bluuebunny/crossref_metadata_2025 huggingface dataset:
Strenuous physical exercise adversely affects monocyte chemotaxis
Authors: Caidahl Kenneth , Olieslagers Servé , Krook Anna , Rickenlund Anette , Rickenlund Anette , Zierath Juleen , Czepluch Frauke , Barrès Romain , Waltenberger Johannes
Published: October 2010

Physical exercise is important for proper cardiovascular function and disease prevention, but it may influence the immune system. We evaluated the effect of strenuous exercise on monocyte chemotaxis. Monocytes were isolated from blood of 13 young, healthy, sedentary individuals participating in a three-week training program which consisted of repeated exercise bouts. Monocyte chemotaxis and serological biomarkers were investigated at baseline, after three weeks training and after four weeks recovery. Chemotaxis towards vascular endothelial growth factor-A (VEGF-A) and transforming growth factor-β1 (TGF-β1) was completely inhibited immediately after training (p<0.01), and remained so after four weeks recovery. Likewise, monocyte chemoattractant protein-1 (MCP-1)-induced migration declined after training (p<0.01) and improved only partially during the recovery period. MCP-1 serum levels were significantly reduced after four weeks recovery compared to baseline (p<0.01). Total blood antioxidant capacity was enhanced at this time point (p<0.01). Monocyte chemokinesis, TGF-β1 and nitric oxide serum levels remained unchanged during the study. Strenuous three-week training consisting of repeated exercise bouts in healthy, sedentary individuals reduces monocyte chemotaxis. It remains to be established, whether this is a sound adaptation to increased stimuli or an untoward reaction to overtraining. Nevertheless, the effect remains for several weeks with no exercise.
Increased risk of gestational vascular complications in women with low free tissue factor pathway inhibitor plasma levels out of pregnancy
Authors: Ittel Antoine , Bretelle Florence , Gris Jean-Christophe , Chau Cécile , Sébahoun Gérard , Boubli Léon , Arnoux Dominique
Published: October 2010

Tissue factor pathway inhibitor (TFPI) plays a crucial role in haemostasis by regulating TF-induced initiation of coagulation. Since it is expressed by endothelial and trophoblastic cells, TFPI is of particular importance at the placental level and might be involved in the occurrence of gestational vascular complications (GVC). In the present study, we investigated plasma free TFPI antigen in four groups of women: healthy non-pregnant women without history of pregnancy complications; women at the beginning (<12 weeks) and women during the third trimester of a normal pregnancy; women with late pregnancy complications (pre-eclampsia / HELLP syndrome, intra-uterine fetal death, fetal growth retardation) at the time of obstetrical event and/or at distance from pregnancy. In normal pregnancy, TFPI increased between first trimester and delivery (median 5.0 ng/ml vs. 7.1 ng/ml; p<0.0001) but remained lower than in non-pregnant controls (median 8.2 ng/ml; p<0.0001). In patients, when measured concomitantly to the obstetrical event, TFPI showed no difference with normal late pregnancy levels. In contrast, at distance from pregnancy, in the absence of any hormonal influence, TFPI was significantly lower than in non-pregnant controls (median 5.9 vs. 8.2ng/ml, p < 0.0001). After categorisation into quartiles, an inverse dose-effect relationship was demonstrated between TFPI categories recorded apart from pregnancy and GVC risk, with a crude odds ratio of 43.5 (95% confidence interval 8.2–230) for patients with TFPI values in the lowest quartile (< 5.7 ng/ml). In conclusion, low free TFPI at distance from pregnancy appears to be a strong indicator of GVC risk.
Stability of the high on-treatment platelet reactivity phenotype over time in clopidogrel-treated patients
Authors: Jaitner Juliane , Stegherr Julia , Morath Tanja , Braun Siegmund , Bernlochner Isabell , Schömig Albert , Kastrati Adnan , Dirk Sibbing
Published: October 2010

Interindividual response variability to clopidogrel treatment is a well established phenomenon. In recent studies and ongoing large-scale trials where patients with high on-treatment platelet reactivity (HPR) to clopidogrel are being randomised to an intensified antiplatelet treatment, confirmation of the HPR phenotype is based on one single platelet function assessment. The stability of the HPR phenotype over time has never been investigated but should be considered crucial for justification of intensified antiplatelet treatment regimens beyond clinical trials. The goal of this study was to test for the stability of the HPR phenotype over time in clopidogrel-treated patients. Patients (n=31) under chronic clopidogrel treatment (75 mg/day) were investigated by serial adenosine diphosphate (ADP)-induced platelet aggregation assessment with multiple electrode aggregometry (MEA) on a Multiplate analyser and light transmission aggregometry (LTA) at three different time points (once per week) during monitored antiplatelet treatment. On the basis of a cut-off level approach (468 AU*min for MEA, 53% for LTA) patients were classified into patients with (n=27) or without (n=4) HPR. For MEA, the phenotype was stable in 93.5% (n=29) of patients whereas 6.5% (n=2) crossed the cut-off level. For LTA, the phenotype was stable in 68% (n=21) of patients whereas 32% (n=10) patients crossed the cut-off level (chi-square P=0.01 for comparison of pheno-type stability between both assays). In conclusion, the HPR phenotype is stable over time in the majority of clopidogrel-treated patients. Comparative assessment of phenotype stability across available platelet function assays warrants further investigation.
Phylogeography of Psammodromus algirus (Lacertidae) revisited: systematic implications
Authors: Carranza Salvador , Salvador Alfredo , Verdú-Ricoy Joaquín , Díaz José , Busack Stephen
Published: November 2010

Relationships among Psammodromus algirus populations from the Iberian Peninsula and North Africa, including recently described P. jeanneae and P. manuelae, were estimated from mitochondrial DNA gene sequences. This enlarged data set confirmed the presence of two divergent eastern and western mitochondrial DNA lineages on the Iberian Peninsula, the distributions for which are separated by a narrow zone of contact across the centre of the Peninsula. Paratypes of P. jeanneae and topotypes of P. manuelae represent southern and northern clades of the western lineage, respectively, making P. algirus paraphyletic. This, together with the low level of allozymic and mitochondrial DNA substructuring within western populations, is not sufficient to retain P. jeanneae and P. manuelae as valid species, and we relegate them to the status of junior synonyms of P. algirus.
The mitochondrial genome complete sequence and organization of the Pig-nosed Turtle Carettochelys insculpta (Testudines, Carettochelyidae) and its phylogeny position in Testudines
Authors: Xiong Lei , Li Xiao-san , Wang Ling , Zhou Ke , Nie Liu-wang
Published: November 2010

The Pig-nosed Turtle Carettochelys insculpta (Testudines; Cryptodira; Carettochelyidae) is the sole living representative of the Carettochelyidae. The phylogenetic position of C. insculpta within Testudines has not yet been determined unequivocally. To address this issue, we sequenced the whole mitochondrial DNA (mtDNA) of C. insculpta using the long-and-accurate PCR (LA-PCR) method. The results show that the length of C. insculpta mtDNA is 16 439 bp and its structure is conserved compared to those of other turtles and other vertebrates except the NADH4 gene beginning with an ATC start codon. The 3′-side of the control region in mtDNA has two tandem repeat motifs, each consisting of nine 5′-CA-3′ units and sixteen 5′-AT-3′ units. To assess the phylogenetic position of C. insculpta, Maximum parsimony (MP), Maximum likelihood (ML) and Bayesian (BI) analyses were conducted based on complete mtDNA from 22 taxa. MP analyses robustly supported that the earliest phylogenetic tree splits separated into three basal branches: the Pelomedusidae (Pelomedusa subrufa), the Carettochelyidae (C. insculpta) and an assemblage of 18 cryptodiran turtle species; while ML and BI analyses suggested that Carettochelyidae and Trionychidae formed a clade, and that this clade was the sister taxon to all other cryptodiran turtles.
Truth Commissions: A Barrier to the Provision of Judicial Assistance?
Authors: Bisset Alison
Published: October 2010

Truth commissions and criminal trials have come to be perceived as complementary transitional justice mechanisms. However, where effective prosecutions are dependent on the exchange of information and transfer of suspects between states under existing mutual legal assistance and extradition arrangements, the operation of a truth commission in the state of territoriality may act as an obstacle to international cooperation. At the same time, requests for assistance from a third state pursuing prosecutions may impact negatively on the truth commission process in the requested state by inhibiting those reluctant to become involved in criminal proceedings from offering testimony. This article demonstrates a practical discord between these bodies when they operate in different states and questions whether they can truly be considered “complementary”.
Japanese Tourism Values
Authors: Watkins Leah J. , Gnoth Juergen
Published: October 2010

This study evaluates the research method of means–end in a cross-cultural research context in order to understand Japanese tourists’ values that drive travel choices in New Zealand. It contributes an extensive critique of means–end analysis and its advantages over quantitative research methods in cross-cultural research. Its theoretical contribution comes in the form of a set of values or travel motivators, including a number of culturally motivated values that reveal unique insights into Japanese travel experiences. The article argues that meaningful values research must consider not only those values that are commonly understood across cultures but also those that are particular to the culture of interest, in order to understand what drives perception and satisfaction relevant for destination management and marketing. The data can be used to address a number of practical issues facing tourism practitioners such as segmenting the Japanese market, positioning tourism offerings within this market, and developing communication strategies.
First-Time and Recurrent Inmates’ Experiences of Imprisonment
Authors: Souza Karen A. , Dhami Mandeep K.
Published: October 2010

The authors surveyed 267 first-time ( n = 102) and recurrent ( n = 165) adult male inmates from two medium-security prisons in England. The findings revealed significant differences between the two groups of inmates: A relatively higher proportion of recurrent inmates were enrolled in drug treatment programs; a relatively higher proportion of first-time inmates had given up smoking and drinking, whereas more recurrent inmates had given up drugs; recurrent inmates thought about sex significantly more often, whereas first-time inmates were more concerned about being attacked; and finally, the highest proportion of recurrent inmates cited “improved health” as the best thing about being in prison, compared to the highest proportion of first-time inmates who cited “opportunity for rehabilitation.” Results were partially explained by differences in aspects of prisoners’ lives before prison and their differential exposure to imprisonment, and not by prison security, prison regime, or sentence variables. The findings can inform the development of prison regimes and policies that facilitate adjustment to imprisonment.
Lactobacillus GG as Treatment for Diarrhea During Enteral Feeding in Critical Illness
Authors: Ferrie Suzie , Daley Mark
Published: October 2010

Background: Diarrhea is a common problem in critical illness. The aim of this study was to investigate the effect of probiotic treatment with Lactobacillus rhamnosus GG on established diarrhea in critically ill patients. Methods: This prospective randomized blinded trial in the adult intensive care unit of a large tertiary referral teaching hospital compared probiotic treatment with placebo. Thirty‐six consecutive critically ill enterally fed adults with diarrhea were randomized to receive 2 capsules per day for 7 days of either Lactobacillus GG in an inulin base (Culturelle) or inulin alone (placebo). Diarrhea was defined as ≥3 unformed stools or >200 mL stool volume within 24 hours. Prospectively defined primary end point was duration of diarrhea, and secondary end point was mean number of loose stools per day during the 14 days from the first capsule. Results by intention‐to‐treat analysis: No significant difference was observed for any end point. There was a trend toward more diarrhea in the probiotic treatment group. Mean (standard deviation) duration of diarrhea was 3.83 (2.39) days for the probiotic group and 2.56 (1.85) days for the placebo group (P = .096). Mean number of loose stools per day during the 14 days from the first capsule was 1.58 (0.88) in the probiotic group and 1.10 (0.79) in the placebo group (P = .150). Conclusions: This study does not support the use of Lactobacillus GG as a treatment for established diarrhea in enterally fed critically ill patients.
Public support for redistribution: what explains cross-national differences?
Authors: Dallinger Ursula
Published: October 2010

Rising levels of income inequality in almost all industrialized countries as a consequence of globalization and de-industrialization might lead one to assume that voters will demand more redistribution and exert influence on their governments to set up redistributive programmes. However, this is not always the case. Citizens do not react directly to actual levels of inequality, as research on the attitudes towards inequality and redistribution has shown. In this article the complex relation between cross-national variation of inequality and public support for redistribution is analysed. The article draws on explanations from both a political economy perspective as well as drawing on comparative welfare regime research. While the former conceives cross-national variations in support for redistribution as the aggregate effect of a demand of rational actors reacting to country context, the latter focuses on the impact of institutions and culture superimposing itself over self-interest. The empirical analysis tests the explanations of both the political economy and welfare regimes approach. Since the article focuses on the impact of context variables on individual attitudes, a multilevel analysis is adopted. Data are taken from the 1999 ‘International Social Survey Program’ and are complemented by macro-economic variables. Based on the results, a model of contingent support for redistribution is put forward, where culturally influenced definitions are embedded in economic processes.
Is there an extended family of Mediterranean welfare states?
Authors: Gal John
Published: October 2010

The goal of this article is to suggest that an extended family of Mediterranean welfare states exists and that it consists of eight different nations, some of which have been ignored in the ongoing discourse on Mediterranean welfare states. More specifically, it is claimed that the extended family of Mediterranean welfare states includes Cyprus, Greece, Israel, Italy, Malta, Spain, Portugal and Turkey. The article underscores a number of features common to members of this extended family of welfare states. Finally, three overarching themes that, in the past and present, appear to underlie the commonalities of Mediterranean welfare states and that can offer potential fruitful avenues for further study will be identified and discussed. These are religion, family and the role of clientelist—particularist relations in the structuring and functioning of welfare state institutions.
Can in-work benefits improve social inclusion in the southern European countries?
Authors: Figari Francesco
Published: October 2010

This paper analyses the effects of implementing a family-based and an individual in-work benefit in the southern European countries using EUROMOD, the EU-wide tax-benefit microsimulation model. In-work benefits are means-tested cash transfers given to individuals, through the tax system, conditional on their employment status. They are intended to enhance the incentives to accept work and redistribute resources to low income groups. The family-based in-work benefits seem to be more redistributive, in particular in Italy and Portugal, but the presence of extended families does not enable such policies to be well targeted on the very poorest, especially in Spain. Individual policies lead to better incentives to work than family-based in-work benefits, in particular for Spanish and Italian women in couples whose labour market participation is far below the European average.
Examining the impact of the Open Method of Coordination on sub-state employment and social inclusion policies: evidence from the UK
Authors: MacPhail Eilidh
Published: October 2010

Given its emphasis on a decentralised approach involving a range of actors, the Open Method of Coordination (OMC) would be expected to have an impact on the sub-state level in EU member states, particularly when sub-state authorities have competence for policy areas governed by the OMC. This study of the Employment and Social Inclusion OMC processes in the United Kingdom explores changes to the policy, polity and politics dimensions in these policy areas to determine the impact of the OMC on the sub-state level. Its findings suggest that, while the OMC process is far from facilitating ‘deliberative polyarchy’, in the UK case the limited engagement of sub-state authorities with the OMCs in Employment and Social Inclusion owes more to the internal division of power and the perception of the UK as a leader in these fields than to the structure and nature of the EU process itself.
The Influence of Maternal Behaviors During Childhood on Self-Efficacy in Individuals With Sickle Cell Disease
Authors: Jenerette Coretta M. , Valrie Cecelia R.
Published: November 2010

Little is known about the influence of maternal behaviors during childhood on the self-efficacy of individuals with sickle cell disease (SCD).This study retrospectively investigated the relationship between maternal overprotection and caring during childhood and self-efficacy in adulthood. Using a cross-sectional survey design, 32 adults with SCD completed questionnaires about demographics, maternal parenting behaviors, and self-efficacy. On average, adults with SCD reported moderate levels of SCD self-efficacy, high levels of overprotection, and high levels of caring. Self-efficacy was significantly related to educational level ( r = .39, p = .04), number of SCD crises per year ( r = —.41, p = .04), and caring ( r = .48, p = .01). Using simultaneous regression modeling, maternal caring was significantly predictive of self-efficacy (β = .44, p = .03). Results suggest that maternal caring during childhood may promote the development of self-efficacy in adults with SCD.
Maternal Navigational Strategies: Examining Mother-Daughter Dyads in Adolescent Families of Color
Authors: Biederman Donna J. , Nichols Tracy R. , Durham Danielle D.
Published: November 2010

Mother—daughter relationships are critical to the health and well-being of adolescent girls. Understanding mothers’ and daughters’ perspectives on the relationship can inform health promotion strategies that may benefit both. In-depth semistructured interviews were conducted with mothers ( N = 12) and their adolescent daughters ( N = 16). Narrative profiles were constructed to identify participants’ perceptions of each other and the relationship. Profiles were condensed into analytic poems that were compared and contrasted across roles and within and across dyads. Maternal navigational strategies of protection and preparation, and subthemes of maternal self-protection and daughter reverse protection emerged. The fabric of maternal strategies changed by girls’ developmental stage, with mothers of older daughters describing an interweaving of protection and preparation. Suggestions for future family nursing and health promotion research and campaigns are provided.
The Essence of the Family Critical Illness Experience and Nurse-Family Meetings
Authors: Nelms Tommie P. , Eggenberger Sandra K.
Published: November 2010

Nursing care of families is essential to strong family support and maintenance of family health during a critical illness. Secondary data analysis of interviews conducted with 11 families with a family member in the intensive care unit revealed two essences: the family critical illness experience and the family vision for the kind of care families required and desired from nurses. The purpose of this article was to explicate the essence of these phenomena and their implications for family nursing practice. Findings affirm the need for a family intervention described in the literature, that of regularly scheduled nurse—family meetings. Although developed for work with families experiencing a chronic illness, bringing families together and inviting meaningful conversation about their experiences is appropriate for families experiencing critical illness. Nurse—family meetings acknowledge suffering and vulnerability of families when a loved one is critically ill and afford families an opportunity for honest sensitive communication with nurses.
Extending Family Nursing: Concepts From Positive Psychology
Authors: Skerrett Karen
Published: November 2010

This article identifies the burgeoning field of positive psychology as an important extension to the knowledge base of family nursing. Representing a new emphasis from the traditional social and human sciences, which have largely focused on problem- and deficit-based approaches, positive psychology focuses on optimal functioning and is an ideal complement to the strengths-based orientation of family nursing. Domains of positive psychology are presented and exemplars of supporting research offered. Finally, suggestions are given for ways to apply concepts from positive psychology to family nursing practice, research, and education.
Telling Our Stories: The Importance of Women’s Narratives of Resistance
Authors: Cermele Jill
Published: October 2010

While more research is emerging on women’s capacity for successful resistance and the benefits of self-defense training for women, “resistance” to the idea of women’s resistance remains high. In this note, I describe the importance of bringing true accounts of successful resistance to both academic and lay communities, and the benefits to women of recounting their own experiences of successful resistance to violence and harassment. Such accounts provide new scripts for women’s options in responding to violence, mark attempted but thwarted rape as a visible event, and remind women of their own agency in the face of assault.
Deconstructing Self-Blame Following Sexual Assault: The Critical Roles of Cognitive Content and Process
Authors: Miller Audrey K. , Handley Ian M. , Markman Keith D. , Miller Janel H.
Published: October 2010

As part of a larger study, predictors of self-blame were investigated in a sample of 149 undergraduate sexual assault survivors. Each participant completed questionnaires regarding their preassault, peritraumatic, and postassault experiences and participated in an individual interview. Results confirmed the central hypothesis that, although several established correlates independently relate to self-blame, only cognitive content and process variables— negative self-cognitions and counterfactual-preventability cognitions—uniquely predict self-blame in a multivariate model.
Developmental Impact Evaluation for Facilitating Learning in Innovation Networks
Authors: Saari Eveliina , Kallio Katri
Published: October 2010

Innovations and new project ideas often emerge in networks of researchers, users of research, and societal actors. This article analyzes and discusses how research scientists learn to conduct research that has an impact on their clients, scientific community, and society. We describe a new developmental impact evaluation method based on the theory of expansive learning. The pilot process was conducted for bioenergy researchers at MTT Agrifood Research Finland. Developmental impact evaluation offers networks a process for evaluating completed projects, learning from them, and constructing a new research concept via pilot projects. The method opens up the concept of ‘research impact’ as a qualitative learning challenge, rather than an accountable target to be judged. It may be adopted as a continuous way of managing and renewing cross-disciplinary research programs, research groups, or networks.
Liberal democracy and political Islam: The search for common ground
Authors: Benhenda Mostapha
Published: October 2010

We seek to establish a dialogue between democratic and Islamic normative political theories. To that aim, we show that the conception of democracy underlying a prominent Islamic political model is procedural. We distinguish proceduralism from a liberal conception of democracy. Then, we explain how bringing together Islamic political theory and democracy alters the meaning of the latter. In other words, we show that democracy within Islam often means democracy within Islamic limits.
An Update on Diabetic Renal Disease
Authors: Walker James D
Published: October 2010

The hope that diabetic nephropathy would lessen with improvements in management appears not to have been realised. Current epidemiological studies report a continued high frequency of this important micro-vascular complication, with a continued excess mortality when increased levels of urinary albumin loss or reduced filtration function occur. While good glycaemic control ameliorates the development of microalbuminuria in type 1 and type 2 diabetes there is increasing evidence that angiotensin-converting enzyme inhibition and angiotensin receptor blockade are ineffective as primary prevention strategies. Blood pressure control remains the mainstay of treating established diabetic renal disease and a multi-factorial intervention approach in those with type 2 diabetes and microalbuminuria appears to be effective in reducing mortality based on data from one study. The Quality Outcomes Framework initiative for general practice in the United Kingdom has resulted in increased screening for diabetic renal disease with an assumed earlier treatment of blood pressure and introduction of blockers of the renin-angiotensin system. Some novel therapies are under investigation but overall the landscape is largely unchanged.
An Overview of Diabetic Eye Disease
Authors: Gupta Abha , Styles Caroline
Published: October 2010

Diabetic retinopathy (DR) is a leading cause of preventable blindness. It is estimated that by 2010 there will be a doubling of its prevalence since 1994. The national development of retinal screening programmes aims to manage this increase in numbers and prevent sight loss. Many have developed a classification system based on retinal features seen on fundus photography. There have also been changes to the classification schemes of diabetic retinal disease used by ophthalmologists which reflect the risk of developing sight threatening retinopathy. Although laser therapy and surgery remain the cornerstones of treatment of diabetic eye disease, there are other treatments which may prove to be effective and evidence of their long-term use is awaited. Glycaemic control and blood pressure management are vital in preventing progression of retinal disease and managing these risk factors is particularly important when sight threatening DR is being treated. An understanding of the classifications and retinopathy status of those with diabetes can thereby aid management decisions by other professionals involved in diabetes care.
The Muscle Metaboreflex in Patients with Diabetic Autonomic Neuropathy
Authors: Grieve Douglas AA , Mukhopadhyay Babulayeb , Cotton Mark M , Fisher Miles
Published: October 2010

The autonomic nervous system plays a critical role in cardiovascular responses to exercise through activation of the muscle metaboreflex. Subjects with diabetic autonomic neuropathy demonstrate impaired cardiovascular responses to exercise. We hypothesised that such patients would demonstrate impaired metaboreflex function. We assessed metaboreflex activity in six subjects with type 1 diabetes mellitus and autonomic neuropathy and eight subjects with type 1 diabetes mellitus without autonomic neuropathy. We used rhythmic handgrip exercise to fatigue followed by post-exercise muscle ischaemia, an established method of assessing metaboreflex function. Subjects with autonomic neuropathy had an attenuated heart rate response to exercise. Blood pressure remained elevated during post-exercise muscle ischaemia in both groups, suggesting intact metaboreflex function. Heart rate fell rapidly to baseline in both groups, suggesting normal baroreflex buffering of the metaboreflex. We conclude that the metaboreflex is important in the control of blood pressure during exercise in patients with diabetic autonomic neuropathy.
Diabetes and Ramadan: How to Achieve a Safer Fast for Muslims with Diabetes
Authors: Hassanein Mohamed M
Published: October 2010

Ramadan is a holy month for all Muslims, when they fast from dawn to sunset. Although the Qur'an exempts the sick from fasting, many Muslims with diabetes passionately fast despite their medical condition. The main risks encountered during fasting include worsening of glycaemic control or hypoglycaemia. A better understanding about fasting Ramadan and its risks is an important step for all healthcare professionals managing Muslim people with diabetes. This entails improving patient education as well as tailoring the treatment to meet the needs of this group of people with diabetes to minimise the possible risks.
Advocacy 2.0: Advocating in the Digital Age
Authors: Galer-Unti Regina A.
Published: November 2010

Advocacy for the individual health needs of others, for the health of the public, and for the profession have always been critical underpinnings of the field of health education. The explosion of technology and freedom of the Internet provide a multitude of possibilities for revitalized advocacy efforts. This article suggests just a few examples of how we might engage in Advocacy 2.0. Developing advocacy campaigns that use both tested and untested methods gives us an opportunity to achieve new victories in health education advocacy.
Novel therapeutic agents for B-cell lymphoma: developing rational combinations
Authors: Reeder Craig B. , Ansell Stephen M.
Published: October 2010

Several novel targeted therapies have recently emerged as active in the treatment of non-Hodgkin lymphoma, including small molecules that inhibit critical signaling pathways, promote apoptotic mechanisms, or modulate the tumor microenvironment. Other new agents target novel cell surface receptors or promote DNA damage. Although most of these drugs have single-agent activity, none have sufficient activity to be used alone. This article reviews the utility and potential role of these new agents in the treatment of non-Hodgkin lymphoma with a specific focus on data that highlight how these agents may be incorporated into current standard treatment approaches.
Quality of life of homosexual males with genital warts: a qualitative study
Authors: Lee Mortensen Gitte , Larsen Helle K
Published: November 2010

Background

A recent qualitative study in Denmark showed that genital warts (GWs) can considerably lower the quality of life of heterosexual patients. In this follow-up study, we interviewed men having sex with men (MSM) suffering from GWs to obtain an in-depth understanding of their perception of GWs and determine the extent to which minority (homosexual) cultural issues affect these patients' experiences. Qualitative interviews with six MSM were performed using a semi-structured interview guide. Questions were formulated on the basis of the earlier qualitative study in heterosexual patients with GWs along with a literature review. Data were analysed using a medical anthropological approach.

Findings

Many MSM worried about being stigmatised and excluded from the small homosexual'scene', their key social group, thereby lowering their chances of finding sex and love. Most participants had suffered from GWs for several years which added to the negative psycho-sexual and social effects of the disease. Participants' fears of developing anal cancer were similar to those expressed about cervical cancer by females with GWs.

Conclusions

Ano-genital human papillomavirus (HPV) infection is common and has a serious psychological and sexual impact among MSM. However, they do not benefit to the same extent as heterosexual men from the herd immunity effect of HPV vaccination of girls. The pathological profile and concerns specific to MSM should be addressed when communicating with these patients, and should be taken into account when considering HPV vaccination of boys.
Epratuzumab targeting of CD22 affects adhesion molecule expression and migration of B-cells in systemic lupus erythematosus
Authors: Daridon Capucine , Blassfeld Daniela , Reiter Karin , Mei Henrik E , Giesecke Claudia , Goldenberg David M , Hansen Arne , Hostmann Arwed , Frölich Daniela , Dörner Thomas
Published: November 2010

Introduction

Epratuzumab, a humanized anti-CD22 monoclonal antibody, is under investigation as a therapeutic antibody in non-Hodgkin's lymphoma and systemic lupus erythematosus (SLE), but its mechanism of action on B-cells remains elusive. Treatment of SLE patients with epratuzumab leads to a reduction of circulating CD27negative B-cells, although epratuzumab is weakly cytotoxic to B-cells in vitro. Therefore, potential effects of epratuzumab on adhesion molecule expression and the migration of B-cells have been evaluated.

Methods

Epratuzumab binding specificity and the surface expression of adhesion molecules (CD62L, β7 integrin and β1 integrin) after culture with epratuzumab was studied on B-cell subsets of SLE patients by flow cytometry. In addition, in vitro transwell migration assays were performed to analyze the effects of epratuzumab on migration towards different chemokines such as CXCL12, CXCL13 or to CXCR3 ligands, and to assess the functional consequences of altered adhesion molecule expression.

Results

Epratuzumab binding was considerably higher on B-cells relative to other cell types assessed. No binding of epratuzumab was observed on T-cells, while weak non-specific binding of epratuzumab on monocytes was noted. On B-cells, binding of epratuzumab was particularly enhanced on CD27negative B-cells compared to CD27positive B-cells, primarily related to a higher expression of CD22 on CD27negative B-cells. Moreover, epratuzumab binding led to a decrease in the cell surface expression of CD62L and β7 integrin, while the expression of β1 integrin was enhanced. The effects on the pattern of adhesion molecule expression observed with epratuzumab were principally confined to a fraction of the CD27negative B-cell subpopulation and were associated with enhanced spontaneous migration of B-cells. Furthermore, epratuzumab also enhanced the migration of CD27negative B-cells towards the chemokine CXCL12.

Conclusions

The current data suggest that epratuzumab has effects on the expression of the adhesion molecules CD62L, β7 integrin and β1 integrin as well as on migration towards CXCL12, primarily of CD27negative B-cells. Therefore, induced changes in migration appear to be part of the mechanism of action of epratuzumab and are consistent with the observation that CD27negative B-cells were found to be preferentially reduced in the peripheral blood under treatment.
Phosphoinositide 3-kinase γ plays a critical role in bleomycin-induced pulmonary inflammation and fibrosis in mice
Authors: Russo Remo C , Garcia Cristiana C , Barcelos Lucíola S , Rachid Milene A , Guabiraba Rodrigo , Roffê Ester , Souza Adriano L S , Sousa Lirlândia P , Mirolo Massimiliano , Doni Andrea , Cassali Geovanni D , Pinho Vanessa , Locati Massimo , Teixeira Mauro M
Published: November 2010

PI3Kγ is central in signaling diverse arrays of cellular functions and inflammation. Pulmonary fibrosis is associated with pulmonary inflammation, angiogenesis, and deposition of collagen and is modeled by instillation of bleomycin. The role of PI3Kγ in mediating bleomycin-induced pulmonary inflammation and fibrosis in mice and potential mechanisms involved was investigated here. WT or PI3Kγ KO mice were instilled with bleomycin and leukocyte subtype influx, cytokine and chemokine levels, and angiogenesis and tissue fibrosis evaluated. The activation of lung-derived leukocytes and fibroblasts was evaluated in vitro. The relevance of PI3Kγ for endothelial cell function was evaluated in HUVECs. PI3Kγ KO mice had greater survival and weight recovery and less fibrosis than WT mice after bleomycin instillation. This was associated with decreased production of TGF-β1 and CCL2 and increased production of IFN-γ and IL-10. There was reduced expression of collagen, fibronectin, α-SMA, and von Willebrand factor and decreased numbers and activation of leukocytes and phosphorylation of AKT and IκB-α. PI3Kγ KO mice had a reduced number and area of blood vessels in the lungs. In vitro, treatment of human endothelial cells with the PI3Kγ inhibitor AS605240 decreased proliferation, migration, and formation of capillary-like structures. AS605240 also decreased production of collagen by murine lung-derived fibroblasts. PI3Kγ deficiency confers protection against bleomycin-induced pulmonary injury, angiogenesis, and fibrosis through the modulation of leukocyte, fibroblast, and endothelial cell functions. Inhibitors of PI3Kγ may be beneficial for the treatment of pulmonary fibrosis.
Introduction to this special section: Reverse time migration
Authors: Etgen John T. , Michelena Reinaldo J.
Published: November 2010

Reverse time migration (RTM) received its name because its inventors were literally running the time axis of their modeling programs backward and computationally sending waves back into a model of the Earth to make images. By extrapolating waves in time, rather than along the vertical direction, waves could go all directions rather than just within some angle of the vertical. Initial RTM images were astounding for the steep dips they rendered that other methods missed. Equally importantly, because the wave propagation in an RTM algorithm is “complete”, the velocity model didn't have to be smoothed; complex models were no problem as they were with Kirchhoff methods, the main competing steep-dip imaging method. These advantages are easily understood in the context of poststack migration and the exploding reflector model. Prestack RTM is slightly more complicated, requiring simulations of both source and receiver wavefields, but the advantages of extrapolating the time axis remain. Even though this “time reversal of the physics” is conceptually appealing, practical application of RTM languished over the years since its inception in the early 1980s. We think this was partly due to cost, partly due to issues such as internal scattering leading to image artifacts and the difficulties and cost of producing high-quality image gathers, and, finally, partly due to the insufficiency of the data we acquired. We think it's fair to say that RTM is only truly justified on 3D data; so, RTM had to wait for the 3D revolution.
The Involvement of Specific PKC Isoenzymes in Phorbol Ester-Mediated Regulation of Steroidogenic Acute Regulatory Protein Expression and Steroid Synthesis in Mouse Leydig Cells
Authors: Manna Pulak R. , Soh Jae-Won , Stocco Douglas M.
Published: November 2010

Protein kinase C (PKC) is a multigene family of serine/threonine kinases. PKC is involved in regulating adrenal and gonadal steroidogenesis; however, the functional relevance of the different PKC isoenzymes remains obscure. In this study, we demonstrate that MA-10 mouse Leydig tumor cells express several PKC isoforms to varying levels and that the activation of PKC signaling, by phorbol 12-myristate 13-acetate (PMA) elevated the expression and phosphorylation of PKCα, -δ, -ε, and -μ/protein kinase D (PKD). These responses coincided with the expression of the steroidogenic acute regulatory (StAR) protein and progesterone synthesis. Targeted silencing of PKCα, δ, and ε and PKD, using small interfering RNAs, resulted in deceases in basal and PMA-mediated StAR and steroid levels and demonstrated the importance of PKD in steroidogenesis. PKD was capable of controlling PMA and cAMP/PKA-mediated synergism involved in the steroidogenic response. Further studies pointed out that the regulatory events effected by PKD are associated with cAMP response element-binding protein (CREB) and c-Jun/c-Fos-mediated transcription of the StAR gene. Chromatin immunoprecipitation studies revealed that the activation of phosphorylated CREB, c-Jun, and c-Fos by PMA was correlated with in vivo protein-DNA interactions and the recruitment of CREB-binding protein, whereas knockdown of PKD suppressed the association of these factors with the StAR promoter. Ectopic expression of CREB-binding protein enhanced the trans-activation potential of CREB and c-Jun/c-Fos in StAR gene expression. Using EMSA, a −83/−67-bp region of the StAR promoter was shown to bind PKD-transfected MA-10 nuclear extract in a PMA-responsive manner, targeting CREB and c-Jun/c-Fos proteins. These findings provide evidence for the presence of multiple PKC isoforms and demonstrate the molecular events by which selective isozymes, especially PKD, influence PMA/PKC signaling involved in the regulation of the steroidogenic machinery in mouse Leydig cells.
Identification of Adipocyte Genes Regulated by Caloric Intake
Authors: Franck Niclas , Gummesson Anders , Jernås Margareta , Glad Camilla , Svensson Per-Arne , Guillot Gilles , Rudemo Mats , Nyström Fredrik H. , Carlsson Lena M. S. , Olsson Bob
Published: November 2010

abstract

Context:

Changes in energy intake have marked and rapid effects on metabolic functions, and some of these effects may be due to changes in adipocyte gene expression that precede alterations in body weight.

Objective:

The aim of the study was to identify adipocyte genes regulated by changes in caloric intake independent of alterations in body weight.

Research Design and Methods:

Obese subjects given a very low-caloric diet followed by gradual reintroduction of ordinary food and healthy subjects subjected to overfeeding were investigated. Adipose tissue biopsies were taken at multiple time-points, and gene expression was measured by DNA microarray. Genes regulated in the obese subjects undergoing caloric restriction followed by refeeding were identified using two-way ANOVA corrected with Bonferroni. From these, genes regulated by caloric restriction and oppositely during the weight-stable refeeding phase were identified in the obese subjects. The genes that were also regulated, in the same direction as the refeeding phase, in the healthy subjects after overfeeding were defined as being regulated by caloric intake. Results were confirmed using real-time PCR or immunoassay.

Results:

Using a significance level of P < 0.05 for all comparisons, 52 genes were down-regulated, and 50 were up-regulated by caloric restriction and regulated in the opposite direction by refeeding and overfeeding. Among these were genes involved in lipogenesis (ACLY, ACACA, FASN, SCD), control of protein synthesis (4EBP1, 4EBP2), β-oxidation (CPT1B), and insulin resistance (PEDF, SPARC).

Conclusions:

Metabolic genes involved in lipogenesis, protein synthesis, and insulin resistance are central in the transcriptional response of adipocytes to changes in caloric intake.
TNF-α Antagonism with Etanercept Decreases Glucose and Increases the Proportion of High Molecular Weight Adiponectin in Obese Subjects with Features of the Metabolic Syndrome
Authors: Stanley Takara L. , Zanni Markella V. , Johnsen Stine , Rasheed Sarah , Makimura Hideo , Lee Hang , Khor Victor K. , Ahima Rexford S. , Grinspoon Steven K.
Published: November 2010

Context and Objective: Obesity is associated with activation of the TNF-α system, increased inflammatory markers, and insulin resistance. Although studies in rodents suggest that attenuation of TNF activity improves glucose homeostasis, the effect of prolonged inhibition of TNF-α with etanercept on inflammation and glucose homeostasis in a human model of obesity is not known.

Design and Participants: Forty obese subjects with features of metabolic syndrome were randomized to etanercept or placebo, 50 mg twice weekly for 3 months, followed by 50 mg once weekly for 3 months.

Outcome Measures: Subjects underwent oral glucose tolerance testing and measurement of serum inflammatory biomarkers and adipokines. Subcutaneous fat biopsy was performed in a subset for measurement of adipokine and TNF-α mRNA expression.

Results: Visceral adiposity was significantly associated with serum concentrations of TNF receptor 1 (TNFR1), TNFR2, and vascular cell adhesion molecule-1 and adipose tissue expression of TNF-α and SOCS-3 (all P < 0.05). Insulin resistance as assessed by homeostasis model assessment was significantly associated with TNFR1, C-reactive protein, IL-6, and soluble intracellular adhesion molecule-1 (sICAM-1) (all P < 0.05). Etanercept significantly improved fasting glucose (treatment effect vs. placebo over 6 months, −10.8 ± 4.4%, P = 0.02). Etanercept also increased the ratio of high molecular weight adiponectin to total adiponectin (+22.1 ± 9.2% vs. placebo, P = 0.02), and decreased levels of sICAM-1 (−11 ± 2% vs. placebo, P < 0.0001). In contrast, body composition, lipids, C-reactive protein, and IL-6 were unchanged after 6 months.

Conclusions: Prolonged therapy with etanercept improved fasting glucose, increased the ratio of high molecular weight to total adiponectin, and decreased sICAM-1 in obese subjects with abnormal glucose homeostasis and significant subclinical inflammation.
The Effects of Pharmaceutical Marketing and Promotion on Adverse Drug Events and Regulation
Authors: David Guy , Markowitz Sara , Richards-Shubik Seth
Published: October 2010

This paper analyzes the relationship between postmarketing promotional activity and reporting of adverse drug reactions (ADRs) by modeling the interaction between a regulator (the FDA) and a pharmaceutical firm. Promotion-driven market expansions enhance profitability yet may involve the risk of inappropriate drug prescriptions, leading to regulatory actions against the firm. We empirically test the relationship between drug promotion and reporting of ADRs using an innovative combination of commercial data on pharmaceutical promotion and FDA data on regulatory interventions and ADRs. We provide some evidence that increased levels of promotion and advertising lead to increased reporting of ADRs for certain conditions. (JEL L51, L65, M31, M37)
Short-Run Impacts of Accountability on School Quality
Authors: Rockoff Jonah , Turner Lesley J
Published: October 2010

In the fall of 2007, New York City began using student tests and other measures to assign each school a grade (A to F), and linked grades to rewards and consequences, including possible school closure. These grades were released in late September, arguably too late for schools to make major changes in programs or personnel, and students were tested again in January (English) and March (math). Despite this time frame, regression discontinuity estimates indicate that receipt of a low grade significantly increased student achievement, more so in math than English, and improved parental evaluations of school quality. (JEL H75, I21, I28, J45)