bluuebunny/crossref_metadata_2025 huggingface dataset:
Streptococcus mutans autolysin AtlA is a fibronectin‐binding protein and contributes to bacterial survival in the bloodstream and virulence for infective endocarditis
Authors: Jung Chiau‐Jing , Zheng Quan‐Hau , Shieh Ya‐Hsiung , Lin Chi‐Shuan , Chia Jean‐San
Published: October 2009

Streptococcus mutans, a commensal of the human oral cavity, can survive in the bloodstream and cause infective endocarditis (IE). However, the virulence factors associated with this manifestation of disease are not known. Here, we demonstrate that AtlA, an autolysin of S. mutans is a newly identified fibronectin (Fn) binding protein and contributes to bacterial resistance to phagocytosis and survival in the bloodstream. Interestingly, prior exposure to plasma at low concentrations was sufficient to enhance bacterial survival in the circulation. Calcium ions at physiological plasma concentrations induced maturation of AtlA from the 104–90 kDa isoform resulting in increased Fn binding and resistance to phagocytosis. An isogenic mutant strain defective in AtlA expression exhibited reduced survival and virulence when tested in a rat model of IE compared with the wild‐type and complemented strains. The data presented suggest that plasma components utilized by S. mutans enhanced survival in the circulation and AtlA is a virulence factor associated with infective endocarditis.
The γ‐glutamylcysteine synthetase gene of Leishmania is essential and involved in response to oxidants
Authors: Mukherjee Angana , Roy Gaétan , Guimond Chantal , Ouellette Marc
Published: October 2009

Gamma‐glutamylcysteine synthetase, encoded by the GSH1 gene, is the rate‐limiting enzyme in the biosynthesis of glutathione and of trypanothione in Leishmania. The importance of GSH1 was assessed by generating GSH1 null mutants in Leishmania infantum. Removal of even a single wild‐type allelic copy of GSH1 invariably led to the generation of an extra copy of GSH1, maintaining two intact wild‐type alleles. However, by first supplementing the parasites with a rescue plasmid, we succeeded in obtaining both a single and null chromosomal GSH1 mutants. Parasites with one intact GSH1 chromosomal allele lost the rescuing plasmid but not the double knockout, when grown in the absence of antibiotic, indicating the essentiality of the GSH1 gene in Leishmania. Heterozygous mutants with one allele‐inactivated transcribed less GSH1 mRNA and synthesized less glutathione and trypanothione. These mutants were more susceptible to oxidative stresses in vitro as promastigotes and showed decreased survival inside activated macrophages producing reactive oxygen or nitrogen species. These mutants showed a significant decreased survival in the presence of antimony (SbV) compared with control cells. All phenotypes were reverted in the add‐back mutant, thus proving the importance of thiols in dealing with oxidants including the action of antimonials.
Human milk fortifier in preterm babies: source of cow’s milk protein sensitization?
Authors: Vlieghe V. , Roches A. D. , Payot A. , Lachance C. , Nuyt A. M.
Published: October 2009

Supplements added to human milk might expose infants to allergens such as cow’s milk protein.
Prevalence of gastroesophageal reflux disease in patients with asthma and chronic obstructive pulmonary disease
Authors: Bor Serhat , Kitapcioglu Gul , Solak Zeynep Aytemur , Ertilav Muhittin , Erdinc Munevver
Published: October 2009

Background and Aim:  It is speculated that the prevalence of gastroesophageal reflux disease (GERD) might increase with asthma or chronic obstructive pulmonary disease (COPD). The aim of the present study was to evaluate the prevalence of GERD in patients with asthma and COPD in an area representative of developing countries.

Methods:  A validated GERD questionnaire was conducted face‐to‐face with 308 consecutive asthma (240 women) and 133 COPD (35 women) patients in the tertiary referral pulmonary outpatient clinic, and 694 controls from the research area. Detailed histories of patients and pulmonary function tests were also recorded.

Results:  The prevalence of GERD (heartburn/regurgitation once a week or more) was 25.4%, 17.0%, 19.4% and occasional symptoms (less than weekly) were 21.2%, 16.3% and 27.0% of patients with asthma, COPD and controls, respectively. The prevalence was higher in the asthma group compared with the controls and the COPD group. No significant difference was found between the COPD group and the controls. Heartburn started following pulmonary disease in 24.1% of the asthma group, and 26.4% of the COPD group. The majority of additional symptoms were significantly higher in asthmatics compared with the controls. No difference was found in the consumption of pulmonary medications in asthmatic patients in groups with different symptom frequency. Heartburn was increased 13.8% by the consumption of inhaler medications.

Conclusions:  These results implicate that the prevalence of GERD in asthma and COPD are lower than in published reports in a tertiary referral center. These differences might be related to the characteristics of developing countries, increased consumption of powerful medications in GERD and pulmonary diseases, or methodological flaws in earlier studies.
The use of recombinant tissue plasminogen activator in the management of infective intracardiac thrombi in pre‐term infants with thrombocytopaenia
Authors: Anderson Ben , Urs Prasanth , Tudehope David , Ward Cameron
Published: October 2009

Bacterial endocarditis complicated by the development of intra‐cardiac thrombus presents a difficult management dilemma in the pre‐term infant. Here we present our experience with three infants who had this condition, all of whom were successfully managed using therapy with recombinant tissue plasminogen activator (r‐TPA). Therapy in one of the infants was particularly instructive, as the condition was further complicated by severe thrombocytopaenia, making the decision to treat using r‐TPA difficult.
Frequency of dosing and comparative doses of mometasone furoate: A meta‐analysis
Authors: HART Kelli , WEATHERALL Mark , SHIRTCLIFFE Philippa , BEASLEY Richard
Published: October 2009

Background and objective:  To examine the evidence for the efficacy of once daily dosing of mometasone furoate (MF) and to establish the dose–response relationship for MF in asthma.

Methods:  Meta‐analysis of double‐blind, randomized controlled clinical trials, identified through a Medline and EMBASE search, comparing once versus twice daily dosing with the same dose and/or comparing two different doses that presented data on measurements of clinical efficacy. Main outcome measures were FEV1 change from baseline, PEF, withdrawals for any reason and treatment failure as defined by the authors.

Results:  Nine studies with 2533 subjects were identified, although not all had usable data for the different doses/schedules. There was no evidence of superiority of twice versus once daily dosing of MF with a pooled difference of 0.02 L (95% CI: −0.06–0.10) for FEV1 change from baseline. 400 µg was superior to 200 µg with a pooled difference of 0.09 L (95% CI: 0.04–0.13) for FEV1. Data on doses >400 µg/day were limited but did not support that 800 µg was superior to 400 µg.

Conclusions:  For the outcome variables considered, once daily dosing of MF is as effective as twice daily dosing, which may be useful in improving compliance in the treatment of asthma. There was insufficient data to compute a dose–response curve for MF.
Anomalous isolated segmental pulmonary vein dilatation detected by computerized tomography of the chest
Authors: MIYAKE Hidetoshi , ORIBE Hiroshi
Published: October 2009

This report presents findings detected on computerized tomography of the chest in three patients with dilatation of a segmental pulmonary vein and its branches. Each patient had dilatation of an isolated segmental pulmonary vein and its branches with a normal distribution, and no associated cardiovascular anomalies; in two patients, ground glass opacity corresponding to the distribution of the dilated pulmonary veins was observed. The CT features are consistent with a rare subtype of congenital pulmonary varix.
Role of ‘atypical pathogens’ among adult hospitalized patients with community‐acquired pneumonia
Authors: LUI Grace , IP Margaret , LEE Nelson , RAINER Timothy H. , MAN Shin Y. , COCKRAM Clive S. , ANTONIO Gregory E. , NG Margaret H.L. , CHAN Michael H.M. , CHAU Shirley S.L. , MAK Paulina , CHAN Paul K.S. , AHUJA Anil T. , SUNG Joseph J.Y. , HUI David S.C.
Published: October 2009

Background and objective:  Agents such as Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella pneumophila are recognized as important causes of community‐acquired pneumonia (CAP) worldwide. This study examined the role of these ‘atypical pathogens’ (AP) among adult hospitalized patients with CAP.

Methods:  A prospective, observational study of consecutive adult CAP (clinico‐radiological diagnosis) patients hospitalized during 2004–2005 was conducted. Causal organisms were determined using cultures, antigen testing and paired serology. Clinical/laboratory/radiological variables and outcomes were compared between different aetiologies, and a clinical prediction rule for AP was constructed.

Results:  There were 1193 patients studied (mean age 70.8 ± 18.0 years, men 59.3%). Causal organisms were identified in 468 (39.2%) patients: ‘bacterial’ (48.7%), ‘viral’ (26.9%), ‘AP’ (28.6%). The AP infections comprised Mycoplasma or Chlamydophila pneumoniae (97.8%) and co‐infection with bacteria/virus (30.6%). The majority of AP infections involved elderly patients (63.4%) with comorbidities (41.8%), and more than one‐third of patients were classified as ‘intermediate’ or ‘high’ risk CAP on presentation (pneumonia severity index IV–V (35.1%); CURB‐65 2–5 (42.5%)). Patients with AP infections had disease severities and outcomes similar to patients with CAP due to other organisms (oxygen therapy 29.1% vs 29.8%; non‐invasive ventilation 3.7% vs 3.3%; admission to the intensive care unit 4.5% vs 2.7%; length of hospitalization 6 day vs 7 day; 30‐day mortality: 2.2% vs 6.0%; overall P > 0.05). Age <65 years, female gender, fever ≥38.0°C, respiratory rate <25/min, pulse rate <100/min, serum sodium >130 mmol/L, leucocyte count <11 × 109/L and Hb < 11 g/dL were features associated with AP infection, but the derived prediction rule failed to reliably discriminate CAP caused by AP from bacterial CAP (area under the curve 0.75).

Conclusions:  M. pneumoniae and C. pneumoniae as single/co‐pathogens are important causes of severe pneumonia among older adults. No reliable clinical indicators exist, so empirical antibiotic coverage for hospitalized CAP patients may need to be considered.
Health and aging in a Chinese population: urban and rural disparities
Authors: Dong XinQi , Simon Melissa Andrea
Published: October 2009

Aim:  The objective of this study was to compare the rural and urban differences in sociodemographic, health and psychosocial factors in a Chinese aging population.

Methods:  A cross‐sectional descriptive study of 135 rural and 269 urban subjects aged 60 years or greater was performed in a community‐dwelling Chinese population. Variables collected included sociodemographic, health‐related and psychosocial measures.

Results:  Rural subjects, compared with urban subjects, were significantly younger, more likely to be women, have lower education and income, and more likely to be widowed. Rural subjects also reported significant lower overall health status, lower quality of life and worse change in recent health. In addition, rural subjects had a significantly higher proportion of depressive symptomatology, feelings of loneliness and lower levels of social support measures.

Conclusion:  In this older Chinese population, rural subjects had significantly poorer characteristics of health and well‐being. These differences in characteristics were found across sociodemographic, health‐related quality of life and psychosocial measures.
Novel non‐invasive approach for visualizing inflamed atherosclerotic plaques using fluorodeoxyglucose‐positron emission tomography
Authors: Kai Hisashi
Published: October 2009

There is an increasing body of evidence that a dynamic inflammatory process plays a role in the initiation, progression and destabilization of atherosclerotic plaques. The biological composition and inflammatory state of an atherosclerotic plaque, rather than the degree of stenosis or its size, are the major determinants of life‐threatening events, such as ischemic cerebrovascular accident and acute coronary syndrome. To date, there is no non‐invasive method clinically available for visualizing inflammation of individual plaques. Recently, we and others have shown that 18(F)‐fluorodeoxyglucose (FDG) uptake, namely inflammation, can be evaluated quantitatively in the aortic, carotid, iliac and femoral plaques by using FDG positron emission tomography (PET) co‐registered with computed tomography (FDG‐PET/CT). Therefore, FDG‐PET/CT, a combined functional and structural wholebody imaging modalities, holds great promise for non‐invasive evaluation of inflammation – namely, activity – of atherosclerotic plaques of large arteries.
Colonic mucosal lesions associated with long‐term or short‐term administration of nonsteroidal anti‐inflammatory drugs
Authors: Shibuya Tomoyoshi , Ohkusa Toshifumi , Yokoyama Tetsuji , Harada Akira , Beppu Kazuko , Sakamoto Naoto , Osada Taro , Nagahara Akihito , Terai Takeshi , Otaka Michiro , Ogihara Tatsuo , Watanabe Sumio
Published: October 2009

Aim  The effects of short‐ or long‐term administration of nonsteroidal anti‐inflammatory drugs (NSAIDs) on the colon have not been well characterized. We assessed the risk of developing colonic mucosal lesions according to the duration of exposure to NSAIDs: short‐term and/or long‐term use.

Method  A case‐controlled study was performed by reviewing medical records for endoscopic findings, underlying disease, pre‐endoscopic symptoms, category of NSAIDs used and duration of use. The patients underwent colonoscopy between January and October 2004, and 75 colitis cases and 1801 non‐colitis controls were identified. The prevalence of NSAID use was compared between the cases and controls. The age‐ and sex‐ adjusted odds ratios (OR) were estimated using multiple logistic regression models.

Results  NSAIDs had been used in colitis cases and non‐colitis controls for over six months in 20.0% and 12.7%, and for one week in 4.0% and 2.1%. Overall 76.0% and 85.2% had not received NSAIDs. The adjusted OR (95% confidence interval) for colonic mucosal lesions with short‐ and long term NSAID administration combined vs. non‐use was 2.04 (1.16–3.61). When determined separately for short‐ and long‐term NSAID users, the adjusted ORs were 1.48 (0.42–5.25) and 2.21 (1.19–4.11), compared to non‐users. These values signify a trend toward an increased frequency of colonic mucosal lesions with longer use of NSAIDs (P=0.011 for trend).

Conclusion  Long‐term use of NSAIDs increased the risk of colonic mucosal lesions, suggesting that NSAIDs may contribute to the pathogenesis of colonic ulcer or colitis.
Short‐term outcomes of the prospective multicentre ‘Prostate Cancer Research International: Active Surveillance’ study
Authors: Van Den Bergh Roderick C.N. , Vasarainen Hanna , Van Der Poel Henk G. , Vis‐Maters Jenneke J. , Rietbergen John B. , Pickles Tom , Cornel Erik B. , Valdagni Riccardo , Jaspars Joris J. , Van Der Hoeven John , Staerman Frederic , Oomens Eric H.G.M. , Rannikko Antti , Roemeling Stijn , Steyerberg Ewout W. , Roobol Monique J. , Schröder Fritz H. , Bangma Chris H.
Published: October 2009

Study Type – Therapy (prospective cohort) Level of Evidence 2b

OBJECTIVE

To evaluate the short‐term outcomes of the prospective international Prostate Cancer Research International: Active Surveillance (‘PRIAS’) study (Dutch Trial Register NTR1718), as active surveillance (AS) for early prostate cancer might provide a partial solution to the current overtreatment dilemma in this disease.

PATIENTS AND METHODS

The first 500 (of >950) participants with asymptomatic T1c/T2 prostate cancer, with a prostate‐specific antigen (PSA) level of ≤10.0 ng/mL, a PSA density of <0.2 ng/mL/mL, a Gleason score of ≤3 + 3 = 6, and one or two positive biopsy cores, were analysed. The follow‐up protocol consisted of frequent PSA measurements, digital rectal examinations, and standard repeat biopsies (the first after 1 year). The primary outcome is survival free of active therapy; the secondary endpoints are reasons for stopping AS, findings in 1‐year repeat biopsies, and outcomes after radical prostatectomy (RP).

RESULTS

Patients were included between December 2006 and July 2008. The median (25–75th percentile) follow‐up after diagnosis was 1.02 (0.6–1.5) years. The 2‐year survival rate free from active therapy was 73%. Of the 82 men who changed to active therapy during the follow‐up, 68 (83%) did so based on the protocol. Of the 261 repeat biopsies available for analysis, 90 (34%) showed no cancer, while 57 (22%) showed a Gleason score of >6 or more than two positive biopsy cores. There was a relatively unfavourable PSA doubling time of 0–10 years in 53% (102/194) and 62% (33/53) of men with favourable and unfavourable re‐biopsy results, respectively. After RP, four of 24 (17%) men had T3 disease and 12 (50%) had a Gleason score of >6.

CONCLUSION

AS seems feasible, but mortality outcomes are unknown. A strict follow‐up protocol including standard 1‐year repeat biopsies resulted in a quarter of men stopping AS after 2 years.
Characterization of the anatomical extension pattern of localized prostate cancer arising in the peripheral zone
Authors: Muramaki Mototsugu , Miyake Hideaki , Kurahashi Toshifumi , Takenaka Atsushi , Fujisawa Masato
Published: October 2009

Study Type – Diagnostic (non‐consecutive series) Level of Evidence 3b

OBJECTIVES

To characterize the anatomical extension pattern of prostate cancer arising in the peripheral zone (PZ) in radical prostatectomy (RP) specimens and to evaluate its prognostic significance.

PATIENTS AND METHODS

Of 174 consecutive patients undergoing RP, 128 diagnosed as having PZ cancer (PZC) were enrolled. The maximum tumour area (MTA) and maximum tumour volume (MTV) in RP specimens were measured using digital planimetry. A circle with an area equal to the MTA, in which the central point was the intersection of the longest line of the MTA and the line perpendicularly bisecting the first line, was defined as a hypothetical extension area, regardless of anatomical structure. The area within this circle that did not overlap the MTA was defined as ΔTA.

RESULTS

There was a significant correlation between the MTV and ΔTA/MTA, introduced as a variable representing the degree of PZC extension along the anatomical shape of the PZ. The ΔTA/MTA in patients with a MTV of >5 mL was significantly greater than that in those with a MTV of ≤5 mL. Furthermore, ΔTA/MTA was significantly associated with several prognostic indicators, including extracapsular extension, surgical margin status and perineural invasion. Multivariate analysis identified ΔTA/MTA in addition to preoperative serum prostate‐specific antigen level, extracapsular extension and surgical margin status as independent predictors of biochemical recurrence after RP.

CONCLUSIONS

PZC tends to extend along the anatomical shape of the PZ during progression, resulting in higher ΔTA/MTA value in advanced PZC than that in early PZC.
Accuracy and Biases in Newlyweds' Perceptions of Each Other
Authors: Luo Shanhong , Snider Anthony G.
Published: October 2009

There has been a long-standing debate about whether having accurate self-perceptions or holding positive illusions of self is more adaptive. This debate has recently expanded to consider the role of accuracy and bias of partner perceptions in romantic relationships. In the present study, we hypothesized that because accuracy, positivity bias, and similarity bias are likely to serve distinct functions in relationships, they should all make independent contributions to the prediction of marital satisfaction. In a sample of 288 newlywed couples, we tested this hypothesis by simultaneously modeling the actor effects and partner effects of accuracy, positivity bias, and similarity bias in predicting husbands' and wives' satisfaction. Findings across several perceptual domains suggest that all three perceptual indices independently predicted the perceiver's satisfaction. Accuracy and similarity bias, but not positivity bias, made unique contributions to the target's satisfaction. No sex differences were found.
No Retrieval-Induced Forgetting Under Stress
Authors: Koessler Susanne , Engler Harald , Riether Carsten , Kissler Johanna
Published: October 2009

Stress affects memory, yet no study has investigated the effects of stress on memory inhibition: Remembering not only facilitates later recall, but also inhibits retrieval of related material, a phenomenon known as retrieval-induced forgetting. We investigated the effects of stress on this mechanism, which is thought to adaptively guide memory selection. Participants learned categorized lists and were then exposed to either a psychosocial laboratory stressor or a cognitively challenging control treatment. They then actively retrieved parts of the previously learned material. Finally, memory for all initially learned items was tested. In the stress group, unlike in the control group, intervening retrieval practice did not impair final recall. Moreover, salivary Cortisol levels increased and psychological well-being decreased in the stress group only. Thus, psychosocial stress abolishes retrieval-induced forgetting. This effect may result from stress-induced hormone release from the hypothalamic-pituitary-adrenal (HPA) axis and may have implications for educational, legal, and clinical issues.
Predicting Soccer Matches After Unconscious and Conscious Thought as a Function of Expertise
Authors: Dijksterhuis Ap , Bos Maarten W. , van der Leij Andries , van Baaren Rick B.
Published: October 2009

In two experiments, we investigated the effects of expertise and mode of thought on the accuracy of people's predictions. Both experts and nonexperts predicted the results of soccer matches after conscious thought, after unconscious thought, or immediately. In Experiment 1, experts who thought unconsciously outperformed participants in all other conditions. Whereas unconscious thinkers showed a correlation between expertise and accuracy of prediction, no such relation was observed for conscious thinkers or for immediate decision makers. In Experiment 2, this general pattern was replicated. In addition, experts who thought unconsciously were better at applying diagnostic information than experts who thought consciously or who decided immediately. The results are consistent with unconscious-thought theory.
EXILE FROM PERFECTION IN IRIS MURDOCH'S PHILOSOPHICAL TEXTS
Authors: MILLIGAN TONY
Published: October 2009

Iris Murdoch's philosophical texts set out the egocentric dangers of guilt but still endorse an account of original sin. This might seem like an unstable combination as these two are in tension, but I argue that Murdoch manages to use this tension in a productive manner. The human condition is treated as one of fallenness, in the sense of an exile from perfection. We are aware of moral failure and also aware of the standard by which we fail. Guilt is reined in, however, by the fact that such failure is a matter of commonplace flawed moral vision and not an Augustinian perversity of the will. This reining in of guilt is still accompanied by a recognition of our unbridgeable remoteness from perfection.
INTENTIONALISM, INTENTIONALITY, AND REPORTING BELIEFS1
Authors: MITROVIĆ BRANKO
Published: October 2009

The dominant view of twentieth‐century analytic philosophy has been that all thinking is always in a language, that languages are vehicles of thought. The same view has been widespread in continental philosophy as well. In recent decades, however, the opposite view—that languages serve merely to express language‐independent thought‐contents or propositions—has been more widely accepted. The debate has a direct equivalent in the philosophy of history: when historians report the beliefs of historical figures, do they report the sentences or propositions that these historical figures believed to be true or false? In this paper I argue in favor of the latter, intentionalist, view. My arguments center mostly on the problems with translation that are likely to arise when a historian reports the beliefs of historical figures who expressed them in a language other than the one in which the historian is writing. In discussing these problems the paper presents an application of John Searle's theory of intentionality to the philosophy of history.
2. THE VICTIM'S VOICE AND MELODRAMATIC AESTHETICS IN HISTORY1
Authors: GOLDBERG AMOS
Published: October 2009

Saul Friedländer's recent Nazi Germany and the Jews: The Years of Extermination offers a brilliant new literary mode for historical representation of extreme events such as the Holocaust. He has produced an authoritative historical narrative of the Holocaust, within which he integrates the victims' authentic voices, as recorded (mostly) in their contemporary writings. This article offers a comparative assessment of Friedländer's achievement with regard to the integration of Jewish sources into the historical account. It begins with a contextualization of Friedländer's book within a framework that compares the ways in which Jewish sources are addressed by different historiographical approaches. In the second part it seeks to contextualize analytically and critically Friedländer's concept of “disbelief”—a concept by which he defines the role of the “victims’ voices” in his narrative. I claim that in our current “era of the witness,” set within a culture addicted to the “excessive,” the voices of the victims and the witnesses appear to have lost their radical political and ethical force. They seem no longer to bear the excess of history, and can thus hardly claim to be the guardians of disbelief. Excess and disbelief have thus become the most commonplace cultural topos. In our current culture, I contend, the excessive voices of the victims have, to some extent, exchanged their epistemological, ontological, and ethical revolutionary function for an aesthetic one. They operate according to the pleasure principle in order to bring us, the consumers of Holocaust images, the most expected image of the “unimaginable,” which therefore generates a melancholic pleasure and involves the narrative in melodramatic aesthetics. The article concludes by briefly suggesting some guidelines for an alternative approach to the study of contemporary Jewish Holocaust sources.
The Role of the Business Press as an Information Intermediary
Authors: BUSHEE BRIAN J. , CORE JOHN E. , GUAY WAYNE , HAMM SOPHIA J.W.
Published: October 2009

This paper investigates whether the business press serves as an information intermediary. The press potentially shapes firms' information environments by packaging and disseminating information, as well as by creating new information through journalism activities. We find that greater press coverage reduces information asymmetry (i.e., lower spreads and greater depth) around earnings announcements, with broad dissemination of information having a bigger impact than the quantity or quality of press‐generated information. These results are robust to controlling for firm‐initiated disclosures, market reactions to the announcement, and other information intermediaries. Our findings suggest that the press helps reduce information problems around earnings announcements.
Political Cost Incentives for Managing the Property‐Liability Insurer Loss Reserve
Authors: GRACE MARTIN F. , LEVERTY J. TYLER
Published: October 2009

This paper examines the effect of rate regulation on the management of the property‐liability insurer loss reserve. The political cost hypothesis predicts that managers make accounting choices to reduce wealth transfers resulting from the regulatory process. Managers may under‐state reserves to justify lower rates to regulators. Alternatively, managers may have an incentive to report loss inflating discretionary reserves to reduce the cost of regulatory rate suppression. We find insurers over‐state reserves in the presence of stringent rate regulation. Investigating the impact along the conditional reserve error distribution, we discover that a majority of the response occurs from under‐reserving firms under‐reserving less because of stringent rate regulation.
Cloning and pharmacological characterization of the dog P2X7 receptor
Authors: Roman S , Cusdin FS , Fonfria E , Goodwin JA , Reeves J , Lappin SC , Chambers L , Walter DS , Clay WC , Michel AD
Published: October 2009

Background and purpose:  Human and rodent P2X7 receptors exhibit differences in their sensitivity to antagonists. In this study we have cloned and characterized the dog P2X7 receptor to determine if its antagonist sensitivity more closely resembles the human or rodent orthologues.

Experimental approach:  A cDNA encoding the dog P2X7 receptor was isolated from a dog heart cDNA library, expressed in U‐2 OS cells using the BacMam viral expression system and characterized in electrophysiological, ethidium accumulation and radioligand binding studies. Native P2X7 receptors were examined by measuring ATP‐stimulated interleukin‐1β release in dog and human whole blood.

Key results:  The dog P2X7 receptor was 595 amino acids long and exhibited high homology (>70%) to the human and rodent orthologues although it contained an additional threonine at position 284 and an amino acid deletion at position 538. ATP possessed low millimolar potency at dog P2X7 receptors. 2′‐&3′‐O‐(4benzoylbenzoyl) ATP had slightly higher potency but was a partial agonist. Dog P2X7 receptors possessed relatively high affinity for a number of selective antagonists of the human P2X7 receptor although there were some differences in potency between the species. Compound affinities in human and dog blood exhibited a similar rank order of potency as observed in studies on the recombinant receptor although absolute potency was considerably lower.

Conclusions and implications:  Dog recombinant and native P2X7 receptors display a number of pharmacological similarities to the human P2X7 receptor. Thus, dog may be a suitable species for assessing target‐related toxicity of antagonists intended for evaluation in the clinic.
Dysfunction of endothelial and smooth muscle cells in small arteries of a mouse model of Marfan syndrome
Authors: Syyong HT , Chung AWY , Yang HHC , van Breemen C
Published: October 2009

Background and purpose:  Marfan syndrome, a connective tissue disorder caused by mutations in FBN1 encoding fibrillin‐1, results in life‐threatening complications in the aorta, but little is known about its effects in resistance vasculature.

Experimental approach:  Second‐order mesenteric arteries from mice at 3, 6 and 10 months of age (n= 30) heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1C1039G/+) were compared with those from age‐matched control littermates.

Key results:  Stress–strain curves indicated that arterial stiffness was increased at 6 and 10 months of age in Marfan vessels. Isometric force measurement revealed that contraction in response to potassium (60 mM)‐induced membrane depolarization was decreased by at least 28% in Marfan vessels at all ages, while phenylephrine (3 µM)‐induced contraction was reduced by at least 40% from 6 months. Acetylcholine‐induced relaxation in Marfan vessels was reduced to 70% and 45% of control values, respectively, at 6 and 10 months. Sensitivity to sodium nitroprusside was reduced at 6 months (pEC50= 5.64 ± 0.11, control pEC50= 7.34 ± 0.04) and 10 months (pEC50= 5.99 ± 0.07, control pEC50= 6.99 ± 0.14). Pretreatment with Nω‐Nitro‐L‐arginine methyl ester (200 µM) had no effect on acetylcholine‐induced relaxation in Marfan vessels, but reduced vasorelaxation in control vessels to 57% of control values. Addition of indomethacin (10 µM) and catalase (1000 U·mL−1) further inhibited vasorelaxation in Marfan vessels to a greater degree compared with control vessels.

Conclusions and implications:  Pathogenesis of Marfan syndrome in resistance‐sized arteries increases stiffness and impairs vasomotor function.
Tobacco smoke affects expression of peroxisome proliferator‐activated receptor‐γ in monocyte/macrophages of patients with coronary heart disease
Authors: Amoruso A , Gunella G , Rondano E , Bardelli C , Fresu LG , Ferrero V , Ribichini F , Vassanelli C , Brunelleschi S
Published: October 2009

Background and purpose: Tobacco smoke represents a relevant risk factor for coronary heart disease (CHD). Although peroxisome proliferator‐activated receptor (PPAR)γ activation reduces inflammation and atherosclerosis, expression of PPARγ in cells and its modulation by smoking are poorly investigated. We previously reported that monocyte/macrophages from healthy smokers exhibited an enhanced constitutive expression of PPARγ. Here, we evaluated PPARγ expression and basal cytokine release in monocytes and monocyte‐derived macrophages (MDMs) from 85 CHD patients, classified by their smoking habit (smokers, non‐smokers and ex‐smokers), and assessed the role of PPARγ ligands in this context.

Experimental approach: PPARγ protein was detected by Western blot and semi‐quantified by PPARγ/β‐actin ratio; cytokine release was measured byelisaand nuclear factor‐kappaB (NF‐κB) translocation by electrophoretic mobility shift assays.

Key results: As compared to the other groups, MDMs from smoker CHD patients exhibited a reduced PPARγ/β‐actin ratio and an increased spontaneous release of tumour necrosis factor‐α (TNF‐α) and interleukin‐6, but with no major variations in monocytes. In cells from selected CHD patients, rosiglitazone inhibited TNF‐α release and NF‐κB translocation induced by phorbol‐12‐myristate 13‐acetate. The selective PPARγ antagonist GW9662 reversed these effects, with some variations related to smoking habit.

Conclusions and implications: In CHD patients, exposure to tobacco smoke profoundly affected PPARγ expression, and this was related to levels of secretion of pro‐inflammatory cytokines. MDMs from CHD smokers showed the lowest PPARγ expression and released more inflammatory cytokines. Moreover, rosiglitazone's ability to inhibit cytokine release and its reversal by GW9662 clearly indicated PPARγ involvement in these changes in CHD patients.
Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertension
Authors: Agard C , Rolli‐Derkinderen M , Dumas‐de‐La‐Roque E , Rio M , Sagan C , Savineau JP , Loirand G , Pacaud P
Published: October 2009

Background and purpose:  Pulmonary arterial hypertension (PAH) is associated with increased contraction and proliferation of pulmonary vascular smooth muscle cells. The anti‐diabetic drug metformin has been shown to have relaxant and anti‐proliferation properties. We thus examined the effect of metformin in PAH.

Experimental approach:  Metformin effects were analysed in hypoxia‐ and monocrotaline‐induced PAH in rats. Ex vivo and in vitro analyses were performed in lungs, pulmonary artery rings and cells.

Key results:  In hypoxia‐ and monocrotaline‐induced PAH, the changes in mean pulmonary arterial pressure and right heart hypertrophy were nearly normalized by metformin treatment (100 mg·kg−1·day−1). Pulmonary arterial remodelling occurring in both experimental models of PAH was also inhibited by metformin treatment. In rats with monocrotaline‐induced PAH, treatment with metformin significantly increased survival. Metformin increased endothelial nitric oxide synthase phosphorylation and decreased Rho kinase activity in pulmonary artery from rats with PAH. These effects are associated with an improvement of carbachol‐induced relaxation and reduction of phenylephrine‐induced contraction of pulmonary artery. In addition, metformin inhibited mitogen‐activated protein kinase activation and strongly reduced pulmonary arterial cell proliferation during PAH. In vitro, metformin directly inhibited pulmonary artery smooth muscle cell growth.

Conclusions and implications:  Metformin protected against PAH, regardless of the initiating stimulus. This protective effect may be related to its anti‐remodelling property involving improvement of endothelial function, vasodilatory and anti‐proliferative actions. As metformin is currently prescribed to treat diabetic patients, assessment of its use as a therapy against PAH in humans should be easier.
FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system
Authors: Brinkmann Volker
Published: October 2009

FTY720 (fingolimod) is a first‐in‐class sphingosine 1‐phosphate (S1P) receptor modulator that was highly effective in Phase II clinical trials for Multiple Sclerosis (MS). FTY720 is phosphorylated in vivo by sphingosine kinase‐2 to form the active moiety FTY720‐phosphate that binds to four of the five G protein‐coupled S1P receptor subtypes. Studies using conditional S1P1 receptor‐deficient and sphingosine kinase‐deficient mice showed that the egress of lymphocytes from lymph nodes requires signalling of lymphocytic S1P1 receptors by the endogenous ligand S1P. The S1P mimetic FTY720‐phosphate causes internalization and degradation of cell membrane‐expressed S1P1, thereby antagonizing S1P action at the receptor. In models of human MS and demyelinating polyneuropathies, functional antagonism of lymphocytic S1P1 slows S1P‐driven egress of lymphocytes from lymph nodes, thereby reducing the numbers of autoaggressive TH17 cells that recirculate via lymph and blood to the central nervous system and the sciatic/ischiatic nerves. Based on its lipophilic nature, FTY720 crosses the blood–brain barrier, and ongoing experiments suggest that the drug also down‐modulates S1P1 in neural cells/astrocytes to reduce astrogliosis, a phenomenon associated with neurodegeneration in MS. This may help restore gap‐junctional communication of astrocytes with neurons and cells of the blood–brain barrier. Additional effects may result from (down‐) modulation of S1P3 in astrocytes and of S1P1 and S1P5 in oligodendrocytes. In conclusion, FTY720 may act through immune‐based and central mechanisms to reduce inflammation and support structural restoration of the central nervous system parenchyma. Beyond the autoimmune indications, very recent studies suggest that short‐term, low‐dose administration of FTY720 could help treat chronic (viral) infections. Differential effects of the drug on the trafficking of naïve, central memory and effector memory T cell subsets are discussed.
Expanding Access to Triptans: Assessment of Clinical Outcome
Authors: Cady Roger K. , Goldstein Jerome , Silberstein Stephen , Juhász Márta , Ramsey Karen , Rodgers Anthony , Hustad Carolyn M. , Ho Tony
Published: October 2009

Objective.— To evaluate whether access to more liberal quantities of rizatriptan improves clinical outcome in patients with episodic migraine.

Background.— Currently many pharmacy benefit programs limit the number of triptan tablets/injections per month based on perceived cost savings and the belief that too‐frequent use of triptans may lead to medication overuse headache and headache chronification.

Methods.— This observer‐blind, randomized, parallel‐group study enrolled 197 subjects with migraine with or without aura. Subjects completed a 3‐month baseline period to establish migraine frequency and then were randomly assigned to receive 9 (formulary limit [FL]) or 27 (clinical limit [CL]) tablets of 10 mg rizatriptan orally disintegrating tablet (ODT) per month for 3 months. The primary endpoint was change in the mean number of migraine days from the baseline to treatment period.

Results.— There was no statistically significant difference between the FL and CL groups in mean number of migraine days (FL‐CL LS mean: −0.08 [−0.39, 0.23]; P = .613). Subjects in the CL group treated attacks at lower headache severity. No CL subjects were reported to have developed chronic migraine despite utilization of greater than 10 rizatriptan ODT tablets per month. Rizatriptan was generally well tolerated by both groups.

Conclusion.— Providing a greater quantity of rizatriptan ODT 10 mg did not reduce the number of migraine days compared with providing 9 tablets per month for this population with episodic migraine with a frequency of 3‐8 migraines per month. Regardless of quantity provided, rizatriptan was generally well tolerated.
Adherence to Acute Migraine Medication: What Does It Mean, Why Does It Matter?
Authors: Katić Božena J. , Krause Steven J. , Tepper Stewart J. , Hu Henry X. , Bigal Marcelo E.
Published: October 2009

(Headache 2010;50:117‐129)

Proper use of medications is an important part of successfully managing migraine headache, yet migraineurs frequently switch, discontinue, or delay taking effective prescription therapies such as triptans. Medication persistence in the treatment of chronic‐episodic disorders such as migraine is not well understood. In this article we review this topic, by critically reviewing studies conducted using pharmacy claims, clinical records, survey, and patient‐reported data to explore acute medication use for migraine headache. While efficacy, cost, drug tolerability, and side effects impact whether a patient takes migraine medication, low perceived disease importance and factors related to the patient's internal decision‐making process play a strong role in the sustained use of acute medication for migraine attack. We propose a model that combines the patient's perceived severity of migraine, their beliefs regarding the safety of acute medications, and factors related to the physician–patient relationship to identify migraineurs at high risk for medication adherence problems.
Cerebellar Tonsillar Herniation After Weight Loss in a Patient With Idiopathic Intracranial Hypertension
Authors: Graber Jerome J. , Racela Rikki , Henry Katherine
Published: October 2009

(Headache 2010;50:146‐148)

Acquired cerebellar tonsillar herniation is a known complication of lumboperitoneal shunt (LPS) for any indication, including idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri.1 While the underlying pathophysiology of IIH remains unknown, increasing body mass index is a clear risk factor for the development of IIH. We describe an obese patient with IIH unresponsive to LPS who developed symptoms of intracranial hypotension and cerebellar tonsillar herniation after bariatric surgery and a 50‐kg weight loss.
Refractory status epilepticus: A prospective observational study
Authors: Novy Jan , Logroscino Giancarlo , Rossetti Andrea O.
Published: October 2009

Purpose:  Status epilepticus (SE) that is resistant to two antiepileptic compounds is defined as refractory status epilepticus (RSE). In the few available retrospective studies, estimated RSE frequency is between 31% and 43% of patients presenting an SE episode; almost all seem to require a coma induction for treatment. We prospectively assessed RSE frequency, clinical predictors, and outcome in a tertiary clinical setting.

Methods:  Over 2 years we collected 128 consecutives SE episodes (118 patients) in adults. Clinical data and their relationship to outcome (mortality and return to baseline clinical conditions) were analyzed.

Results:  Twenty‐nine of 128 SE episodes (22.6%) were refractory to first‐ and second‐line antiepileptic treatments. Severity of consciousness impairment and de novo episodes were independent predictors of RSE. RSE showed a worse outcome than non‐RSE (39% vs. 11% for mortality; 21% vs. 63% for return to baseline clinical conditions). Only 12 patients with RSE (41%) required coma induction for treatment.

Discussion:  This prospective study identifies clinical factors predicting the onset of SE refractoriness. RSE appears to be less frequent than previously reported in retrospective studies; furthermore, most RSE episodes were treated outside the intensive care unit (ICU). Nonetheless, we confirm that RSE is characterized by high mortality and morbidity.
An optimized voxel‐based morphometric study of gray matter changes in patients with left‐sided and right‐sided mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE/HS)
Authors: Pail Martin , Brázdil Milan , Mareček Radek , Mikl Michal
Published: October 2009

Purpose:  To determine whether changes in gray matter volume (GMV) differ according to the affected side in mesial temporal lobe epilepsy/hippocampal sclerosis (MTLE/HS) syndrome, and moreover to test the hypothesis of more pronounced structural changes in right‐sided MTLE/HS. This hypothesis (especially that the contralateral thalamus is more affected in right‐sided MTLE/HS) arose from the results of our recent study, wherein more expressed structural and functional changes were observed in a small sample of patients with right‐sided MTLE/HS (Brázdil et al., 2009).

Methods:  Twenty patients with left‐sided and 20 with right‐sided MTLE/HS and 40 sex‐ and age‐matched healthy controls were included in the study. Voxel‐based morphometry (VBM) with a modulation step was applied to magnetic resonance imaging (MRI) brain images. Statistical parametric maps were used to compare structural changes between patients and controls separately for the left‐ and right‐sided MTLE/HS subgroups. We also compared the local GMV of the brain structures (insula and thalamus) between the subgroups of patients.

Results:  In the subgroup with right‐sided MTLE/HS, a reduction of GMV was detected in the mesiotemporal structures and the ipsilateral thalamus (as in left‐sided MTLE/HS), but also notably in the ipsilateral insula and contralateral thalamus. A statistical analysis revealed a significantly more extensive reduction of GMV in the ipsilateral/contralateral insula and the contralateral thalamus in the subgroup with right‐sided compared to left‐sided MTLE/HS.

Conclusion:  We found asymmetrical morphologic changes in patients with left‐ and right‐sided MTLE/HS syndrome (more pronounced in right‐sided MTLE/HS). These differences could be theoretically explained by different neuronal networks and pathophysiologic changes in temporolimbic structures.
Clinical significance of glutamic acid decarboxylase antibodies in patients with epilepsy
Authors: Liimatainen Suvi , Peltola Maria , Sabater Lidia , Fallah Mahdi , Kharazmi Elham , Haapala Anna‐Maija , Dastidar Prasun , Knip Mikael , Saiz Albert , Peltola Jukka
Published: October 2009

Purpose:  Glutamic acid decarboxylase antibodies (GADAs) have been detected in patients with epilepsy, but the clinical determinants of epilepsy associated with GADA have not been defined.

Methods:  We analyzed GADA with a radioimmunoassay in sera of 253 well‐characterized patients with epilepsy and 200 control subjects. The positive samples were confirmed by immunohistochemistry and western blotting (WB). Sera were screened for other autoantibodies.

Results:  GADA were detected in 15 patients (5.9%) and in three control subjects (1.5%) (p = 0.026). Seven patients (2.8%) had high GADA titers [≥1,000 relative units (RUs)/ml], six of whom had temporal lobe epilepsy (TLE). All three GADA‐positive control subjects had low titers. Two of the five patients with high GADA titers and available cerebrospinal fluid (CSF) samples had intrathecal synthesis (IS) of GADA; one patient had CSF oligoclonal bands. The prevalence of increased levels of GADA tended to be higher in patients with TLE than in patients with extra‐TLE [odds ratio (OR) 1.32, 95% confidence interval (CI) 0.39–4.42; p = 0.657]. The patients with high GADA titers had significantly higher number of other autoantibodies compared to the patients with low GADA titers (p = 0.001) and the patients with normal GADA (p < 0.001).

Discussion:  High GADA titers were present in a subgroup of patients; close to 90% had TLE. The immunologic profile of these patients suggests that the most probable origin of their epilepsy is autoimmune. A positive IS of GADA may be a marker of an ongoing immune response that could identify those patients in whom a trial with immunosuppressive therapy might be warranted.