Cetuximab-Plus-Irinotecan Therapy in Irinotecan-Refractory Korean Metastatic Colorectal Cancer Patients
Authors: Sohn Byeong Seok , Kim Tae Won , Lee Jae-Lyun , Ryu Min-Hee , Chang Heung Moon , Kang Yoon-Koo , Park Hyo Suk , Na Young-Soon , Jang Se Jin , Kim Jin Cheon , Lee Jung Shin
Published: September 2009

Objective: This study evaluated the clinical relevance of KRAS and BRAF mutational status in 66 irinotecan-refrac- tory Korean metastatic colorectal cancer (mCRC) patients treated with cetuximab-plus-irinotecan-based chemotherapy. Methods: A total of 66 irinotecan-refractory mCRC patients treated with cetuximab-plus-irinotecan-based chemotherapy were included. Tumors were screened for KRAS mutations (codons 12 and 13) and a BRAF mutation (V600E) using direct sequencing and the Snapshot assay. Results: The objective response rate (RR) for treatment was 21.2% (14/66) and skin rashes were observed in 43 (65.2%) of the 66 patients. A KRAS mutation was detected in 27 (40.9%) tumors, and was associated with lower RR (wild-type vs. mutated KRAS: 33.3 vs. 3.7%, p = 0.005) and shorter progression-free survival (PFS) and overall survival (OS; PFS: 6.4 vs. 2.0 months, p = 0.005; OS: 17.8 vs. 7.1 months, p = 0.001). Severe skin toxicity was associated with better RR and longer PFS and OS. BRAF mutations were not detected. Multivariate analysis revealed that KRAS status and skin toxicity were independent predictive factors of PFS and OS. Conclusions: This study indicates the clinical relevance of KRAS mutations in predicting the efficacy of cetuximab-plus-irinotecan-based chemotherapy in irinotecan-refractory Korean mCRC patients.
Activation of Sonic Hedgehog Signaling Pathway in Olfactory Neuroblastoma
Authors: Mao Ling , Xia Yuan-peng , Zhou Yu-nan , Dai Ruo-lian , Yang Xue , Wang Yan-jun , Duan Shu-jie , Qiao Xian , Mei Yuan-wu , Hu Bo
Published: September 2009

Objectives: Sonic hedgehog (Shh) signaling pathway is associated with tumor development; however, the role of Shh signaling in the development of olfactory neuroblastoma (ONB) is unknown. This study aimed to investigate the relationship between the regulation of Shh signaling and the pathogenesis of ONB. Methods: The expression of Shh signaling components was characterized by immunohistochemistry in human non-tumor olfactory epithelium and ONB specimens, and by RT-PCR and immunoblotting in human ONB cell lines. The impact of the treatment with cyclopamine (a selective inhibitor of the Shh pathway) and/or exogenous Shh on ONB cell proliferation, cycle and apoptosis was examined by MTT, soft agar colony formation and flow cytometry assays, respectively. The influence of Shh signaling on the expression of Shh signaling components and cell cycle-related regulators was determined by immunoblotting and quantitative RT-PCR, respectively. Results: The expression of Pacthed1, Gli1 and Gli2 was detected in 70, 70, and 65% of human ONB specimens, respectively, and in proportion of ONB cell lines, but not in non-tumor olfactory epithelium. Treatment with cyclopamine inhibited the proliferation and colony formation of ONB cells, induced ONB cell cycle arrest and apoptosis, and down-regulated the expression of Pacthed1, Gli1 and cyclin D1, but up-regulated p21 expression in vitro. These regulatory effects of cyclopamine were partially or completely erased by exogenous Shh. Conclusion: These data suggest that the Shh signaling pathway is crucial for the growth of ONB.
Costs Associated with Capecitabine or 5-Fluorouracil Monotherapy after Surgical Resection in Patients with Colorectal Cancer
Authors: Chu Edward , Shi Nianwen , Wei Wenhui , Bendell Johanna C. , Cartwright Thomas
Published: September 2009

Objective: To compare chemotherapy-related and total medical costs among patients with colorectal cancer (CRC) receiving capecitabine or 5-fluorouracil (5-FU) monotherapy after surgical resection. Methods: This retrospective, claim-based study utilized the Thomson Reuters Market Scan® databases to identify 1,396 CRC patients who received capecitabine or 5-FU monotherapy within 90 days of surgical resection from 2003 through 2006. Propensity score matching addressed selection bias, and multivariate models estimated adjusted relative risks of treatment-related complications and medical costs of matched cohorts. Results: Capecitabine users incurred USD 740 less in total direct medical costs (p = 0.003) and USD 785 less in chemotherapy-related costs (p < 0.0001) than 5-FU users. Although drug acquisition cost was higher for capecitabine than for 5-FU (USD 958 vs. USD 71, p < 0.0001), chemotherapy administration cost was lower (USD 76 vs. USD 1,062, p < 0.0001). The unadjusted (610 vs. 1,960 events per 1,000 person-months) and adjusted risks (47%) were lower for capecitabine than 5-FU for any complication, and specifically for bone marrow (67%), gastrointestinal (50%), and constitutional (41%) complications (p < 0.0001, all comparisons). Conclusions: Adjuvant capecitabine monotherapy was associated with lower total medical and chemotherapy-related costs than 5-FU. Reduced complications and costs associated with capecitabine administration offset the higher acquisition cost.
Ion Mobility Analysis of Lipoprotein Subfractions Identifies Three Independent Axes of Cardiovascular Risk
Authors: Musunuru Kiran , Orho-Melander Marju , Caulfield Michael P. , Li Shuguang , Salameh Wael A. , Reitz Richard E. , Berglund Göran , Hedblad Bo , Engström Gunnar , Williams Paul T. , Kathiresan Sekar , Melander Olle , Krauss Ronald M.
Published: September 2009

Objective—

Whereas epidemiological studies show that levels of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) predict incident cardiovascular disease (CVD), there is limited evidence relating lipoprotein subfractions and composite measures of subfractions to risk for CVD in prospective cohort studies.

Methods and Results—

We tested whether combinations of lipoprotein subfractions independently predict CVD in a prospective cohort of 4594 initially healthy men and women (the Malmö Diet and Cancer Study, mean follow-up 12.2 years, 377 incident cardiovascular events). Plasma lipoproteins and lipoprotein subfractions were measured at baseline with a novel high-resolution ion mobility technique. Principal component analysis (PCA) of subfraction concentrations identified 3 major independent (ie, zero correlation) components of CVD risk, one representing LDL-associated risk, a second representing HDL-associated protection, and the third representing a pattern of decreased large HDL, increased small/medium LDL, and increased triglycerides. The last corresponds to the previously described “atherogenic lipoprotein phenotype.” Several genes that may underlie this phenotype—
CETP
,
LIPC
,
GALNT2
,
MLXIPL
,
APOA1/A5
,
LPL
—are suggested by SNPs associated with the combination of small/medium LDL and large HDL.

Conclusion—

PCA on lipoprotein subfractions yielded three independent components of CVD risk. Genetic analyses suggest these components represent independent mechanistic pathways for development of CVD.
Simvastatin Inhibits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Apolipoprotein E-Knockout Mice
Authors: Zhang Yali , Naggar Jack C. , Welzig C. Michael , Beasley Debbie , Moulton Karen S. , Park Ho-Jin , Galper Jonas B.
Published: September 2009

Objective—

Abdominal aortic aneurysm (AAA) is a life-threatening disease affecting almost 10% of the population over age 65. Generation of AAAs by infusion of angiotensin (Ang) II in apolipoprotein E-knockout (ApoE
−/−
) mice is an animal model which supports an imbalance of the renin-angiotensin system in the pathogenesis of AAA. The effect of statins on AngII-mediated AAA formation and the associated neovascularization is not known. Here we determined the effect of simvastatin and the ERK inhibitor, CI1040, on AngII-stimulated AAA formation.

Methods and Results—

ApoE
−/−
mice infused for 28 days with AngII using osmotic minipumps were treated with placebo, 10 mg/kg/d simvastatin, or 100 mg/kg/d CI1040. 95% of AngII-treated mice developed AAA with neovascularization of the lesion, increased ERK phosphorylation, MCP-1 secretion, and MMP activity. These effects were markedly reversed by simvastatin and in part by CI1040. Furthermore, simvastatin and the ERK inhibitor U0126 reversed AngII-stimulated angiogenesis and MMP secretion by human umbilical vein endothelial cells.

Conclusions—

These data support the conclusion that simvastatin interferes with AAA formation induced by AngII in ApoE
−/−
mice at least in part via ERK inhibition.
Heat Shock Protein 27 Protects Against Atherogenesis via an Estrogen-Dependent Mechanism
Authors: Rayner Katey , Sun Jiangfeng , Chen Yong-Xiang , McNulty Melissa , Simard Trevor , Zhao Xiaoling , Wells Dominic J. , de Belleroche Jacqueline , O'Brien Edward R.
Published: September 2009

Objective—

We recently identified HSP27 as an atheroprotective protein that acts extracellularly to prevent foam cell formation and atherogenesis in female but not male mice, where serum levels of HSP27 were increased and inversely correlated with degree of lesion burden. In the current study we sought to determine whether estrogens are required for the observed atheroprotective benefits of HSP27 as well as its extracellular release.

Methods and Results—

In vitro estrogens prompted the release of HSP27 from macrophages in an ERβ specific manner that involved exosomal trafficking. Ovariectomy nullified the previously recognized attenuation in aortic lesion area in HSP27
o/e
apoE
−/−
mice compared to apoE
−/−
mice. Supplementation with 17β-estradiol resulted in a >15× increase in uterine weight and attenuation of atherogenesis in all mice, although HSP27
o/e
apoE
−/−
had 34% less lesion burden compared to apoE
−/−
mice. Mice treated with the ERβ-specific agonist, DPN had no effect on uterine weight but a 28% decrease in aortic lesion area in HSP27
o/e
apoE
−/−
compared to apoE
−/−
mice. HSP27 serum levels showed a similar gradual increase with E2 and DPN replacement treatment but did not change in untreated mice.

Conclusions—

The extracellular release of and atheroprotection provided by HSP27 is estrogen dependent.
Influence of Myocardial Fibrosis on Left Ventricular Diastolic Function
Authors: Moreo Antonella , Ambrosio Giuseppe , De Chiara Benedetta , Pu Min , Tran Tam , Mauri Francesco , Raman Subha V.
Published: September 2009

Background—

Fibrosis is a common end point of many pathological processes affecting the myocardium and may alter myocardial relaxation properties. By measuring myocardial fibrosis with cardiac magnetic resonance and diastolic function with Doppler echocardiography, we sought to define the influence of fibrosis on left ventricular diastolic function.

Methods and Results—

Two hundred four eligible subjects from 252 consecutive subjects undergoing late postgadolinium myocardial enhancement (LGE) cardiac magnetic resonance and Doppler echocardiography were investigated. Subjects with normal diastolic function exhibited no or minimal fibrosis (median LGE score, 0; interquartile range, 0 to 0). In contrast, the majority of patients with cardiomyopathy (regardless of underlying cause) had abnormal diastolic function indices and substantial fibrosis (median LGE score, 3; interquartile range, 0 to 6.25). Prevalence of LGE positivity by diastolic filling pattern was 13% in normal, 48% in impaired relaxation, 78% in pseudonormal, and 87% in restrictive filling (
P
<0.0001). Similarly, LGE score was significantly higher in patients with deceleration time <150 ms (
P
<0.012), and it progressively increased with increasing left ventricular filling pressure estimated by tissue Doppler imaging–derived E/E′ (
P
<0.0001). After multivariate analysis, LGE remained significantly correlated with degree of diastolic dysfunction (
P
=0.0001).

Conclusions—

Severity of myocardial fibrosis by LGE significantly correlates with the degree of diastolic dysfunction in a broad range of cardiac conditions. Noninvasive assessment of myocardial fibrosis may provide valuable insights into the pathophysiology of left ventricular diastolic function and therapeutic response.
Aldose Reductase Protects Against Early Atherosclerotic Lesion Formation in Apolipoprotein E-Null Mice
Authors: Srivastava Sanjay , Vladykovskaya Elena , Barski Oleg A. , Spite Matthew , Kaiserova Karin , Petrash J. Mark , Chung Stephen S. , Hunt Greg , Dawn Buddhadeb , Bhatnagar Aruni
Published: September 2009

Rationale
:

Atherosclerotic lesion formation is associated with the accumulation of oxidized lipids. Products of lipid oxidation, particularly aldehydes, stimulate cytokine production and enhance monocyte adhesion; however, their contribution to atherosclerotic lesion formation remains unclear.

Objective
:

To test the hypothesis that inhibition of aldehyde removal by aldose reductase (AR), which metabolizes both free and phospholipid aldehydes, exacerbates atherosclerotic lesion formation.

Methods and Results
:

In atherosclerotic lesions of apolipoprotein (apo)E-null mice, AR protein was located in macrophage-rich regions and its abundance increased with lesion progression. Treatment of apoE-null mice with AR inhibitors sorbinil or tolrestat increased early lesion formation but did not affect the formation of advanced lesions. Early lesions of AR
−/−
/apoE
−/−
mice maintained on high-fat diet were significantly larger when compared with age-matched AR
+/+
/apoE
−/−
mice. The increase in lesion area attributable to deletion of the AR gene was seen in both male and female mice. Pharmacological inhibition or genetic ablation of AR also increased the lesion formation in male mice made diabetic by streptozotocin treatment. Lesions in AR
−/−
/apoE
−/−
mice exhibited increased collagen and macrophage content and a decrease in smooth muscle cells. AR
−/−
/apoE
−/−
mice displayed a greater accumulation of the AR substrate 4-hydroxy
trans
-2-nonenal (HNE) in the plasma and protein-HNE adducts in arterial lesions than AR
+/+
/apoE
−/−
mice.

Conclusions
:

These observations indicate that AR is upregulated in atherosclerotic lesions and it protects against early stages of atherogenesis by removing toxic aldehydes generated in oxidized lipids.