bluuebunny/crossref_metadata_2025 huggingface dataset:
PPARγ expression profile and its cytokine driven regulation in atopic dermatitis
Authors: Dahten A. , Mergemeier S. , Worm M.
Published: July 2007

Background:  Recent studies point to the pathophysiological role of the peroxisome proliferators‐activated receptor gamma (PPARγ) in the inflammatory immune response. We have showed that activation of PPARγ by specific ligands attenuates the allergic immune response via monocytes and lymphocytes. The objective of this study was to analyse the PPARγ expression and its regulation via inflammatory cytokines.

Methods:  We examined the PPARγ expression in the lesional and nonlesional skin of atopic patients by immunohistochemistry. The expression patterns of PPARγ mRNA and its isoforms were investigated in peripheral mononuclear blood cells of atopic and nonatopic donors and in cytokine‐stimulated populations by quantitative real‐time RT‐PCR.

Results:  Our data show an increased PPARγ expression in lesional skin from atopic dermatitis patients. The analysis of PPARγ mRNA reveals a significantly up‐regulated expression of PPARγ1 but not of PPARγ2 in monocytes and CD4+ T‐cells from atopic dermatitis patients. Furthermore, we demonstrate that Th‐cytokines, like IL‐4, IL‐13 and IFNγ, which regulate the biphasic atopic immune response, directly regulate the expression of PPARγ1.

Conclusion:  Taken together, these data demonstrate that PPARγ isoforms are differently expressed and regulated by the local cytokine‐milieu. Whether the increased expression of the PPARγ1 receptor may be beneficial or not for a PPARγ ligand‐based treatment of atopic dermatitis, is currently under investigation.
Validation study of the lambda model for predicting the BRCA1 or BRCA2 mutation carrier status of North American Ashkenazi Jewish women
Authors: Apicella C , Dowty JG , Dite GS , Jenkins MA , Senie RT , Daly MB , Andrulis IL , John EM , Buys SS , Li FP , Glendon G , Chung W , Ozcelik H , Miron A , Kotar K , Southey MC , Foulkes WD , Hopper JL
Published: July 2007

lambda is a model that estimates the probability an Ashkenazi Jewish (AJ) woman carries an ancestral BRCA1 or BRCA2 mutation from her personal and family cancer history. lambda is relevant to clinical practice, and its implementation does not require a computer. It was developed principally from Australian and UK data. We conducted a validation study using 1286 North American AJ women tested for the mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Most had a personal or family history of breast cancer. We observed 197 carriers. The area under the receiver operator characteristic (ROC) curve (a measure of ranking) was 0.79 [95% confidence interval (CI) = 0.77–0.81], similar to that for the model‐generating data (0.78; 95% CI = 0.75–0.82). lambda predicted 232 carriers (18% more than observed; p = 0.002) and was overdispersed (p = 0.009). The Bayesian computer program brcapro gave a similar area under the ROC curve (0.78; 95% CI = 0.76–0.80), but predicted 367 carriers (86% more than observed; p < 0.0001), and was substantially overdispersed (p < 0.0001). Therefore, lambda is comparable to brcapro for ranking AJ women according to their probability of being a BRCA1 or BRCA2 mutation carrier and is more accurate than brcapro which substantially overpredicts carriers in this population.
High‐resolution oligonucleotide array‐CGH applied to the detection and characterization of large rearrangements in the hereditary breast cancer gene BRCA1
Authors: Rouleau E , Lefol C , Tozlu S , Andrieu C , Guy C , Copigny F , Nogues C , Bieche I , Lidereau R
Published: July 2007

We have developed a new method for detecting and characterizing large rearrangements in the BRCA1 gene based on high‐resolution oligonucleotide array‐CGH technology. We designed a specific CGH array for the BRCA1 gene and its flanking regions. We then used this approach to analyze nine DNA samples known to contain large deletions and large duplications. When possible, the deleted or duplicated region was sequenced to identify the break point. All the large rearrangements were detected by the new method, and their size was estimated to be within 1–2 kb. This enabled us to develop a simple polymerase chain reaction screening test for other family members. A refined choice of oligonucleotides should improve the precision of the breakpoint determination. Finally, the high resolution of oligonucleotide array‐CGH should help to detect new large rearrangements missed by other current methods.
Doctor – How do I use my EpiPen?
Authors: Mehr Sam , Robinson Marnie , Tang Mimi
Published: July 2007

Parents and children who have been prescribed an Epipen are often unable to demonstrate its correct administration. One contributory factor may be that doctors are unfamiliar with the EpiPen and are unable to demonstrate the correct administration of the pen to the family. The aim of this study was to determine the rate of correct EpiPen demonstration by junior and Senior Medical Staff at a major tertiary paediatric Hospital. Junior and Senior medical staff were scored on their ability to correctly use the EpiPen trainer. A 6 step scoring system was used. One‐hundred doctors were recruited (Residents n = 31, Senior Residents n = 39, Fellow/Consultants n = 30). Junior and Senior Medical staff had similar scores for EpiPen demonstration, the number that needed to read the EpiPen instructions prior to use and the frequancy of accidental self‐injection into the thumb. Only two doctors (2%) demonstrated all 6 administration steps correctly. The most frequent errors made were not holding the pen in place for >5 seconds (57%), failure to apply pressure to activate (21%), and self‐injection into the thumb (16%). Ninety five doctors needed to read the instructions, and of these, only 39 (41%) then proceeded to correctly demonstrate the remaining 5 steps. Forty‐five doctors had previously dispensed an EpiPen, but only three demonstrated its use to parents/children with a trainer. The majority of doctors do not know how to use an Epipen and are unable to provide appropriate education to parents/children. In 37% of cases, the demonstration would not have delivered adrenaline to a patient.
Suppressive effects of ketotifen on Th1‐ and Th2‐related chemokines of monocytes
Authors: Hung Chih‐Hsing , Suen Jau‐Ling , Hua Yi‐Ming , Chiang Wen , Chang Hui‐Chiu , Chen Chun‐Nan , Jong Yuh‐Jyh
Published: July 2007

Ketotifen is a mast cell stabilizer and useful in younger children with allergic diseases such as asthma and allergic rhinitis. Macrophage‐derived chemokine (MDC) is a T‐helper cell type 2 (Th2)‐related chemokine involved in recruitment of Th2 cells toward allergen‐challenged inflammation. However, the Th1‐related chemokines, interferon‐inducible protein 10 (IP‐10) /CXCL10, and the monokine induced by interferon‐gamma (MIG)/CXCL9 are also important in allergen‐induced asthma in animal models. We investigated the effects of ketotifen on the expression of Th1‐ and Th2‐related chemokines of human monocytesin vitroandex vivo. Ketotifen (5–50 μm) significantly down‐regulated lipopolysaccharide (LPS)‐induced MDC, MIG and IP‐10 (p < 0.05, each comparison) in THP‐1 cells and human primary monocytes in a dose‐dependent manner. SB203580 [p38‐mitogen‐activated protein kinase (MAPK) inhibitor] suppressed LPS‐induced MDC and IP‐10 expression, and PD98059 (ERK–MAPK inhibitor) could only suppress LPS‐induced IP‐10, but not MDC expression. LPS‐induced pp38 and p‐ERK expression of THP‐1 monocytic cells was suppressed by ketotifen. These data demonstrate that ketotifen is effective in down‐regulating LPS‐induced MDC, MIG and IP‐10, which play important roles in the pathogenesis of airway inflammation. The suppressive effect on MDC and IP‐10 may, at least in part, involve the down‐regulation of LPS‐induced p38 and ERK–MAPK expression.
Influence of measles vaccination on the progression of atopic dermatitis in infants
Authors: Hennino Anà , Cornu Catherine , Rozieres Aurore , Augey Frédéric , Villard‐Truc Florence , Payot François , Lachaux Alain , Nicolas Jean‐François , Horvat Branka
Published: July 2007

Atopic dermatitis (AD) is a chronic inflammatory skin disease, affecting 10–20% of children. Measles vaccination has been reported to have contradictory effects on incidence of AD in children. Therefore, we performed the first prospective, double‐blind, placebo‐controlled study to analyze the evolution of AD in infants after measles vaccination. The study included 12 infants (10–14 months old) with AD, randomly assigned to two groups: while the first group received a single dose of a standard measles vaccine ROUVAX, the second was treated with placebo (vehicle). Infants were followed‐up for 6 months after administration of ROUVAX/placebo for the clinical signs associated with AD, by determination of SCORAD index. In addition, serum was taken before vaccination and 1 month later to determine the presence of seroconversion and to analyze the progression of serum levels of CCL18 (PARC) and E‐selectin, known to be distinct serum markers that reflect clinical features of AD. In the vaccinated group, five of six children seroconverted 1 month after treatment and one infant showed a 50% improvement of SCORAD. Serum levels of CCL18 were significantly decreased in two treated infants (of four analyzed for this group) and E‐selectin slightly decreased in one infant (of three analyzed by this test). In placebo‐treated group the SCORAD improved in one patient and serum levels of CCL18 and E‐selectin did not change. These data suggest that measles vaccination not only does not aggravate AD, but may also improve some of the immunological parameters of this allergic disease. Inclusion of a higher number of patients in a similar study should give a more comprehensive overview of the benefit of measles vaccination on the clinical evolution of AD patients, and potentially open new avenues to the clinical application of the anti‐inflammatory effect of measles virus proteins.
Comparison of the efficacy and safety of ciclesonide 160 μg once daily vs. budesonide 400 μg once daily in children with asthma
Authors: Von Berg Andrea , Engelstätter Renate , Minic Predrag , Sréckovic Miodrag , Garcia Maria Luz Garcia , Latoś Tadeusz , Vermeulen Jan H. , Leichtl Stefan , Hellbardt Stefan , Bethke Thomas D.
Published: July 2007

Ciclesonide is an onsite‐activated inhaled corticosteroid (ICS) for the treatment of asthma. This study compared the efficacy, safety and effect on quality of life (QOL) of ciclesonide 160 μg (ex‐actuator; nominal dose 200 μg) vs. budesonide 400 μg (nominal dose) in children with asthma. Six hundred and twenty‐one children (aged 6–11 yr) with asthma were randomized to receive ciclesonide 160 μg (ex‐actuator) once daily (via hydrofluoroalkane metered‐dose inhaler and AeroChamber PlusTM spacer) or budesonide 400 μg once daily (via Turbohaler®) both given in the evening for 12 wk. The primary efficacy end‐point was change in forced expiratory volume in 1 s (FEV1). Additional measurements included change in daily peak expiratory flow (PEF), change in asthma symptom score sum, change in use of rescue medication, paediatric and caregiver asthma QOL questionnaire [PAQLQ(S) and PACQLQ, respectively] scores, change in body height assessed by stadiometry, change in 24‐h urinary cortisol adjusted for creatinine and adverse events. Both ciclesonide and budesonide increased FEV1, morning PEF and PAQLQ(S) and PACQLQ scores, and improved asthma symptom score sums and the need for rescue medication after 12 wk vs. baseline. The non‐inferiority of ciclesonide vs. budesonide was demonstrated for the change in FEV1 (95% confidence interval: −75, 10 ml, p = 0.0009, one‐sided non‐inferiority, per‐protocol). In addition, ciclesonide and budesonide showed similar efficacy in improving asthma symptoms, morning PEF, use of rescue medication and QOL. Ciclesonide was superior to budesonide with regard to increases in body height (p = 0.003, two‐sided). The effect on the hypothalamic–pituitary–adrenal axis was significantly different in favor of ciclesonide treatment (p < 0.001, one‐sided). Both ciclesonide and budesonide were well tolerated. Ciclesonide 160 μg once daily and budesonide 400 μg once daily were effective in children with asthma. In addition, in children treated with ciclesonide there was significantly less reduction in body height and suppression of 24‐h urinary cortisol excretion compared with children treated with budesonide after 12 wk.
Home environment and suspected atopic eczema in Japanese infants: The Osaka Maternal and Child Health Study
Authors: Miyake Yoshihiro , Ohya Yukihiro , Tanaka Keiko , Yokoyama Tetsuji , Sasaki Satoshi , Fukushima Wakaba , Ohfuji Satoko , Saito Kyoko , Kiyohara Chikako , Hirota Yoshio ,   for the Osaka Maternal and Child Health Study Group
Published: July 2007

Atopic eczema is most commonly diagnosed in children under the age of 5 yr. Environmental factors during pregnancy or in early life may confer risk for childhood atopic eczema. The present prospective study examined the relationship of the perinatal home environment and the risk of suspected atopic eczema among Japanese infants under the age of 1. Study subjects were 865 parent–child pairs. The term ‘suspected atopic eczema’ was used to define an outcome based on our questionnaire at 2–9 months postpartum. Adjustment was made for maternal age, gestation, family income, maternal and paternal education, maternal and paternal history of asthma, atopic eczema, and allergic rhinitis, time of delivery before the second survey, baby's older siblings, baby's sex, and baby's birth weight. A high mite allergen level from maternal bedclothes and mold in the kitchen during pregnancy were significantly associated with an increased risk of suspected atopic eczema. Frequent vacuuming practices during pregnancy and giving the infant a bath or shower at least once a day were significantly inversely related to the risk of suspected atopic eczema. Maternal smoking, maternal use of a synthetic duvet and pillow, carpet use in the living room and maternal bedroom, indoor domestic pets, no ducted heating appliance, and gas use for cooking during pregnancy and household smoking in the same room as the infant, infant's synthetic duvet, carpet use in the infant's room, or vacuuming the infant's room were not related to the risk of suspected atopic eczema. High house dust mite allergen levels and mold in the kitchen during pregnancy may increase the risk of infantile atopic eczema, whereas frequent vacuuming practices during pregnancy and giving the infant a bath or shower at least once a day may protect against infantile atopic eczema.
Food‐dependent exercise‐induced anaphylaxis in childhood
Authors: Toit George Du
Published: July 2007

The clinical syndrome of food‐dependent exercise‐induced anaphylaxis (FDEIA) is typified by the onset of anaphylaxis during (or soon after) exercise which was preceded by the ingestion of the causal food allergen/s. In FDEIA, both the food allergen/s and exercise are independently tolerated. FDEIA is an uncommon allergic condition in childhood, but nonetheless is an important differential diagnosis to be considered when faced by a child who has experienced exercise‐associated anaphylaxis. The diagnosis of FDEIA is heavily dependent on the clinical history. Allergy tests may need to be performed to a broad panel of food and food additives. Modified exercise challenges (performed with and without prior ingestion of food) are frequently required as allergy test results frequently return low‐positive results. A diagnosis of FDEIA facilitates the safe independent return to exercise and reintroduction of foods for patients who otherwise may unnecessarily avoid exercise and/or restrict their diet. The natural history of FDEIA is unknown; however, a safe return is usually achieved when the ingestion of the causal food allergen/s and exercise are separated.
Two compromises: Victorian and Bismarckian
Authors: Rintala Marvin
Published: July 2007

EVERY POLITICAL SYSTEM, WHETHER IT IS PREDEMOCRATIC, DEMOcratic, or postdemocratic totalitarian, has both leaders and followers. All those who are leaders – in other words, all those who exercise power over followers – can be grouped together under the category of the ruling class. Any ruling class, to be such, obviously must be accepted by those who are ruled. Human beings are followers only if they choose to follow. Leaders must have recognition and at least some degree of consent from followers to be leaders. This is the necessary condition for possession of power by the ruling class. If the ruling class does not provide those elements which are necessary for the survival of the political system, both its power and that system are in peril. In return for the security which it provides its followers, the ruling class gives the tone to politics. It does not, however, have to occupy the actual administrative posts to be the ruling class, but it must possess a prestige position.
Stable or Fragile Democracy? Political Cleavages and Party System in Hungary
Authors: Körösényi András
Published: July 2007

The Transition Process in Hungary Produced Well-established parties and a developed party system. Parties came into existence along political and ideological lines. Parties had an organization, party programme, membership and party discipline similar to those of political parties in the Western European countries. The organization and structure of these parties resembled those of middle-class parties more than socialist or communis/fascist parties. Hungarian parties also had ‘direct structure’ with individual membership. All of them were closer to mass parties than to cadre parties, i.e. their primary aim was electoral success. But none of them became a mass party in terms of membership figures, which were rather low (the total membership of the six parliamentary parties was below 200,000 in 1990, so it was about 2.5 – 3 per cent of the electorate. There were ‘catch-all’ parties (HDF, AFD), parties with specific interest representation (SHP) and parties organized along some ideological principle (CDPP).
Shaping a New World Order: Political Capacities and Policy Challenges
Authors: Gamble Andrew
Published: July 2007

ONE OF THE MOST NOTICED FEATURES OF OUR TIME IS that global problems are increasing at a faster rate than the evolution of the political capacities to manage them. This is not a new observation, or even a new condition. It has long been part of a pessimistic assessment of the prospects for modern industrial technological civilization that can be traced back to its origins, but has been particularly strong throughout the twentieth century. H. G. Wells's famous comment that ‘human history becomes more and more a race between education and catastrophe’ is even more apposite to the contemporary mood than it was when first written. The spectre of communism no longer haunts Europe, but other spectres now haunt the global civilization which developed out of Europe. Some of the key trends of this global civilization threaten at best an era of mounting disorder and chaos in the world system, at worst the survival of the human species itself. The problems are increasing far faster than the ability to find solutions for them.
Beveridge and the Reform of Social Security — Then and Now
Authors: Wilson Thomas , Wilson Dorothy
Published: July 2007

THE COLLAPSE OF COMMUNISM HAS COINCIDED WITH A crisis of capitalism. At the very time when discredited Marxist dogmas have been abandoned and the former Communist countries are seeking to privatize their industries and replace planning with the market, the capitalist economies have again displayed their traditional weaknesses. For inequality has widened, and large numbers of people are still said to be in poverty notwithstanding the fact that expenditure on the welfare state in its various forms absorbs much the larger part of public expenditure. Increasing scepticism about the welfare state has been accompanied by a loss of faith in macro-economic policy. Not only has mass unemployment returned on a scale that would once have been thought inconceivable but it appears to be assumed, with gloomy resignation, that the number without work, even if reduced by a cyclical recovery, will remain high for an indefinite period ahead. In these respects, the rich West presents a discouraging prospect to the aspiring East.
Crisis of Constraint: The Federal Republic of Germany's Current Refugee Imbroglio
Authors: Gibney Matthew J.
Published: July 2007

THE WEST GERMAN STATE HAS FACED TWO DAUNTING challenges brought about by the movement of refugees into its territory since the end of the Second World War. The first occurred immediately after the end of the war and involved the resettlement of ten million refugees of German nationality expelled from East European countries and 3.5 million evacuees from Soviet-controlled East Germany. It was a challenge that was met with dramatic success. With the help of a number of governmental programmes, and a rapidly expanding economy, these refugees were fully integrated into West German society in the two decades after 1945. Indeed, by the end of the 1960s, the success of this massive resettlement attempt, along with the country's uniquely broad constitutional article which recognized a right of asylum for all political refugees, had rendered the Federal Republic, in spite of its catastrophic past, something of a model for all states in the handling of refugees
Politics and Theatrical Culture in Restoration England
Authors: Walkling Andrew R.
Published: July 2007

This article explores the relationship between politics and the theatre in England between 1660 and 1688. Following a discussion of the place of the theatre within the broader political landscape, the article looks at the political nature of the drama during this period, outlining the various ways in which plays could comment upon contemporary politics, ranging from overt political satire to ‘impressionistic’ allegory to complexroman à clef. Additional political opportunities afforded by the publication of playtexts are also discussed. The article then examines the operation of politics in the playhouses themselves, including the behavior of actors, both onstage and off, and the close connections between the public theatres and the world of the royal court.
Communication and Contention: The Role of Literacy in Conflicts with ‘Abbāsid Officials
Authors: Van Berkel Maaike
Published: July 2007

‘Abbāsid officials of the late ninth and early tenth centuries operated in a highly bureaucratized and literate environment and they expressed their identity in terms of expertise in writing. However, in their daily business they had to communicate with all kinds of social groups, some of which had not – or only to a certain level – been introduced to writing. During the last three decades a series of groundbreaking studies appeared on the introduction and dissemination of writing in Medieval Europe. The role of literacy in Arab and Islamic societies in this period have as yet received very little, and mainly rather specialized, attention. The communication between ‘Abbāsid officials and other social groups will be studied in cases of conflict and their settlements. Conflict settlement is also a field of research that recently witnessed important new insights. Studying the use of written documents in dispute settlements – a situation in which communication is of vital importance to all parties involved – forms therefore an excellent opportunity to analyse familiarity with, and confidence in, writing among the various groups within the ‘Abbāsid caliphate.
History for the Anthropocene
Authors: Robin Libby , Steffen Will
Published: July 2007

Global history has become the business of more than just historians. This paper explores the history of scientific historiography, particularly a recent initiative of the Global Change community to write anIntegrated History and future Of People on Earth(IHOPE). A new geological epoch, the Anthropocene, has been declared, reflecting the scientific fact that anthropogenic change is now shaping planetary systems. Describing changes to the Earth system over time demands understanding of the history of the biophysical factors, the human factors and their integration. While global warming has motivated the recent initiative to write global history, the global atomic era also provided an incentive for scientists to write global history, as was revealed in the 1940s UNESCO initiatives for aScientific and Cultural History of Mankindand an International Union for the History of Science. We review recent developments in world and environmental historiography, and popular ‘millennial’ projects, such as the Clock of the Long Now, to identify potential common interests between historians and non‐historians writing world history at very different scales, and for different audiences.
Behavioral and Physiological Components of Communication Training: Does the Topic Affect Outcome?
Authors: Cornelius Tara L. , Alessi Galen
Published: July 2007

This study experimentally examined the Speaker‐Listener technique when couples (N= 30) were instructed to either discuss an issue within or outside their marriage, on marital satisfaction, and communication behaviors. This study examined the J. M. Gottman, J. Coan, S. Carrere, and C. Swanson (1998) hypothesis that the Speaker‐Listener technique may lead to improved marital satisfaction when the couple is discussing a third party issue, but discussing an issue about each other may weaken the marital relationship. Behavioral and physiological data during marital interactions were sequentially analyzed. Results suggested that the Speaker‐Listener technique reduced negativity but did not increase positivity in marital interactions. There were significant differences in positive reciprocity across the 2 experimental groups, but no differences in negativity. Additionally, adherence to the Speaker‐Listener technique was poor, which has implications for both research and theory. Possible interpretations and areas for further investigation are suggested.
Parent‐Child Value Similarity: The Role of Zeitgeist
Authors: Boehnke Klaus , Hadjar Andreas , Baier Dirk
Published: July 2007

Reporting a study of German 2‐child families, the article focuses on a neglected issue in value transmission studies: contemporaneous societal context. Parent‐child value similarity depends not only on family characteristics but also on zeitgeist, the modal value climate of a society. To evaluate the role of zeitgeist in value transmission, differences in parent‐child value similarity between families agreeing and disagreeing with the zeitgeist are studied, focusing on a core value of modern societies: hierarchic self‐interest. Results show a weak general zeitgeist effect. A family’s relative position vis‐à‐vis the societal value climate, however, is shown to strongly influence intergenerational similarity in hierarchic self‐interest, families distant from the zeitgeist showing a much higher intergenerational value similarity than families close to the zeitgeist.
A Genetically Informed Study of the Intergenerational Transmission of Marital Instability
Authors: D’Onofrio Brian M. , Turkheimer Eric , Emery Robert E. , Harden K. Paige , Slutske Wendy S. , Heath Andrew C. , Madden Pamela A. F. , Martin Nicholas G.
Published: July 2007

Environmental or genetic influences, or both could account for the increased risk of divorce among the offspring of separated parents. Previous studies have used covariates to statistically control for confounds, but the present research is the first genetically informed study of the topic. The investigation used the Children of Twins Design with twins, their spouses, and their young adult offspring (n = 2,310) from the Australian Twin Registry to test whether selection on the basis of genetic or shared environment factors accounted for part of the intergenerational association. The analyses also controlled for measured characteristics of both parents. The results suggest that both environmentally mediated and genetic risk account for the intergenerational transmission, supporting the roles of both selection and causation.
Therapeutic approaches for prion and Alzheimer's diseases
Authors: Wisniewski Thomas , Sigurdsson Einar M.
Published: July 2007

Alzheimer's and prion diseases belong to a category of conformational neurodegenerative disorders [Prusiner SB (2001) N Eng J Med344, 1516–1526; Sadowski M & Wisniewski T (2007) Curr Pharm Des 13, 1943–1954; Beekes M (2007) FEBS J 274, 575]. Treatments capable of arresting or at least effectively modifying the course of disease do not yet exist for either one of these diseases. Alzheimer's disease is the major cause of dementia in the elderly and has become an ever greater problem with the aging of Western societies. Unlike Alzheimer's disease, prion diseases are relatively rare. Each year only approximately 300 people in the USA and approximately 100 people in the UK succumb to various forms of prion diseases [Beekes M (2007) FEBS J 274, 575; Sigurdsson EM & Wisniewski T (2005) Exp Rev Vaccines 4, 607–610]. Nevertheless, these disorders have received great scientific and public interest due to the fact that they can be transmissible among humans and in certain conditions from animals to humans. The emergence of variant Creutzfeld–Jakob disease demonstrated the transmissibility of the bovine spongiform encephalopathy to humans [Beekes M (2007) FEBS J 274, 575]. Therefore, the spread of bovine spongiform encephalopathy across Europe and the recently identified cases in North America have put a large human population at risk of prion infection. It is estimated that at least several thousand Britons are asymptomatic carriers of prion infections and may develop variant Creutzfeld–Jakob disease in the future [Hilton DA (2006) J Pathol 208, 134–141]. This delayed emergence of human cases following the near elimination of bovine spongiform encephalopathy in the UK may occur because prion disease have a very prolonged incubation period, ranging from months to decades, which depends on the amount of inoculum, the route of infection and the genetic predisposition of the infected subject [Hilton DA (2006) J Pathol 208, 134–141]. Therefore, there is a great need for effective therapies for both Alzheimer's disease and prion diseases.
The evolving role of voluntarism in ageing rural communities
Authors: Skinner Mark W. , Joseph Alun E.
Published: July 2007

Abstract:  This paper conceptualizes voluntarism as a critical process at the intersection of changes underway in rural communities, and in health and social care systems. Three aspects of the evolving role of the voluntary sector are identified and set within a descriptive model of rural change. Initially, voluntarism is cast as a ‘barometer of change’ in health and social services, and in rural communities, then considered as a ‘mechanism of adjustment’ and, ultimately, as an emerging ‘space of resistance’ to these same changes. The nature and significance of each of the three dimensions of voluntarism is illustrated using results from suites of case studies of ageing in Ontario and the Waikato. The efficacy of the descriptive model and its tripartite view of voluntarism is discussed in light of the under‐theorized and under‐researched rural dimensions of ageing, voluntarism, and health and social care.
Strategies for Enhanced Photodynamic Therapy Effects†
Authors: Verma Sarika , Watt Gregory M. , Mai Zhiming , Hasan Tayyaba
Published: July 2007

Photodynamic therapy (PDT) is a treatment modality for the selective destruction of cancerous and nonneoplastic pathologies that involves the simultaneous presence of light, oxygen and a light‐activatable chemical called a photosensitizer (PS) to achieve a cytotoxic effect. The photophysics and mechanisms of cell killing by PDT have been extensively studied in recent years, and PDT has received regulatory approval for the treatment of a number of diseases worldwide. As the application of this treatment modality expands with regard to both anatomical sites and disease stages, it will be important to develop strategies for enhancing PDT outcomes. This article focuses on two broad approaches for PDT enhancement: (1) mechanism‐based combination treatments in which PDT and a second modality can be designed to either increase the susceptibility of tumor cells to PDT or nullify the treatment outcome‐mitigating molecular responses triggered by PDT of tumors, and (2) the more recent approaches of PS targeting, either by specific cellular function‐sensitive linkages or via conjugation to macromolecules.
ELDONET—A Decade of Monitoring Solar Radiation on Five Continents
Authors: Häder Donat‐Peter , Lebert Michael , Schuster Martin , Ciampo Lineu del , Helbling E. Walter , McKenzie Richard
Published: July 2007

The European light dosimeter network (ELDONET) comprises more than 40 stations in 24 countries on 5 continents. The present report compares solar radiation data in the photosynthetic active radiation, UV‐A (315–400 nm) and UV‐B (280–315 nm) wavelength ranges for 17 stations at different latitudes on the northern and southern hemispheres for up to 10 years of monitoring. While the maximal irradiances on clear days follow a latitudinal gradient due to the cosine dependence on the solar angle, the total doses strongly depend on the local climate and atmospheric conditions as well as the day‐length distribution over the year. UV‐B irradiances and doses are strongly influenced by the total column ozone, which is recorded for all covered stations.
Photodynamic Therapy of Vertebral Metastases: Evaluating Tumor‐to‐Neural Tissue Uptake of BPD‐MA and ALA‐PpIX in a Murine Model of Metastatic Human Breast Carcinoma†
Authors: Akens Margarete K. , Yee Albert J. M. , Wilson Brian C. , Burch Shane , Johnson Crystal L. , Lilge Lothar , Bisland Stuart K.
Published: July 2007

Photodynamic therapy has been successfully applied to numerous cancers. Its potential to treat cancer metastases in the spine has been demonstrated previously in a preclinical animal model. The aim of this study was to test two photosensitizers, benzoporphyrin‐derivative monoacid ring A (BPD‐MA) and by 5‐aminolevulinic acid (5‐ALA)‐induced protoporphyrin IX (PpIX), for their potential use to treat bony metastases. The difference in photosensitizer concentration in the spinal cord and the surrounding tumor‐bearing vertebrae was of particular interest to assess the risk of potential collateral damage to the spinal cord. Vertebral metastases in a rat model were generated by intracardiac injection of human breast cancer cells. When tumor growth was confirmed, photosensitizers were injected systemically and the animals were euthanized at different time points. The following tissues were harvested: liver, kidney, ovaries, appendicular bone, spinal cord and lumbar vertebrae. Photosensitizer tissue concentration of BPD‐MA or PpIX was determined by fluorescence spectrophotometry. In contrast to BPD‐MA, ALA‐PpIX did not demonstrate an appreciable difference in the uptake ratio in tumor‐bearing vertebrae compared to spinal cord. The highest ratio for BPD‐MA concentration was found 15 min after injection, which can be recommended for therapy in this model.
Depolarization activates the phosphoinositide phosphatase Ci‐VSP, as detected in Xenopus oocytes coexpressing sensors of PIP2
Authors: Murata Yoshimichi , Okamura Yasushi
Published: July 2007

Voltage‐evoked signals play critical roles in neural activities, muscle contraction and exocytosis. Ciona voltage‐sensor containing phosphatase (Ci‐VSP) consists of the transmembrane voltage sensor domain (VSD) and a cytoplasmic domain of phosphoinositide phosphatase, homologous to phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Previous experiments utilizing potassium channels as the sensor for phosphoinositides have demonstrated that phosphatase activities of Ci‐VSP are voltage dependent. However, it still remained unclear whether enzyme activity is activated by depolarization or hyperpolarization. Further, a large gap in voltage dependency was found between the charge movement of the VSD and potassium channel‐reporting phosphatase activities. In this study, voltage‐dependent dynamics of phosphoinositides mediated by Ci‐VSP were examined by confocal imaging and electrical measurements in Xenopus oocytes. Imaging of phosphatidylinositol‐4,5‐bisphosphate (PtdIns(4,5)P2) using green fluorescent protein (GFP)‐tagged pleckstrin homology (PH) domains from phospholipase C δ subunit (PLC‐δ) showed that PtdIns(4,5)P2 concentration is reduced during depolarization. In the presence of Ci‐VSP, IRK1 channels with higher sensitivity to phosphoinositide than GIRK2 channels decreased their magnitude during depolarization over 0 mV, indicating that the PtdIns(4,5)P2 level is reduced upon depolarization. KCNQ2/3 channels coexpressed with Ci‐VSP exhibited voltage‐dependent decay of the outward current that became sharper with higher depolarization in a voltage range up to 100 mV. These results indicate that Ci‐VSP has an activity that depletes PtdIns(4,5)P2 unlike PTEN and that depolarization‐activated voltage sensor movement is translated into activation of phosphatase activity.
Properties of spontaneous Ca2+transients recorded from interstitial cells of Cajal‐like cells of the rabbit urethrain situ
Authors: Hashitani Hikaru , Suzuki Hikaru
Published: July 2007

Interstitial cells of Cajal‐like cells (ICC‐LCs) in the urethra may act as electrical pacemakers of spontaneous contractions. However, their propertiesin situand their interaction with neighbouring urethral smooth muscle cells (USMCs) remain to be elucidated. To further explore the physiological role of ICC‐LCs, spontaneous changes in [Ca2+]i(Ca2+transients) were visualized in fluo‐4 loaded preparations of rabbit urethral smooth muscle. ICC‐LCs were sparsely distributed, rather than forming an extensive network. Ca2+transients in ICC‐LCs had a lower frequency and a longer half‐width than those of USMCs. ICC‐LCs often exhibited Ca2+transients synchronously with each other, but did not often show a close temporal relationship with Ca2+transients in USMCs. Nicardipine (1 μm) suppressed Ca2+transients in USMCs but not in ICC‐LCs. Ca2+transients in ICC‐LCs were abolished by cyclopiazonic acid (10 μm), ryanodine (50 μm) and caffeine (10 mm) or by removing extracellular Ca2+, and inhibited by 2‐aminoethoxydiphenyl borate (50 μm) and 3‐morpholino‐sydnonimine (SIN‐1; 10 μm), but facilitated by increasing extracellular Ca2+or phenylephrine (1–10 μm). These results indicated that Ca2+transients in urethral ICC‐LCsin siturely on both Ca2+release from intracellular Ca2+stores and Ca2+influx through non‐L‐type Ca2+channel pathways. ICC‐LCs may not act as a coordinated pacemaker electrical network as do ICC in the gastrointestinal (GI) tract. Rather they may randomly increase excitability of USMCs to maintain the tone of urethral smooth muscles.
Sympathetic vasoconstrictor regulation of mouse colonic submucosal arterioles is altered in experimental colitis
Authors: Lomax A. E. , O'Reilly M. , Neshat S. , Vanner S. J.
Published: July 2007

Recent studies suggest that altered neural regulation of the gastrointestinal microvasculature contributes to the pathogenesis of inflammatory bowel disease. Therefore, we employed video microscopy techniques to monitor nerve‐evoked vasoconstrictor responses in mouse colonic submucosal arterioles in vitro and examined the effect of 2,4,6‐trinitrobenzene sulphonic acid (TNBS) colitis. Nerve stimulation (2–20 Hz) caused frequency‐dependent vasoconstrictor responses that were abolished by tetrodotoxin (300 nm) and guanethidine (10 μm). The P2 receptor antagonist suramin (100 μm) or the α1‐adrenoceptor antagonist prazosin (100 nm) reduced the vasoconstriction and the combination of suramin and prazosin completely abolished responses. Nerve‐evoked constrictions of submucosal arterioles from mice with TNBS colitis were inhibited by prazosin but not suramin. Superfusion of ATP (10 μm) resulted in large vasoconstrictions in control mice but had no effect in mice with colitis whereas constrictions to phenylephrine (3 μm) were unaffected. P2X1 receptor immunohistochemistry did not suggest any alteration in receptor expression following colitis. However, Western blotting revealed that submucosal P2X1 receptor expression was increased during colitis. In contrast to ATP, αβ‐methylene‐ATP (1 μm), which is resistant to catabolism by nucleotidases, constricted control and TNBS arterioles. This indicates that reduced purinergic transmission to submucosal arterioles may be due to increased degradation of ATP during colitis. These data comprise the first description of the neural regulation of mouse submucosal arterioles and identify a defect in sympathetic regulation of the GI vasculature during colitis due to reduced purinergic neurotransmission.
Roles of phospholipase Cβ and NMDA receptor in activity‐dependent endocannabinoid release
Authors: Hashimotodani Yuki , Ohno‐Shosaku Takako , Watanabe Masahiko , Kano Masanobu
Published: July 2007

Endocannabinoids are released from postsynaptic neurons, activate presynaptic cannabinoid receptors and cause various forms of short‐term and long‐term synaptic plasticity throughout the brain. Using hippocampal and cerebellar neurons, we have revealed that endocannabinoid release can be induced through two different pathways. One is independent of phospholipase Cβ (PLCβ) and driven by Ca2+ elevation alone (Ca2+‐driven endocannabinoid release, CaER), and the other is PLCβ‐dependent and driven by activation of Gq/11‐coupled receptors (receptor‐driven endocannabinoid release, RER). CaER is induced by activation of either voltage‐gated Ca2+ channels or NMDA receptors. RER is functional even at resting Ca2+ levels (basal RER), but markedly enhanced by a small Ca2+ elevation (Ca2+‐assisted RER). In Ca2+‐assisted RER, PLCβ serves as a coincidence detector of receptor activation and Ca2+ elevation. We have also demonstrated that Ca2+‐assisted RER is essential for the endocannabinoid release triggered by synaptic activity. Our anatomical data show that a set of receptors and enzymes required for RER are well organized so that the excitatory input can trigger RER effectively. Certain forms of spike‐timing‐dependent plasticity (STDP) are reported to depend on endocannabinoid signalling. The NMDA receptor and PLCβ might play key roles in the endocannabinoid‐dependent forms of STDP as coincidence detectors with different timing dependences.
Endocannabinoid signalling triggered by NMDA receptor‐mediated calcium entry into rat hippocampal neurons
Authors: Ohno‐Shosaku Takako , Hashimotodani Yuki , Ano Masato , Takeda Sachi , Tsubokawa Hiroshi , Kano Masanobu
Published: July 2007

Endocannabinoids are released from neurons in activity‐dependent manners, act retrogradely on presynaptic CB1 cannabinoid receptors, and induce short‐term or long‐term suppression of transmitter release. The endocannabinoid release is triggered by postsynaptic activation of voltage‐gated Ca2+ channels and/or Gq‐coupled receptors such as group I metabotropic glutamate receptors (I‐mGluRs) and M1/M3 muscarinic receptors. However, the roles of NMDA receptors, which provide another pathway for Ca2+ entry into neurons, in endocannabinoid signalling have been poorly understood. In the present study, we investigated the possible contribution of NMDA receptors in endocannabinoid production by recording IPSCs in cultured hippocampal neurons. Under the conditions minimizing the activation of voltage‐gated Ca2+ channels, local application of NMDA (200 μm) transiently suppressed cannabinoid‐sensitive IPSCs, but not cannabinoid‐insensitive IPSCs. This NMDA‐induced suppression was abolished by blocking NMDA receptors, CB1 receptors and diacylglycerol lipase, but not by inhibiting voltage‐gated Ca2+ channels. When the postsynaptic neuron was dialysed with 30 mm BAPTA, the NMDA‐induced suppression was reduced significantly. A lower dose of NMDA (20 μm) exerted little effect when applied alone, but markedly enhanced the cannabinoid‐dependent suppression driven by muscarinic receptors or I‐mGluRs. These data clearly indicate that the activation of NMDA receptors facilitates the endocannabinoid release either alone or in concert with the Gq‐coupled receptors.
On the physical, spectral, and dosimetric characteristics of a new brachytherapy source
Authors: Pirchio Rosana , Galiano Eduardo , Saraví Margarita , Banchik David , Muñoz Carlos
Published: July 2007

A new source under the name Braquibac™ has been developed in Argentina for interstitial brachytherapy applications. The aim of this work is to study the new seed's design and to calculate its dosimetric parameters. Radiographic and destructive tests were carried out on inactive seeds to determine the physical characteristics of the source. Values of , , , and , were obtained in water and air by simulation using the MCNP5 Monte Carlo code according to the methodology recommended in TG‐43 and updated in TG‐43U1. The dose rate constant was determined to be (overall statistical uncertainty ). per unity activity was calculated to be by simulation of the seed in dry air using point detectors. Spectroscopic studies for both the new and the Amersham model 6711 seed were performed using an HPGe planar detector. The emission spectra of both seeds proved to be very similar. The anisotropy of the total photon intensity in air was measured in planes containing the seed's short and long axes using the HPGe detector. The minimum photon intensity for the new seed was of the transverse intensity.
Compensators for dose and scatter management in cone‐beam computed tomography
Authors: Graham S. A. , Moseley D. J. , Siewerdsen J. H. , Jaffray D. A.
Published: July 2007

The ability of compensators (e.g., bow‐tie filters) designed for kV cone‐beam computed tomography (CT) to reduce both scatter reaching the detector and dose to the patient is investigated. Scattered x rays reaching the detector are widely recognized as one of the most significant challenges to cone‐beam CT imaging performance. With cone‐beam CT gaining popularity as a method of guiding treatments in radiation therapy, any methods that have the potential to reduce the dose to patients and/or improve image quality should be investigated. Simple compensators with a design that could realistically be implemented on a cone‐beam CT imaging system have been constructed to determine the magnitude of reduction of scatter and/or dose for various cone‐beam CT imaging conditions. Depending on the situation, the compensators were shown to reduce x‐ray scatter at the detector and dose to the patient by more than a factor of 2. Further optimization of the compensators is a possibility to achieve greater reductions in both scatter and dose.