The international development of the RGHQoL: a quality of life measure for recurrent genital herpes.

This paper describes the international development and psychometric testing of the Recurrent Genital Herpes Quality of Life Questionnaire (RGHQoL), a condition-specific quality of life (QoL) instrument. The theoretical foundation for the measure is the needs-based model of QoL and the content of the instrument was derived from in-depth qualitative interviews with relevant patients in the UK. Versions of the RGHQoL were required for the UK, USA, Italy, Germany, France and Denmark for use in international clinical trials. The results indicate that the final 20 item measure has good reliability, internal consistency and validity for all language versions. A small responsiveness study in Denmark suggested that the measure is sensitive to changes in QoL associated with the initiation of suppression treatment for recurrent genital herpes (RGH). It is concluded that the RGHQoL is a valuable instrument for inclusion in clinical trials. The psychometric properties of the instrument are such that it may also be used to monitor the progress of individual patients.

The weaker points of fish acute toxicity tests and how tests on embryos can solve some issues.

Fish acute toxicity tests play an important role in environmental risk assessment and hazard classification because they allow for first estimates of the relative toxicity of various chemicals in various species. However, such tests need to be carefully interpreted. Here we shortly summarize the main issues which are linked to the genetics and the condition of the test animals, the standardized test situations, the uncertainty about whether a given test species can be seen as representative to a given fish fauna, the often missing knowledge about possible interaction effects, especially with micropathogens, and statistical problems like small sample sizes and, in some cases, pseudoreplication. We suggest that multi-factorial embryo tests on ecologically relevant species solve many of these issues, and we shortly explain how such tests could be done to avoid the weaker points of fish acute toxicity tests.

Mapping the transcription start points of the Staphylococcus aureus eap, emp, and vwb promoters reveals a conserved octanucleotide sequence that is essential for expression of these genes.

Mapping the transcription start points of the eap, emp, and vwb promoters revealed a conserved octanucleotide sequence (COS). Deleting this sequence abolished the expression of eap, emp, and vwb. However, electrophoretic mobility shift assays gave no evidence that this sequence was a binding site for SarA or SaeR, known regulators of eap and emp.

The career engagement scale : Development and validation of a measure of proactive career behaviors

Careers today increasingly require engagement in proactive career behaviors; however, there is a lack of validated measures assessing the general degree to which somebody is engaged in such career behaviors. We describe the results of six studies with six independent samples of German university students (total N = 2,854), working professionals (total N = 561), and university graduates (N = 141) that report the development and validation of the Career Engagement Scale - a measure of the degree to which somebody is proactively developing her or his career as expressed by diverse career behaviors. The studies provide support for measurement invariance across gender and time. In support of convergent and discriminant validity, we find that career engagement is more prevalent among working professionals than among university students and that this scale has incremental validity above several specific career behaviors regarding its relation to vocational identity clarity and career self-efficacy beliefs among students and to job and career satisfaction among employees. In support of incremental predictive validity, beyond the effects of several more specific career behaviors, career engagement while at university predicts higher job and career satisfaction several months later after beginning work.

Precision of a new tool to measure visceral adipose tissue (VAT) using dual-energy X-Ray absorptiometry (DXA).

OBJECTIVE: A new tool to quantify visceral adipose tissue (VAT) over the android region of a total body dual-energy x-ray absorptiometry (DXA) scan has recently been reported. The measurement, CoreScan, is currently available on Lunar iDXA densitometers. The purpose of the study was to determine the precision of the CoreScan VAT measurement, which is critical for understanding the utility of this measure in longitudinal trials. DESIGN AND METHODS: VAT precision was characterized in both an anthropomorphic imaging phantom (measured on 10 Lunar iDXA systems) and a clinical population consisting of obese women (n = 32). RESULTS: The intrascanner precision for the VAT phantom across 9 quantities of VAT mass (0-1,800 g) ranged from 28.4 to 38.0 g. The interscanner precision ranged from 24.7 to 38.4 g. There was no statistical dependence on the quantity of VAT for either the inter- or intrascanner precision result (p = 0.670). Combining inter- and intrascanner precision yielded a total phantom precision estimate of 47.6 g for VAT mass, which corresponds to a 4.8% coefficient of variance (CV) for a 1 kg VAT mass. Our clinical population, who completed replicate total body scans with repositioning between scans, showed a precision of 56.8 g on an average VAT mass of 1110.4 g. This corresponds to a 5.1% CV. Hence, the in vivo precision result was similar to the phantom precision result. CONCLUSIONS: The study suggests that CoreScan has a relatively low precision error in both phantoms and obese women and therefore may be a useful addition to clinical trials where interventions are targeted towards changes in visceral adiposity.

Development of the Crohn's disease digestive damage score, the Lémann score.

Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. (Inflamm Bowel Dis 2011).

Quantifying the level of eusociality

The evolution of animal societies in which some individuals forego direct reproduction to help others to reproduce poses an evolutionary paradox. Societies where all individuals reproduce equally and societies where a single individual completely monopolizes reproduction represent the end points of a continuum of variance in the reproductive output among group members. This led Sherman et al. (1995) to propose that cooperative breeding and eusociality (a term originally applied only to insects) are not discrete phenomena. Rather they form a continuum whose main difference is the extent to which individuals forego their own reproductive opportunity to help other members of the group. Here we present a new index: the eusociality index. It quantifies the decrease in direct reproduction of group members as a resut of altruistic acts directed to other members of the group (i.e. a measure of the level of eusociality). The rationale for this index lies in the fundamental duality of the reproductive process, in which organisms supply two distinct elements: (i) genetic material (genes); and (ii) power (energy). In non-eusocial animals, all individuals transmit genes and power in the same ratio (notwithstanding individual variance in offspring size and parental investment). By contrast, amongst eusocial animals some individuals contribute proportionally more to gene transfer, and others more to energy, resulting in high interindividual variation in the ratio of gene to power transfer.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: developing European guidelines in clinical microbiology and infectious diseases.

The process to develop a guideline in a European setting remains a challenge. The ESCMID Fungal Infection Study Group (EFISG) successfully achieved this endeavour. After two face-to-face meetings, numerous telephone conferences, and email correspondence, an ESCMID task force (basically composed of members of the Society's Fungal Infection Study Group, EFISG) finalized the ESCMID diagnostic and management/therapeutic guideline for Candida diseases. By appreciating various patient populations at risk for Candida diseases, four subgroups were predefined, mainly ICU patients, paediatric, HIV/AIDS and patients with malignancies including haematopoietic stem cell transplantation. Besides treatment recommendations, the ESCMID guidelines provide guidance for diagnostic procedures. For the guidelines, questions were formulated to phrase the intention of a given recommendation, for example, outcome. The recommendation was the clinical intervention, which was graded by a score of A-D for the 'Strength of a recommendation'. The 'level of evidence' received a score of I-III. The author panel was approved by ESCMID, European Organisation for Research and Treatment of Cancer, European Group for Blood and Marrow Transplantation, European Society of Intensive Care Medicine and the European Confederation of Medical Mycology. The guidelines followed the framework of GRADE and Appraisal of Guidelines, Research, and Evaluation. The drafted guideline was presented at ECCMID 2011 and points of discussion occurring during that meeting were incorporated into the manuscripts. These ESCMID guidelines for the diagnosis and management of Candida diseases provide guidance for clinicians in their daily decision-making process.

Gains from switching and evolutionary stability in multi-player matrix games.

In this paper we unify, simplify, and extend previous work on the evolutionary dynamics of symmetric N-player matrix games with two pure strategies. In such games, gains from switching strategies depend, in general, on how many other individuals in the group play a given strategy. As a consequence, the gain function determining the gradient of selection can be a polynomial of degree N-1. In order to deal with the intricacy of the resulting evolutionary dynamics, we make use of the theory of polynomials in Bernstein form. This theory implies a tight link between the sign pattern of the gains from switching on the one hand and the number and stability of the rest points of the replicator dynamics on the other hand. While this relationship is a general one, it is most informative if gains from switching have at most two sign changes, as is the case for most multi-player matrix games considered in the literature. We demonstrate that previous results for public goods games are easily recovered and extended using this observation. Further examples illustrate how focusing on the sign pattern of the gains from switching obviates the need for a more involved analysis.

Task force IV: Clinical use of ambulatory blood pressure monitoring. Participants of the 1999 Consensus Conference on Ambulatory Blood Pressure Monitoring

OBJECTIVE: To reach a consensus on the clinical use of ambulatory blood pressure monitoring (ABPM). METHODS: A task force on the clinical use of ABPM wrote this overview in preparation for the Seventh International Consensus Conference (23-25 September 1999, Leuven, Belgium). This article was amended to account for opinions aired at the conference and to reflect the common ground reached in the discussions. POINTS OF CONSENSUS: The Riva Rocci/Korotkoff technique, although it is prone to error, is easy and cheap to perform and remains worldwide the standard procedure for measuring blood pressure. ABPM should be performed only with properly validated devices as an accessory to conventional measurement of blood pressure. Ambulatory recording of blood pressure requires considerable investment in equipment and training and its use for screening purposes cannot be recommended. ABPM is most useful for identifying patients with white-coat hypertension (WCH), also known as isolated clinic hypertension, which is arbitrarily defined as a clinic blood pressure of more than 140 mmHg systolic or 90 mmHg diastolic in a patient with daytime ambulatory blood pressure below 135 mmHg systolic and 85 mmHg diastolic. Some experts consider a daytime blood pressure below 130 mmHg systolic and 80 mmHg diastolic optimal. Whether WCH predisposes subjects to sustained hypertension remains debated. However, outcome is better correlated to the ambulatory blood pressure than it is to the conventional blood pressure. Antihypertensive drugs lower the clinic blood pressure in patients with WCH but not the ambulatory blood pressure, and also do not improve prognosis. Nevertheless, WCH should not be left unattended. If no previous cardiovascular complications are present, treatment could be limited to follow-up and hygienic measures, which should also account for risk factors other than hypertension. ABPM is superior to conventional measurement of blood pressure not only for selecting patients for antihypertensive drug treatment but also for assessing the effects both of non-pharmacological and of pharmacological therapy. The ambulatory blood pressure should be reduced by treatment to below the thresholds applied for diagnosing sustained hypertension. ABPM makes the diagnosis and treatment of nocturnal hypertension possible and is especially indicated for patients with borderline hypertension, the elderly, pregnant women, patients with treatment-resistant hypertension and patients with symptoms suggestive of hypotension. In centres with sufficient financial resources, ABPM could become part of the routine assessment of patients with clinic hypertension. For patients with WCH, it should be repeated at annual or 6-monthly intervals. Variation of blood pressure throughout the day can be monitored only by ABPM, but several advantages of the latter technique can also be obtained by self-measurement of blood pressure, a less expensive method that is probably better suited to primary practice and use in developing countries. CONCLUSIONS: ABPM or equivalent methods for tracing the white-coat effect should become part of the routine diagnostic and therapeutic procedures applied to treated and untreated patients with elevated clinic blood pressures. Results of long-term outcome trials should better establish the advantage of further integrating ABPM as an accessory to conventional sphygmomanometry into the routine care of hypertensive patients and should provide more definite information on the long-term cost-effectiveness. Because such trials are not likely to be funded by the pharmaceutical industry, governments and health insurance companies should take responsibility in this regard.

Segmentation of brain structures in presence of a space-occupying lesion.

Brain deformations induced by space-occupying lesions may result in unpredictable position and shape of functionally important brain structures. The aim of this study is to propose a method for segmentation of brain structures by deformation of a segmented brain atlas in presence of a space-occupying lesion. Our approach is based on an a priori model of lesion growth (MLG) that assumes radial expansion from a seeding point and involves three steps: first, an affine registration bringing the atlas and the patient into global correspondence; then, the seeding of a synthetic tumor into the brain atlas providing a template for the lesion; finally, the deformation of the seeded atlas, combining a method derived from optical flow principles and a model of lesion growth. The method was applied on two meningiomas inducing a pure displacement of the underlying brain structures, and segmentation accuracy of ventricles and basal ganglia was assessed. Results show that the segmented structures were consistent with the patient's anatomy and that the deformation accuracy of surrounding brain structures was highly dependent on the accurate placement of the tumor seeding point. Further improvements of the method will optimize the segmentation accuracy. Visualization of brain structures provides useful information for therapeutic consideration of space-occupying lesions, including surgical, radiosurgical, and radiotherapeutic planning, in order to increase treatment efficiency and prevent neurological damage.

Recombinant erythropoietin in acute chemotherapy-induced anemia of children with cancer.

Chemotherapy-induced anemia in children with cancer is usually of acute onset. To investigate an alternate treatment to transfusion (Tx), we undertook a phase I-II clinical trial of daily administrations of recombinant erythropoietin (rHuEPO). Patients with a hemoglobin (Hgb) value < 75 g/l were treated for 14 days in cohorts of 3 at escalating daily doses of 25, 50, 70, 80, 90, and 100 U/kg respectively. The maximum-tolerated dose was not encountered. Of 18 courses given to 15 children aged 0.5-18 years, 7 (39%) were associated with increased or stable Hgb levels (courses without Tx), while 11 (61%) were terminated by a Tx, without evidence of a dose-response relationship. Changes in mean Hgb levels and absolute reticulocyte counts were paralleled by those of mean white blood cell, platelet, and absolute neutrophil counts during the first 7 days and when the end-points of the study were reached. Numbers of circulating burst-forming units-erythroid remained low throughout courses without Tx. No cumulative increase of serially determined serum EPO levels was observed and serum ferritin levels were elevated in both groups of courses. We conclude that daily administration of rHuEPO were safe but ineffective in our trial. Recovery of chemotherapy-induced myelosuppression appeared to be the rate-limiting factor for the outcome, without evidence of an enhanced stimulation of erythropoiesis. The lack of a proliferative response of specific progenitor cells suggested a mechanism of transient primary resistance to rHuEPO.

Treatment of atypical hemolytic uremic syndrome and thrombotic microangiopathies: a focus on eculizumab.

Uncontrolled complement activation is central to the occurrence of atypical hemolytic uremic syndrome (aHUS) and can result in thrombotic microangiopathies (TMAs).These terms encompass a group of heterogenic inherited or acquired diseases that recent research suggests may be triggered by the complement cascade. Pathogenetic triggers of complement activation include immunologic disorders, genetics, infections, systemic diseases, pregnancy, drug administration, metabolic diseases, transplantation, or triggers of mixed cause. Hallmarks of aHUS and other TMAs include increased vascular endothelium thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, coagulation abnormalities, and vascular shear stress, whereas common end points of these mechanisms include hemolytic anemia, thrombocytopenia with microvascular infarction, and predisposition for decreased kidney function and other organ involvement. The central role of the complement cascade as a disease trigger suggests a possible therapeutic target. Eculizumab, a first-in-class humanized monoclonal anti-C5 antibody that has been successful in the treatment of paroxysmal nocturnal hemoglobinuria, a disorder of complement-induced hemolytic anemia, received approval for the treatment of aHUS in the United States and Europe in late 2011. We review the treatment of aHUS and other TMAs, focusing on the role of eculizumab, including its pharmacology, mechanism of action, and approved dosing recommendations and health economic considerations. Finally, the potential for future indications for eculizumab use in other complement-driven diseases is discussed.

Spatial and temporal dynamics of jasmonate synthesis and accumulation in Arabidopsis in response to wounding.

A new metabolite profiling approach combined with an ultrarapid sample preparation procedure was used to study the temporal and spatial dynamics of the wound-induced accumulation of jasmonic acid (JA) and its oxygenated derivatives in Arabidopsis thaliana. In addition to well known jasmonates, including hydroxyjasmonates (HOJAs), jasmonoyl-isoleucine (JA-Ile), and its 12-hydroxy derivative (12-HOJA-Ile), a new wound-induced dicarboxyjasmonate, 12-carboxyjasmonoyl-l-isoleucine (12-HOOCJA-Ile) was discovered. HOJAs and 12-HOOCJA-Ile were enriched in the midveins of wounded leaves, strongly differentiating them from the other jasmonate metabolites studied. The polarity of these oxylipins at physiological pH correlated with their appearance in midveins. When the time points of accumulation of different jasmonates were determined, JA levels were found to increase within 2-5 min of wounding. Remarkably, these changes occurred throughout the plant and were not restricted to wounded leaves. The speed of the stimulus leading to JA accumulation in leaves distal to a wound is at least 3 cm/min. The data give new insights into the spatial and temporal accumulation of jasmonates and have implications in the understanding of long-distance wound signaling in plants.