bluuebunny/crossref_metadata_2025 huggingface dataset:
Campylobacterepidemiology: a descriptive study reviewing 1 million cases in England and Wales between 1989 and 2011
Authors: Nichols Gordon L , Richardson Judith F , Sheppard Samuel K , Lane Chris , Sarran Christophe
Published: July 2012

Objectives

To reviewCampylobactercases in England and Wales over 2 decades and examine the main factors/mechanisms driving the changing epidemiology.

Design

A descriptive study ofCampylobacterpatients between 1989 and 2011. Cases over 3 years were linked anonymously to postcode, population density, deprivation indices and census data. Cases over 5 years were anonymously linked to local weather exposure estimates.

Setting

Patients were from general practice, hospital and environmental health investigations through primary diagnostic laboratories across England and Wales.

Participants

There were 1 109 406 cases.

Outcome measures

Description of changes inCampylobacterepidemiology over 23 years and how the main drivers may influence these.

Results

There was an increase inCampylobactercases over the past 23 years, with the largest increase in people over 50 years. Changes in the underlying population have contributed to this, including the impacts of population increases after World War I, World War II and the ‘baby boom’ of the 1960s. A recent increase in risk or ascertainment within this population has caused an increase in cases in all age groups from 2004 to 2011. The seasonal increase in cases between weeks 18 (Early May) and 22 (Early June) was consistent across ages, years and regions and was most marked in children and in more rural regions.Campylobacterprevalence by week in each region correlated with temperature 2 weeks before. There were higher prevalences in areas with a low population density, low deprivation and lower percentage of people of ethnic origin. Data from sero–phage and multilocus sequence typing show a few common types and many uncommon types.

Conclusions

The drivers/mechanisms influencing seasonality, age distribution, population density, socioeconomic and long-term differences are diverse and their relative contributions remain to be established. Surveillance and typing provide insights intoCampylobacterepidemiology and sources of infection, providing a sound basis for targeted interventions.
Gastrointestinal surgery in adult patients with cystic fibrosis
Authors: Sharma Abhiram , Morton Alison , Peckham Daniel , Jayne David
Published: July 2012

Objective

Gastrointestinal conditions requiring surgical intervention are becoming increasingly frequent in adults with cystic fibrosis (CF) as life expectancy increases. In addition, patients with CF are at risk of specific gastrointestinal complications associated with their disease. This includes distal intestinal obstruction syndrome (DIOS), which may affect up to 15% of patients, and can present diagnostic and therapeutic challenges. The aim of this study was to determine the nature and frequency of general surgical procedures undertaken in a large cohort of adult CF patients so as to guide future care.

Design

The medical records of all surviving adult CF patients followed at a large tertiary referral centre in the UK were scrutinised and details retrieved on those who had undergone abdominal surgery after the age of 16 years.

Results

A total of 377 patients with CF were identified from the prospectively held database. Thirty-three patients had undergone 43 abdominal operations. The median age at surgery was 22.7 years (range 16–58 years). The three most commonly performed operations were: surgery for DIOS (n=9); cholecystectomy (n=8) and fundoplication (n=6). A past history of surgically treated meconium ileus at birth was a significant risk factor for requiring surgery for DIOS as an adult.

Conclusions

The treatment of DIOS-related complications is one of the main reasons for abdominal surgery in the adult CF population. The general surgical community needs to be increasingly aware of the existence of disease-related gastrointestinal conditions in adult CF patients so that treatment can be optimised.
Responsiveness of prehaemolytic copper poisoning in sheep from a specific pathogen‐free environment to a relatively high dose of tetrathiomolybdate
Authors: Suttle N. F.
Published: July 2012

Efficacy of ammonium tetrathiomolybdate (3.4 mg/kg LW, TTM3.4) was monitored in nine, specific pathogen‐free sheep with mild‐to‐severe, prehaemolytic copper poisoning (pre‐HCP). Five sheep were given three subcutaneous injections over seven days and four began a shorter, five‐day course four days later. Plasma bile acid (BA) and glutamate dehydrogenase (GDH) had fallen significantly after six days but BA briefly rose again between days 10 to 18. Aspartate aminotransferase (AST), δ‐glutamyl transferase (GGT) were later to decline but presented little evidence of hepatotoxicity by day 45. Erythrocyte superoxide dismutase (ESOD) was rapidly inhibited, activities falling by 65 per cent within three days and taking 25 days to recover. Trichloroacetic (TCA)‐insoluble copper increased by 6 to 8 μmol/l after three days but had largely disappeared by day 18. Six lambs had become hypercupraemic by day 18 due to a rise in TCA‐soluble Cu. ESOD activity fell again by 188±29.5 U/gHb between days 25 and 45 but had largely recovered by day 62. TTM3.4 gave better control of hepatotoxicity than TTM1.7 had done in more severely affects cohorts but at the expense of greater inhibition of ESOD. Treatment of pre‐HCuP should rely more on reducing copper absorption until more is known of the side effects of TTM on cuproenzymes.
Monthly application of 10 per cent moxidectin and 2·5 per cent imidacloprid spot‐on to prevent relapses in generalised demodicosis: a pilot study
Authors: Colombo S. , Leone F. , Vercelli A. , Cornegliani L.
Published: July 2012

Canine generalised demodicosis (GD) can be difficult to cure, with some dogs requiring life‐long treatment. The aim of this pilot study was to evaluate the effectiveness of monthly 10 per cent moxidectin/2·5 per cent imidacloprid spot‐on in maintaining long‐term (12 months) clinical and parasitological remission in dogs with relapsing GD. Fourteen dogs were included: 10 with juvenile‐onset GD (JOGD) and four with adult‐onset GD (AOGD). All dogs had been treated previously and relapsed (1–4 times). Each dog was treated again with either milbemycin oxime 2 mg/kg or ivermectin 400μg/kg orally once daily, until two consecutive negative skin scrapings at one‐month intervals (total 4–7 months of treatment). After treatment discontinuation, 10 per cent moxidectin/2·5 per cent imidacloprid spot‐on was applied monthly for 12 months. Dogs were rechecked after 1, 2, 3, 6 and 12 months, and multiple skin scrapings were taken. Twelve dogs completed the study and were clinically normal and parasitologically negative at each recheck (four dogs with AOGD and eight with JOGD). One dog died suddenly for unrelated reasons, and one dog relapsed. Results of this pilot study suggest that monthly application of 10 per cent moxidectin/2·5 per cent imidacloprid spot‐on may be effective as maintenance therapy in relapsing cases of GD.
High-Strain-Rate Deformation: Mechanical Behavior and Deformation Substructures Induced
Authors: (Rusty) Gray George T.
Published: July 2012

The influence of increasing strain rate on the mechanical behavior and deformation substructures in metals and alloys that deform predominately by slip is very similar to that seen following quasi-static deformation at increasingly lower temperatures or due to a decrease in stacking-fault energy (γsf). Deformation at higher rates (a) produces more uniform dislocation distributions for the same amount of strain, (b) hinders the formation of discrete dislocation cells, (c) decreases cell size, and (d) increases misorientation, with more dislocations trapped within cell interiors. The suppression of thermally activated dislocation processes in this regime can lead to stresses high enough to activate and grow deformation twins even in high-stacking-fault-energy, face-centered-cubic metals. In this review, examples of the high-strain-rate mechanical behavior and the deformation substructure evolution observed in a range of materials following high and shock-loading strain rates are presented and compared with those seen following quasi-static-loading deformation paths.
Construction, Concentration, and (Dis)Continuities in Social Valuations
Authors: Zuckerman Ezra W.
Published: July 2012

I review and integrate recent sociological research that makes progress on three interrelated questions pertaining to social valuation: (a) the degree of social construction relative to objective constraints; (b) the degree of concentration in social valuations at a single point in time; and (c) the conditions that govern two broad forms of temporal discontinuity—(i) fashion cycles, especially in cultural expression and in managerial practices, and (ii) bubble/crash dynamics, as witnessed in such domains as authoritarian regimes and financial markets. In the course of the review, I argue for the importance of identifying how objective conditions constrain social construction and suggest two contrarian mechanisms by which this is accomplished—valuation opportunism and valuation entrepreneurship—and the conditions under which they are more or less effective.
Resolution of Social Conflict
Authors: Wagner-Pacifici Robin , Hall Meredith
Published: July 2012

For generations, sociological theorists have debated the relative function, utility, and harm of social conflict and its resolution. This review identifies some of the most prominent among recent contested forms of conflict resolution as well as their social histories, worldviews, and ways of operating. In sorting out the myriad theoretical traditions and positions guiding this field, we note that the resolution of social conflict is a thing in itself, and hence any design of its study should be directed at this liminal moment during which change is occurring. We conclude by examining four aspects of resolution—violence, spatiality, temporality, and language—using these themes to demarcate fault lines or gaps in the literature and to suggest new directions for future research.
Novel properties of statins: suppression of the systemic and bone marrow responses induced by exposure to ambient particulate matter (PM10) air pollution
Authors: Miyata Ryohei , Bai Ni , Vincent Renaud , Sin Don D. , Van Eeden Stephan F.
Published: July 2012

Exposure to ambient particulate matter (PM10) elicits systemic inflammatory responses that include the stimulation of bone marrow and progression of atherosclerosis. The present study was designed to assess the effect of repeated exposure of PM10on the turnover and release of polymorphonuclear leukocytes (PMNs) from the bone marrow into the circulation and the effect of lovastatin on the PM10-induced bone marrow stimulation. Rabbits exposed to PM10three times a week for 3 wk, were given a bolus of 5′-bromo-2′-deoxyuridine to label dividing cells in the marrow to calculate the transit time of PMNs in the mitotic or postmitotic pool. PM10exposure accelerated the turnover of PMNs by shortening their transit time through the marrow (64.8 ± 1.9 h vs. 34.3 ± 7.4 h, P < 0.001, control vs. PM10). This was predominantly due to a rapid transit of PMNs through the postmitotic pool (47.9 ± 0.7 h vs. 21.3 ± 4.3 h, P < 0.001, control vs. PM10) but not through the mitotic pool. Lovastatin delayed the transit time of postmitotic PMNs (38.2 ± 0.5 h, P < 0.001 vs. PM10) and shifted the postmitotic PMN release peak from 30 h to 48 h. PM10exposure induced the prolonged retention of newly released PMNs in the lung, which was reduced by lovastatin ( P < 0.01). PM10exposure increased plasma interleukin-6 levels with significant reduction by lovastatin ( P < 0.01). We conclude that lovastatin downregulates the PM10-induced overactive bone marrow by attenuating PM10-induced systemic inflammatory responses.
Severely blunted allergen-induced pulmonary Th2 cell response and lung hyperresponsiveness in type 1 transient receptor potential channel-deficient mice
Authors: Yildirim Eda , Carey Michelle A. , Card Jeffrey W. , Dietrich Alexander , Flake Gordon P. , Zhang Yingpei , Bradbury J. Alyce , Rebolloso Yvette , Germolec Dori R. , Morgan Daniel L. , Zeldin Darryl C. , Birnbaumer Lutz
Published: July 2012

Transient receptor potential channels (TRPCs) are widely expressed and regulate Ca2+entry in the cells that participate in the pathophysiology of airway hyperreactivity, inflammation, and remodeling. In vitro studies point to a role for TRPC1-mediated Ca2+signaling in several of these cell types; however, physiological evidence is lacking. Here we identify TRPC1 signaling as proinflammatory and a regulator of lung hyperresponsiveness during allergen-induced pulmonary response. TRPC1-deficient ( Trpc1−/−) mice are hyposensitive to methacholine challenge and have significantly reduced allergen-induced pulmonary leukocyte infiltration coupled with an attenuated T helper type 2 (Th2) cell response. Upon in vitro allergen exposure, Trpc1−/−splenocytes show impaired proliferation and T cell receptor-induced IL-2 production. A high number of germinal centers in spleens of Trpc1−/−mice and elevated levels of immunoglobulins in their serum are indicative of dysregulated B cell function and homeostasis. Thus we propose that TRPC1 signaling is necessary in lymphocyte biology and in regulation of allergen-induced lung hyperresponsiveness, making TRPC1 a potential target for treatment of immune diseases and asthma.
Uphill running improves rat Achilles tendon tissue mechanical properties and alters gene expression without inducing pathological changes
Authors: Heinemeier K. M. , Skovgaard D. , Bayer M. L. , Qvortrup K. , Kjaer A. , Kjaer M. , Magnusson S. P. , Kongsgaard M.
Published: July 2012

Overuse Achilles tendinopathy is a common and challenging problem in sports medicine. Little is known about the etiology of this disorder, and the development of a good animal model for overuse tendinopathy is essential for advancing insight into the disease mechanisms. Our aim was to test a previously proposed rat model for Achilles tendon overuse. Ten adult male Sprague-Dawley rats ran on a treadmill with 10° incline, 1 h/day, 5 days/wk (17–20 m/min) for 12 wk and were compared with 12 control rats. Histological, mechanical, and gene-expression changes were measured on the Achilles tendons after the intervention, and local tendon glucose-uptake was measured before and after the intervention with positron emission tomography. No differences were detected between runners and controls in tissue histology or in glucose uptake, indicating that tendon pathology was not induced. Greater tendon tissue modulus ( P < 0.005) and failure stress/body weight ( P < 0.02) in runners compared with controls further supported that tendons successfully adapted to uphill running. Several genes of interest were regulated after 12 wk of running. Expression of collagen III and insulin-like growth factor I was increased, while collagen I was unchanged, and decreases were seen in noncollagen matrix components (fibromodulin and biglycan), matrix degrading enzymes, transforming growth factor-β1, and connective tissue growth factor. In conclusion, the tested model could not be validated as a model for Achilles tendinopathy, as the rats were able to adapt to 12 wk of uphill running without any signs of tendinopathy. Improved mechanical properties were observed, as well as changes in gene-expression that were distinctly different from what is seen in tendinopathy and in response to short-term tendon loading.
Mechanics of the canine diaphragm in pleural effusion
Authors: De Troyer André , Leduc Dimitri , Cappello Matteo , Gevenois Pierre Alain
Published: July 2012

Pleural effusion is a complicating feature of many diseases of the lung and pleura, but its effects on the mechanics of the diaphragm have not been assessed. In the present study, radiopaque markers were attached along muscle bundles in the midcostal region of the diaphragm in anesthetized dogs, and the three-dimensional location of the markers during relaxation before and after the stepwise introduction of liquid into the left or right pleural space and during phrenic nerve stimulation in the same conditions was determined using computed tomography. From these data, accurate measurements of diaphragm muscle length and displacement were obtained, and the changes in pleural and abdominal pressure were analyzed as functions of these parameters. The effect of liquid instillation on the axial position of rib 5 was also measured. The data showed that 1) liquid leaked through the dorsal mediastinal sheet behind the pericardium so that effusion was bilateral; 2) effusion caused a caudal displacement of the relaxed diaphragm; 3) this displacement was, compared with passive lung inflation, much larger than the cranial displacement of the ribs; and 4) the capacity of the diaphragm to generate pressure, in particular pleural pressure, decreased markedly as effusion increased, and this decrease was well explained by the decrease in active muscle length. It is concluded that pleural effusion has a major adverse effect on the pressure-generating capacity of the diaphragm and that this is the result of the action of hydrostatic forces on the muscle.
Lowering of blood pressure by chronic suppression of central sympathetic outflow: insight from prolonged baroreflex activation
Authors: Lohmeier Thomas E. , Iliescu Radu
Published: July 2012

Device-based therapy for resistant hypertension by electrical activation of the carotid baroreflex is currently undergoing active clinical investigation, and initial findings from clinical trials have been published. The purpose of this mini-review is to summarize the experimental studies that have provided a conceptual understanding of the mechanisms that account for the long-term lowering of arterial pressure with baroreflex activation. The well established mechanisms mediating the role of the baroreflex in short-term regulation of arterial pressure by rapid changes in peripheral resistance and cardiac function are often extended to long-term pressure control, and the more sluggish actions of the baroreflex on renal excretory function are often not taken into consideration. However, because clinical, experimental, and theoretical evidence indicates that the kidneys play a dominant role in long-term control of arterial pressure, this review focuses on the mechanisms that link baroreflex-mediated reductions in central sympathetic outflow with increases in renal excretory function that lead to sustained reductions in arterial pressure.
Sex differences in thermoeffector responses during exercise at fixed requirements for heat loss
Authors: Gagnon Daniel , Kenny Glen P.
Published: July 2012

To assess potential mechanisms responsible for the lower sudomotor thermosensitivity in women during exercise, we examined sex differences in sudomotor function and skin blood flow (SkBF) during exercise performed at progressive increases in the requirement for heat loss. Eight men and eight women cycled at rates of metabolic heat production of 200, 250, and 300 W/m2 of body surface area, with each rate being performed sequentially for 30 min. The protocol was performed in a direct calorimeter to measure evaporative heat loss (EHL) and in a thermal chamber to measure local sweat rate (LSR) (ventilated capsule), SkBF (laser-Doppler), sweat gland activation (modified iodine-paper technique), and sweat gland output (SGO) on the back, chest, and forearm. Despite a similar requirement for heat loss between the sexes, significantly lower increases in EHL and LSR were observed in women ( P ≤ 0.001). Sex differences in EHL and LSR were not consistently observed during the first and second exercise periods, whereas EHL (348 ± 13 vs. 307 ± 9 W/m2) and LSR on the back (1.61 ± 0.07 vs. 1.20 ± 0.09 mg·min−1·cm−2), chest (1.33 ± 0.06 vs. 1.08 ± 0.09 mg·min−1·cm−2), and forearm (1.53 ± 0.07 vs. 1.20 ± 0.06 mg·min−1·cm−2, men vs. women) became significantly greater in men during the last exercise period ( P < 0.05). At each site, differences in LSR were solely due to a greater SGO in men, as opposed to differences in sweat gland activation. In contrast, no sex differences in SkBF were observed throughout the exercise period. The present study demonstrates that sex differences in sudomotor function are only evidenced beyond a certain requirement for heat loss, solely through differences in SGO. In contrast, the lower EHL and LSR in women are not paralleled by a lower SkBF response.
Obesity, insulin resistance, and skeletal muscle nitric oxide synthase
Authors: Kraus Raymond M. , Houmard Joseph A. , Kraus William E. , Tanner Charles J. , Pierce Joseph R. , Choi Myung Dong , Hickner Robert C.
Published: July 2012

The molecular mechanisms responsible for impaired insulin action have yet to be fully identified. Rodent models demonstrate a strong relationship between insulin resistance and an elevation in skeletal muscle inducible nitric oxide synthase (iNOS) expression; the purpose of this investigation was to explore this potential relationship in humans. Sedentary men and women were recruited to participate (means ± SE: nonobese, body mass index = 25.5 ± 0.3 kg/m2, n = 13; obese, body mass index = 36.6 ± 0.4 kg/m2, n = 14). Insulin sensitivity was measured using an intravenous glucose tolerance test with the subsequent modeling of an insulin sensitivity index (SI). Skeletal muscle was obtained from the vastus lateralis, and iNOS, endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) content were determined by Western blot. SIwas significantly lower in the obese compared with the nonobese group (∼43%; P < 0.05), yet skeletal muscle iNOS protein expression was not different between nonobese and obese groups. Skeletal muscle eNOS protein was significantly higher in the nonobese than the obese group, and skeletal muscle nNOS protein tended to be higher ( P = 0.054) in the obese compared with the nonobese group. Alternative analysis based on SI(high and low tertile) indicated that the most insulin-resistant group did not have significantly more skeletal muscle iNOS protein than the most insulin-sensitive group. In conclusion, human insulin resistance does not appear to be associated with an elevation in skeletal muscle iNOS protein in middle-aged individuals under fasting conditions.
An increase in the redox state during reperfusion contributes to the cardioprotective effect of GIK solution
Authors: Suranadi I. W. , Demaison L. , Chaté V. , Peltier S. , Richardson M. , Leverve X.
Published: July 2012

This study aimed at determining whether glucose-insulin-potassium (GIK) solutions modify the NADH/NAD+ratio during postischemic reperfusion and whether their cardioprotective effect can be attributed to this change in part through reduction of the mitochondrial reactive oxygen species (ROS) production. The hearts of 72 rats were perfused with a buffer containing glucose (5.5 mM) and hexanoate (0.5 mM). They were maintained in normoxia for 30 min and then subjected to low-flow ischemia (0.5% of the preischemic coronary flow for 20 min) followed by reperfusion (45 min). From the beginning of ischemia, the perfusate was subjected to various changes: enrichment with GIK solution, enrichment with lactate (2 mM), enrichment with pyruvate (2 mM), enrichment with pyruvate (2 mM) plus ethanol (2 mM), or no change for the control group. Left ventricular developed pressure, heart rate, coronary flow, and oxygen consumption were monitored throughout. The lactate/pyruvate ratio of the coronary effluent, known to reflect the cytosolic NADH/NAD+ratio and the fructose-6-phosphate/dihydroxyacetone-phosphate (F6P/DHAP) ratio of the reperfused myocardium, were evaluated. Mitochondrial ROS production was also estimated. The GIK solution improved the recovery of mechanical function during reperfusion. This was associated with an enhanced cytosolic NADH/NAD+ratio and reduced mitochondrial ROS production. The cardioprotection was also observed when the hearts were perfused with fluids known to increase the cytosolic NADH/NAD+ratio (lactate, pyruvate plus ethanol) compared with the other fluids (control and pyruvate groups). The hearts with a high mechanical recovery also displayed a low F6P/DHAP ratio, suggesting that an accelerated glycolysis rate may be responsible for increased cytosolic NADH production. In conclusion, the cardioprotection induced by GIK solutions could occur through an increase in the cytosolic NADH/NAD+ratio, leading to a decrease in mitochondrial ROS production.
Approximation Analysis of Gradient Descent Algorithm for Bipartite Ranking
Authors: Chen Hong , He Fangchao , Pan Zhibin
Published: July 2012

We introduce a gradient descent algorithm for bipartite ranking with general convex losses. The implementation of this algorithm is simple, and its generalization performance is investigated. Explicit learning rates are presented in terms of the suitable choices of the regularization parameter and the step size. The result fills the theoretical gap in learning rates for ranking problem with general convex losses.
Synthesis and Characterization of N1-Phenylhydrazine-1,2-bis(carbothioamide) and Its Evaluation for Antimicrobial, Antioxidant, and Brine Shrimp Lethality Bioassay
Authors: Hossain G. M. Golzar , Abedin Md. Mainul , Bachar Sitesh C.
Published: July 2012

The compound N1-phenylhydrazine-1,2-bis(carbothioamide) was synthesised from phenylisothiocyanate reacting with thiosemicarbazide refluxing the mixture in ethanol. The new compound obtained was characterised by various spectral and elemental analyses. It was subjected to antibacterial, antioxidant and brine shrimp lethality bioassay. The compound showed brine shrimp lethality with LC50 value of 12.79 μg which was comparable to vincristine with LC50 value of 0.33 μg. The compound did not exhibit any antimicrobial activity against Gram +ve and Gram −ve organisms, as well as against the tested fungal strains. But very good free radical scavenging activity was observed at concentration range of 0.185–100 μg with IC50 values of 1.43 μg in comparison to reference standard butylated hydroxytoluene (BHT) with IC50 value 16.46 μg.
Stress Analysis of a Class II MO-Restored Tooth Using a 3D CT-Based Finite Element Model
Authors: Chan Yiu Pong , Tang Chak Yin , Gao Bo
Published: July 2012

A computational method has been developed for stress analysis of a restored tooth so that experimental effort can be minimized. The objectives of this study include (i) developing a method to create a 3D FE assembly model for a restored tooth based on CT images and (ii) conducting stress analysis of the restored tooth using the 3D FE model established. To build up a solid computational model of a tooth, a method has been proposed to construct a 3D model from 2D CT-scanned images. Facilitated with CAD tools, the 3D tooth model has been virtually incorporated with a Class II MO restoration. The tooth model is triphasic, including the enamel, dentin, and pulp phases. To mimic the natural constraint on the movement of the tooth model, its corresponding mandible model has also been generated. The relative high maximum principal stress values were computed at the surface under loading and in the marginal region of the interface between the restoration and the tooth phases.
Radiation Analysis and Characteristics of Conformal Reflectarray Antennas
Authors: Nayeri Payam , Yang Fan , Elsherbeni Atef Z.
Published: July 2012

This paper investigates the feasibility of designing reflectarray antennas on conformal surfaces. A generalized analysis approach is presented that can be applied to compute the radiation performance of conformal reflectarray antennas. Using this approach, radiation characteristics of conformal reflectarray antennas on singly curved platforms are studied and the performances of these designs are compared with planar designs. It is demonstrated that a conformal reflectarray antenna can be a suitable choice for applications requiring high-gain antennas on curved platforms.
BRAF
L597 Mutations in Melanoma Are Associated with Sensitivity to MEK Inhibitors
Authors: Dahlman Kimberly Brown , Xia Junfeng , Hutchinson Katherine , Ng Charles , Hucks Donald , Jia Peilin , Atefi Mohammad , Su Zengliu , Branch Suzanne , Lyle Pamela L. , Hicks Donna J. , Bozon Viviana , Glaspy John A. , Rosen Neal , Solit David B. , Netterville James L. , Vnencak-Jones Cindy L. , Sosman Jeffrey A. , Ribas Antoni , Zhao Zhongming , Pao William
Published: July 2012

Kinase inhibitors are accepted treatment for metastatic melanomas that harbor specific driver mutations in BRAF or KIT, but only 40% to 50% of cases are positive. To uncover other potential targetable mutations, we conducted whole-genome sequencing of a highly aggressive BRAF (V600) and KIT (W557, V559, L576, K642, and D816) wild-type melanoma. Surprisingly, we found a somatic BRAFL597R mutation in exon 15. Analysis of BRAF exon 15 in 49 tumors negative for BRAFV600 mutations as well as driver mutations in KIT, NRAS, GNAQ, and GNA11, showed that two (4%) harbored L597 mutations and another two involved BRAF D594 and K601 mutations. In vitro signaling induced by L597R/S/Q mutants was suppressed by mitogen-activated protein (MAP)/extracellular signal–regulated kinase (ERK) kinase (MEK) inhibition. A patient with BRAFL597S mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Collectively, these data show clinical significance to BRAFL597 mutations in melanoma.

Significance: This study shows that cells harboring BRAFL597 mutants are sensitive to MEK inhibitor treatment, providing a rationale for routine screening and therapy of BRAFL597-mutant melanoma. Cancer Discov; 2(9); 791–7. ©2012 AACR.

Read the Commentary on this article by Garraway and Baselga, p. 766.

This article is highlighted in the In This Issue feature, p. 753.
Simvastatin Reduces Myocardial Injury Undergoing Noncoronary Artery Cardiac Surgery
Authors: Almansob Mohammed Ahmed Saad , Xu Bo , Zhou Li , Hu Xiao-Xia , Chen Wen , Chang Feng-Jun , Ci Hong-Bo , Yao Jian-Ping , Xu Ying-Qi , Yao Feng-Juan , Liu Dong-Hong , Zhang Wen-Bo , Tang Bai-Yun , Wang Zhi-Ping , Ou Jing-Song
Published: July 2012

Objective—

Myocardial injury during cardiac surgery is a major cause of perioperative morbidity and mortality. We determined whether perioperative statin therapy is cardioprotective in patients undergoing noncoronary artery cardiac surgery and the potential mechanisms.

Methods and Results—

One hundred fifty-one patients undergoing noncoronary artery cardiac surgery were randomly assigned to either a statin group (n=77) or a control group (n=74). Simvastatin (20 mg) was administered preoperatively and postoperatively. Plasma were analyzed for troponin T, isoenzyme of creatine kinase, C-reaction protein, interleukin-6, interleukin-8, creatinine, and blood urea nitrogen. Cardiac echocardiography was performed. Endothelial nitric oxide synthase (eNOS), Akt, p38, heat shock protein 90, caveolin-1, and nitric oxide (NO) in the heart were detected. Simvastatin significantly reduced plasma troponin T, isoenzyme of creatine kinase, C-reaction protein, blood urea nitrogen , creatinine, interleukin-6, interleukin-8, and the requirement of inotropic postoperatively. Simvastatin increased NO production, the expression of eNOS and phosphorylation at serine1177, phosphorylation of Akt, expression of heat shock protein 90, heat shock protein 90 association with eNOS and decreased eNOS phosphorylation at threonine 495, phosphorylation of p38, and expression of caveolin-1. Simvastatin also improved cardiac function postoperatively.

Conclusion—

Perioperative statin therapy can improve cardiac function and renal function by reducing myocardial injury and inflammatory response through activating Akt-eNOS and attenuating p38 signaling pathways in patients undergoing noncoronary artery cardiac surgery.

Clinical Trial Registration—

URL:

http://www.clinicaltrials.gov

. Unique identifier: NCT01178710.
Lufaxin, a Novel Factor Xa Inhibitor From the Salivary Gland of the Sand Fly
Lutzomyia longipalpis
Blocks Protease-Activated Receptor 2 Activation and Inhibits Inflammation and Thrombosis In Vivo
Authors: Collin Nicolas , Assumpção Teresa C.F. , Mizurini Daniella M. , Gilmore Dana C. , Dutra-Oliveira Angélica , Kotsyfakis Michalis , Sá-Nunes Anderson , Teixeira Clarissa , Ribeiro José M.C. , Monteiro Robson Q. , Valenzuela Jesus G. , Francischetti Ivo M.B.
Published: July 2012

Objective—

Blood-sucking arthropods’ salivary glands contain a remarkable diversity of antihemostatics. The aim of the present study was to identify the unique salivary anticoagulant of the sand fly
Lutzomyia longipalpis
, which remained elusive for decades.

Methods and Results—

Several
L. longipalpis
salivary proteins were expressed in human embryonic kidney 293 cells and screened for inhibition of blood coagulation. A novel 32.4-kDa molecule, named Lufaxin, was identified as a slow, tight, noncompetitive, and reversible inhibitor of factor Xa (FXa). Notably, Lufaxin’s primary sequence does not share similarity to any physiological or salivary inhibitors of coagulation reported to date. Lufaxin is specific for FXa and does not interact with FX, Dansyl-Glu-Gly-Arg-FXa, or 15 other enzymes. In addition, Lufaxin blocks prothrombinase and increases both prothrombin time and activated partial thromboplastin time. Surface plasmon resonance experiments revealed that FXa binds Lufaxin with an equilibrium constant ≈3 nM, and isothermal titration calorimetry determined a stoichiometry of 1:1. Lufaxin also prevents protease-activated receptor 2 activation by FXa in the MDA-MB-231 cell line and abrogates edema formation triggered by injection of FXa in the paw of mice. Moreover, Lufaxin prevents FeCl
3
-induced carotid artery thrombus formation and prolongs activated partial thromboplastin time ex vivo, implying that it works as an anticoagulant in vivo. Finally, salivary gland of sand flies was found to inhibit FXa and to interact with the enzyme.

Conclusion—

Lufaxin belongs to a novel family of slow-tight FXa inhibitors, which display antithrombotic and anti-inflammatory activities. It is a useful tool to understand FXa structural features and its role in prohemostatic and proinflammatory events.
The Chemokine Decoy Receptor D6 Prevents Excessive Inflammation and Adverse Ventricular Remodeling After Myocardial Infarction
Authors: Cochain Clément , Auvynet Constance , Poupel Lucie , Vilar José , Dumeau Edouard , Richart Adèle , Récalde Alice , Zouggari Yasmine , Yin Kiave Yune Ho Wang , Bruneval Patrick , Renault Gilles , Marchiol Carmen , Bonnin Philippe , Lévy Bernard , Bonecchi Raffaella , Locati Massimo , Combadière Christophe , Silvestre Jean-Sébastien
Published: July 2012

Objective—

Leukocyte infiltration in ischemic areas is a hallmark of myocardial infarction, and overwhelming infiltration of innate immune cells has been shown to promote adverse remodeling and cardiac rupture. Recruitment of inflammatory cells in the ischemic heart depends highly on the family of CC-chemokines and their receptors. Here, we hypothesized that the chemokine decoy receptor D6, which specifically binds and scavenges inflammatory CC-chemokines, might limit inflammation and adverse cardiac remodeling after infarction.

Methods and Results—

D6 was expressed in human and murine infarcted myocardium. In a murine model of myocardial infarction, D6 deficiency led to increased chemokine (C-C motif) ligand 2 and chemokine (C-C motif) ligand 3 levels in the ischemic heart. D6-deficient (D6
−/−)
infarcts displayed increased infiltration of pathogenic neutrophils and Ly6Chi monocytes, associated with strong matrix metalloproteinase-9 and matrix metalloproteinase-2 activities in the ischemic heart. D6
−/−
mice were cardiac rupture prone after myocardial infarction, and functional analysis revealed that D6
−/−
hearts had features of adverse remodeling with left ventricle dilation and reduced ejection fraction. Bone marrow chimera experiments showed that leukocyte-borne D6 had no role in this setting, and that leukocyte-specific chemokine (C-C motif) receptor 2 deficiency rescued the adverse phenotype observed in D6
−/−
mice.

Conclusion—

We show for the first time that the chemokine decoy receptor D6 limits CC-chemokine–dependent pathogenic inflammation and is required for adequate cardiac remodeling after myocardial infarction.
Predictors for Neoatherosclerosis
Authors: Yonetsu Taishi , Kato Koji , Kim Soo-Joong , Xing Lei , Jia Haibo , McNulty Iris , Lee Hang , Zhang Shaosong , Uemura Shiro , Jang Yangsoo , Kang Soo-Jin , Park Seung-Jung , Lee Stephen , Yu Bo , Kakuta Tsunekazu , Jang Ik-Kyung
Published: July 2012

Background—

Recent studies have reported development of neoatherosclerosis (NA) inside the stents several years after stent implantation. The aim of this study was to determine the predictors for NA using optical coherence tomography.

Methods and Results—

From a total of 1080 patients who underwent optical coherence tomography, we identified 179 stents in 151 patients in which the mean neointimal thickness was >100 µm. The presence of lipid-laden neointima or calcification inside the stents was defined as NA in the present study. Patient characteristics, stent type, and time since stent implantation (stent age) were compared between stents with or without NA. Univariable and multivariable logistic regression analyses were used to assess the independent predictors. In univariate analysis, stent age ≥48 months (Odds ratio [OR], 4.48; [95% CI 2.68-9.65];
P
<0.001), drug-eluting stents (OR, 2.66; [95% CI, 1.38–5.16];
P
=0.004), age ≥65 years (OR, 1.91; [95% CI, 1.05–3.44];
P
=0.032), current smoking (OR, 2.30; [95% CI, 1.10–4.82];
P
=0.024), chronic kidney disease (OR, 4.17; [95% CI, 1.42–12.23];
P
=0.009), and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockade use (OR, 0.42; [95% CI, 0.22–0.80];
P
=0.008) were significant predictors. In multivariate analysis, stent age ≥48 months, all subtypes of drug-eluting stent, current smoking, chronic kidney disease, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockade use remained independent predictors for NA.

Conclusions—

In addition to the stent type and the stent age, patient characteristics, including current smoking, chronic kidney disease, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockade, were associated with the presence of NA. This result may support the importance of secondary prevention after stent implantation.
PKCα Activation of p120-Catenin Serine 879 Phospho-Switch Disassembles VE-Cadherin Junctions and Disrupts Vascular Integrity
Authors: Vandenbroucke St Amant Emily , Tauseef Mohammad , Vogel Stephen M. , Gao Xiao-Pei , Mehta Dolly , Komarova Yulia A. , Malik Asrar B.
Published: July 2012

Rationale:

Adherens junctions (AJs) are the primary intercellular junctions in microvessels responsible for endothelial barrier function. Homophilic adhesion of vascular endothelial (VE) cadherin forms AJs, which are stabilized by binding of p120-catenin (p120). p120 dissociation from VE-cadherin results in loss of VE-cadherin homotypic interaction and AJ disassembly; however, the signaling mechanisms regulating p120 dissociation from VE-cadherin are not understood.

Objective:

To address the mechanism of protein kinase C (PKC)-α function in increasing endothelial permeability, we determined the role of PKCα phosphorylation of p120 in mediating disruption of AJ integrity.

Methods and Results:

We showed that PKCα phosphorylation of p120 at serine (S)879 in response to thrombin or lipopolysaccharide challenge reduced p120 binding affinity for VE-cadherin and mediated AJ disassembly secondary to VE-cadherin internalization. In studies in mouse lung vessels, expression of the phosphodeficient S879A-p120 mutant prevented the increase in vascular permeability induced by activation of the thrombin receptor PAR-1.

Conclusions:

PKCα phosphorylation of p120 at S879 is a critical phospho-switch mediating disassociation of p120 from VE-cadherin that results in AJ disassembly. Therefore, blocking PKCα-mediated p120 phosphorylation represents a novel targeted anti-inflammatory strategy to prevent disruption of vascular endothelial barrier function.
Phosphorylation of Smooth Muscle 22α Facilitates Angiotensin II–Induced ROS Production Via Activation of the PKCδ-P47
phox
Axis Through Release of PKCδ and Actin Dynamics and Is Associated With Hypertrophy and Hyperplasia of Vascular Smooth Muscle Cells In Vitro and In Vivo
Authors: Lv Pin , Miao Sui-Bing , Shu Ya-Nan , Dong Li-Hua , Liu George , Xie Xiao-Li , Gao Min , Wang Yu-Can , Yin Ya-Juan , Wang Xiao-Juan , Han Mei
Published: July 2012

Rationale:

We have demonstrated that smooth muscle (SM) 22α inhibits cell proliferation via blocking Ras-ERK1/2 signaling in vascular smooth muscle cells (VSMCs) and in injured arteries. The recent study indicates that SM22α disruption can independently promote arterial inflammation through activation of reactive oxygen species (ROS)-mediated NF-κB pathways. However, the mechanisms by which SM22α controls ROS production have not been characterized.

Objective:

To investigate how SM22α disruption promotes ROS production and to characterize the underlying mechanisms.

Methods and Results:

ROS level was measured by dihydroethidium staining for superoxide and TBA assay for malondialdehyde, respectively. We showed that downregulation and phosphorylation of SM22α were associated with angiotensin (Ang) II–induced increase in ROS production in VSMCs of rats and human. Ang II induced the phosphorylation of SM22α at Serine 181 in an Ang II type 1 receptor–PKCδ pathway–dependent manner. Phosphorylated SM22α activated the protein kinase C (PKC)δ-p47
phox
axis via 2 distinct pathways: (1) disassociation of PKCδ from SM22α, and in turn binding to p47
phox
, in the early stage of Ang II stimulation; and (2) acceleration of SM22α degradation through ubiquitin-proteasome, enhancing PKCδ membrane translocation via induction of actin cytoskeletal dynamics in later oxidative stress. Inhibition of SM22α phosphorylation abolished the Ang II–activated PKCδ-p47
phox
axis and inhibited the hypertrophy and hyperplasia of VSMCs in vitro and in vivo, accompanied with reduction of ROS generation.

Conclusions:

These findings indicate that the disruption of SM22α plays pivotal roles in vascular oxidative stress. PKCδ-mediated SM22α phosphorylation is a novel link between actin cytoskeletal remodeling and oxidative stress and may be a potential target for the development of new therapeutics for cardiovascular diseases.
Pharmacological Stabilization of Intracranial Aneurysms in Mice
Authors: Makino Hiroshi , Tada Yoshiteru , Wada Kosuke , Liang Elena I. , Chang Mayland , Mobashery Shahriar , Kanematsu Yasuhisa , Kurihara Chie , Palova Emma , Kanematsu Miyuki , Kitazato Keiko , Hashimoto Tomoki
Published: July 2012

Background and Purpose—

An increasing number of unruptured intracranial aneurysms are being detected, partly due to the increased use of brain imaging techniques. Pharmacological stabilization of aneurysms for the prevention of aneurysmal rupture could potentially be an attractive alternative approach to clipping or coiling in patients with unruptured intracranial aneurysms. We have developed a mouse model of intracranial aneurysm that recapitulates key features of intracranial aneurysms. In this model, subarachnoid hemorrhage from aneurysmal rupture causes neurological symptoms that can be easily detected by a simple neurological examination. Using this model, we tested whether anti-inflammatory agents such as tetracycline derivatives, or a selective inhibitor of matrix metalloproteinases-2 and -9 (SB-3CT), can prevent the rupture of intracranial aneurysms.

Methods—

Aneurysms were induced by a combination of induced hypertension and a single injection of elastase into the cerebrospinal fluid in mice. Treatment with minocycline, doxycycline, or SB-3CT was started 6 days after aneurysm induction. Aneurysmal rupture was detected by neurological symptoms and confirmed by the presence of intracranial aneurysms with subarachnoid hemorrhage.

Results—

Minocycline and doxycycline significantly reduced rupture rates (vehicle versus doxycycline=80% versus 35%,
P
<0.05; vehicle versus minocycline=73% versus 24%,
P
<0.05) without affecting the overall incidence of aneurysms. However, SB-3CT did not affect the rupture rate (62% versus 55%,
P
=0.53).

Conclusions—

Our data established the feasibility of using a mouse model of intracranial aneurysm to test pharmacological stabilization of aneurysms. Tetracycline derivatives could be potentially effective in preventing aneurysmal rupture.
Biological Signatures of Asymptomatic Extra- and Intracranial Atherosclerosis
Authors: López-Cancio Elena , Galán Amparo , Dorado Laura , Jiménez Marta , Hernández María , Millán Mónica , Reverté Silvia , Suñol Anna , Barallat Jaume , Massuet Anna , Alzamora Maria Teresa , Dávalos Antonio , Arenillas Juan Francisco
Published: July 2012

Background and Purpose—

Intracranial atherosclerotic disease (ICAD) remains a challenge for stroke primary and secondary prevention. Molecular pathways involved in the development of ICAD from its asymptomatic stages are largely unknown. In our population-based study, we aimed to compare the risk factor and biomarker profiles associated with intracranial and extracranial asymptomatic cerebral atherosclerosis.

Methods—

The Asymptomatic Intracranial Atherosclerosis (AsIA) study cohort includes a random sample population of 933 white subjects >50 years with a moderate to high vascular risk (based on REGICOR score) and without a history of stroke (64% males; mean age, 66 years). Carotid and intracranial atherosclerosis were screened by cervical and transcranial color-coded Duplex ultrasound, being moderate to severe stenoses confirmed by MR angiography. We registered clinical and anthropometric data and created a biobank with blood samples at baseline. A panel of biomarkers involved in atherothrombogenesis was determined: C-reactive protein, asymmetric-dimethylarginine, resistin, and plasminogen activator inhibitor-1. Insulin resistance was quantified by Homeostasis Model Assessment index.

Results—

After multinomial regression analyses, male sex, hypertension, smoking, and alcoholic habits were independent risk factors of isolated extracranial atherosclerotic disease. Diabetes and metabolic syndrome conferred a higher risk for ICAD than for extracranial atherosclerotic disease. Moreover, metabolic syndrome and insulin resistance were independent risk factors of moderate to severe ICAD but were not risk factors of moderate to severe extracranial atherosclerotic disease. Regarding biomarkers, asymmetric-dimethylarginine was independently associated with isolated ICAD and resistin with combined ICAD–extracranial atherosclerotic disease.

Conclusions—

Our findings show distinct clinical and biological profiles in subclinical ICAD and extracranial atherosclerotic disease. Insulin resistance emerged as an important molecular pathway involved in the development of ICAD from its asymptomatic stage.