CRISPR-Cas system:A new paradigm for bacterial stress response through genome rearrangement

Bacteria can receive genetic material from other bacteria or invading bacteriophages primarily through horizontal gene transfer. These genetic exchanges can result in genome rearrangement and the acquisition of novel traits that assist cells with stresses and adverse environmental conditions. Bacteria have a relatively small genome with >90% of sequences consisting of protein coding genes, stable RNA biomolecules, and gene regulatory sequences. The remaining genome fraction is primarily large repeat elements, such as retrotransposons, interspersed repeat elements, insertion sequences, and the more recently discovered clustered regularly interspaced short palindromic repeats (CRISPRs), with CRISPR-associated gene sequences (cas) that code for various Cas proteins. The CRISPR genetic locus is a series of direct repeats that are interspersed by unique spacer sequences. These unique spacer sequences represent signatures of bacteriophage genomes as the "working memory" for a bacterium to identify and destroy an invading phage genome that has previously infected the host. The protective function of the CRISPR-Cas systems are found in ∼40% of sequenced bacterial genomes, and it is often defined as bacterial acquired immunity. This chapter will elaborate the origin, structure, and function of CRISPR-Cas genetic systems acquired by bacteria, and their role in adaptive fitness while being subjected to environmental stress conditions

T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice

Atherosclerosis is a chronic inflammatory disease driven by hypercholesterolemia. During aging, T cells accumulate cholesterol, potentially affecting inflammation. However, the effect of cholesterol efflux pathways mediated by ATP-binding cassette A1 and G1 (ABCA1/ABCG1) on T cell-dependent age-related inflammation and atherosclerosis remains poorly understood. In this study, we generate mice with T cell-specific Abca1/Abcg1-deficiency on the low-density-lipoprotein-receptor deficient (Ldlr-/-) background. T cell Abca1/Abcg1-deficiency decreases blood, lymph node, and splenic T cells, and increases T cell activation and apoptosis. T cell Abca1/Abcg1-deficiency induces a premature T cell aging phenotype in middle-aged (12-13 months) Ldlr-/- mice, reflected by upregulation of senescence markers. Despite T cell senescence and enhanced T cell activation, T cell Abca1/Abcg1-deficiency decreases atherosclerosis and aortic inflammation in middle-aged Ldlr-/- mice, accompanied by decreased T cells in atherosclerotic plaques. We attribute these effects to T cell apoptosis downstream of T cell activation, compromising T cell functionality. Collectively, we show that T cell cholesterol efflux pathways suppress T cell apoptosis and senescence, and induce atherosclerosis in middle-aged Ldlr-/- mice

The OPTIMIST study: optimisation of cost effectiveness through individualised FSH stimulation dosages for IVF treatment. A randomised controlled trial

Contains fulltext : 109739.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Costs of in vitro fertilisation (IVF) are high, which is partly due to the use of follicle stimulating hormone (FSH). FSH is usually administered in a standard dose. However, due to differences in ovarian reserve between women, ovarian response also differs with potential negative consequences on pregnancy rates. A Markov decision-analytic model showed that FSH dose individualisation according to ovarian reserve is likely to be cost-effective in women who are eligible for IVF. However, this has never been confirmed in a large randomised controlled trial (RCT). The aim of the present study is to assess whether an individualised FSH dose regime based on an ovarian reserve test (ORT) is more cost-effective than a standard dose regime. METHODS/DESIGN: Multicentre RCT in subfertile women indicated for a first IVF or intracytoplasmic sperm injection cycle, who are aged < 44 years, have a regular menstrual cycle and no major abnormalities at transvaginal sonography. Women with polycystic ovary syndrome, endocrine or metabolic abnormalities and women undergoing IVF with oocyte donation, will not be included. Ovarian reserve will be assessed by measuring the antral follicle count. Women with a predicted poor response or hyperresponse will be randomised for a standard versus an individualised FSH regime (150 IU/day, 225-450 IU/day and 100 IU/day, respectively). Participants will undergo a maximum of three stimulation cycles during maximally 18 months. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months after randomisation. Secondary outcomes are parameters for ovarian response, multiple pregnancies, number of cycles needed per live birth, total IU of FSH per stimulation cycle, and costs. All data will be analysed according to the intention-to-treat principle. Cost-effectiveness analysis will be performed to assess whether the health and associated economic benefits of individualised treatment of subfertile women outweigh the additional costs of an ORT. DISCUSSION: The results of this study will be integrated into a decision model that compares cost-effectiveness of the three dose-adjustment strategies to a standard dose strategy. The study outcomes will provide scientific foundation for national and international guidelines. TRIAL REGISTRATION: NTR2657

Adaptation in integrated assessment modeling: where do we stand?

Adaptation is an important element on the climate change policy agenda. Integrated assessment models, which are key tools to assess climate change policies, have begun to address adaptation, either by including it implicitly in damage cost estimates, or by making it an explicit control variable. We analyze how modelers have chosen to describe adaptation within an integrated framework, and suggest many ways they could improve the treatment of adaptation by considering more of its bottom-up characteristics. Until this happens, we suggest, models may be too optimistic about the net benefits adaptation can provide, and therefore may underestimate the amount of mitigation they judge to be socially optimal. Under some conditions, better modeling of adaptation costs and benefits could have important implications for defining mitigation targets. © Springer Science+Business Media B.V. 2009

Miłość jako teologiczne i filozoficzne pojęcie w koncepcji Jana Pawła II

Humankind has been asking the questin about love during the ages. John Paul II took up the theme of Christian love in depth and based it on the theology of body. Pope brought back its real significance by relating this meaning to the betrothal love between woman and man. In his philosophy person is not a means to an end but an end in itself. This love is marked by the common aim, which biases couple in favour of marriage

Exercise therapy and cognitive behavioural therapy to improve fatigue, daily activity performance and quality of life in Postpoliomyelitis Syndrome: the protocol of the FACTS-2-PPS trial

Contains fulltext : 88661.pdf (publisher's version ) (Open Access)BACKGROUND: Postpoliomyelitis Syndrome (PPS) is a complex of late onset neuromuscular symptoms with new or increased muscle weakness and muscle fatigability as key symptoms. Main clinical complaints are severe fatigue, deterioration in functional abilities and health related quality of life. Rehabilitation management is the mainstay of treatment. Two different therapeutic interventions may be prescribed (1) exercise therapy or (2) cognitive behavioural therapy (CBT). However, the evidence on the effectiveness of both interventions is limited. The primary aim of the FACTS-2-PPS trial is to study the efficacy of exercise therapy and CBT for reducing fatigue and improving activities and quality of life in patients with PPS. Additionally, the working mechanisms, patients' and therapists' expectations of and experiences with both interventions and cost-effectiveness will be evaluated. METHODS/DESIGN: A multi-centre, single-blinded, randomized controlled trial will be conducted. A sample of 81 severely fatigued patients with PPS will be recruited from 3 different university hospitals and their affiliate rehabilitation centres. Patients will be randomized to one of three groups i.e. (1) exercise therapy + usual care, (2) CBT + usual care, (3) usual care. At baseline, immediately post-intervention and at 3- and 6-months follow-up, fatigue, activities, quality of life and secondary outcomes will be assessed. Costs will be based on a cost questionnaire, and statistical analyses on GEE (generalized estimated equations). Analysis will also consider mechanisms of change during therapy. A responsive evaluation will be conducted to monitor the implementation process and to investigate the perspectives of patients and therapists on both interventions. DISCUSSION: A major strength of the FACTS-2-PPS study is the use of a mixed methods design in which a responsive and economic evaluation runs parallel to the trial. The results of this study will generate new evidence for the rehabilitation treatment of persons with PPS. TRIAL REGISTRATION: Dutch Trial Register NTR1371

Quality of drug label information on QT interval prolongation

Background: Information regarding QT-prolongation in the drug label may vary between products. This could lead to suboptimal risk minimization strategies. Objective: To systematically assess the variation in the extent and content of information on QT prolongation in the summary of product characteristics (SPC) of recently approved medicinal products. Methods: Drug labels of products centrally approved in Europe between 2006 and 2012 were screened. Of drugs including the term 'QT' in the SPC, the message on QT-prolongation ('no prolongation'/'unclear drug-QT association'/'possibly QT-prolongation'/'QT-prolongation') and the advice on cautionary measures pertaining to QT-prolongation in the label were examined, as well as their association. Results: Of the 175 screened products, 44 contained information on QT in the SPC ('no QT-prolongation': 23%, 'unclear drug-QT association': 43%, 'possibly QT-prolongation': 16%, 'QT-prolongation': 18%). 62% contained advices to act with caution in patients with additional risk factors for QT-prolongation. Products that more likely to have QT-prolonging properties according to the SPC provided more information on QT-prolongation in the SPC ('no prolongation': 10% and for the category 'QT-prolongation': 100%). Conclusions: The extent and content of information on QT-prolongation varies considerably between SPCs, and in almost half of the drugs a clear message on QT-prolongation was lacking in the SPC

CRISPR-Cas system: A new paradigm for bacterial stress response through genome rearrangement

Bacteria can receive genetic material from other bacteria or invading bacteriophages primarily through horizontal gene transfer. These genetic exchanges can result in genome rearrangement and the acquisition of novel traits that assist cells with stresses and adverse environmental conditions. Bacteria have a relatively small genome with >90% of sequences consisting of protein coding genes, stable RNA biomolecules, and gene regulatory sequences. The remaining genome fraction is primarily large repeat elements, such as retrotransposons, interspersed repeat elements, insertion sequences, and the more recently discovered clustered regularly interspaced short palindromic repeats (CRISPRs), with CRISPR-associated gene sequences (cas) that code for various Cas proteins. The CRISPR genetic locus is a series of direct repeats that are interspersed by unique spacer sequences. These unique spacer sequences represent signatures of bacteriophage genomes as the "working memory" for a bacterium to identify and destroy an invading phage genome that has previously infected the host. The protective function of the CRISPR-Cas systems are found in ∼40% of sequenced bacterial genomes, and it is often defined as bacterial acquired immunity. This chapter will elaborate the origin, structure, and function of CRISPR-Cas genetic systems acquired by bacteria, and their role in adaptive fitness while being subjected to environmental stress conditions

Safety information on QT-interval prolongation : comparison of European Union and United States drug labeling

Prolongation of the QT interval can predispose to fatal ventricular arrhythmias. Differences in QT-labeling language can result in miscommunication and suboptimal risk mitigation. We systematically compared the phraseology used to communicate on QT-prolonging properties of 144 drugs newly approved (1st January 2006 to 1st June 2012) in the European Union (EU) and the United States (US), of which 66 mentioned the term 'QT' (two EU only, 28 US only, 36 both). The agreement between authorities about the message on QT prolongation (does not prolong, unclear, possibly prolongs, prolongs) was moderate (kappa 0.434). However, the agreement in expected clinical decisions based on the product labels was much higher (kappa 0.673). The US drug label tends to be more explicit, especially when it considers absence of QT effects. © 2014 Elsevier Ltd. All rights reserved