Lifelong dynamics of human CD4+CD25+ regulatory T cells: insights from in vivo data and mathematical modeling.

Despite their limited proliferation capacity, regulatory T cells (T(regs)) constitute a population maintained over the entire lifetime of a human organism. The means by which T(regs) sustain a stable pool in vivo are controversial. Using a mathematical model, we address this issue by evaluating several biological scenarios of the origins and the proliferation capacity of two subsets of T(regs): precursor CD4(+)CD25(+)CD45RO(-) and mature CD4(+)CD25(+)CD45RO(+) cells. The lifelong dynamics of T(regs) are described by a set of ordinary differential equations, driven by a stochastic process representing the major immune reactions involving these cells. The model dynamics are validated using data from human donors of different ages. Analysis of the data led to the identification of two properties of the dynamics: (1) the equilibrium in the CD4(+)CD25(+)FoxP3(+)T(regs) population is maintained over both precursor and mature T(regs) pools together, and (2) the ratio between precursor and mature T(regs) is inverted in the early years of adulthood. Then, using the model, we identified three biologically relevant scenarios that have the above properties: (1) the unique source of mature T(regs) is the antigen-driven differentiation of precursors that acquire the mature profile in the periphery and the proliferation of T(regs) is essential for the development and the maintenance of the pool; there exist other sources of mature T(regs), such as (2) a homeostatic density-dependent regulation or (3) thymus- or effector-derived T(regs), and in both cases, antigen-induced proliferation is not necessary for the development of a stable pool of T(regs). This is the first time that a mathematical model built to describe the in vivo dynamics of regulatory T cells is validated using human data. The application of this model provides an invaluable tool in estimating the amount of regulatory T cells as a function of time in the blood of patients that received a solid organ transplant or are suffering from an autoimmune disease.

Epithelial Na+ channel mutants causing Liddle's syndrome retain ability to respond to aldosterone and vasopressin.

Liddle's syndrome is a monogenic form of hypertension caused by mutations in the PY motif of the COOH terminus of beta- and gamma-epithelial Na+ channel (ENaC) subunits. These mutations lead to retention of active channels at the cell surface. Because of the critical role of this PY motif in the stability of ENaCs at the cell surface, we have investigated its contribution to the ENaC response to aldosterone and vasopressin. Mutants of the PY motif in beta- and gamma-ENaC subunits (beta-Y618A, beta-P616L, beta-R564stop, and gamma-K570stop) were stably expressed by retroviral gene transfer in a renal cortical collecting duct cell line (mpkCCDcl4), and transepithelial Na+ transport was assessed by measurements of the benzamil-sensitive short-circuit current (Isc). Cells that express ENaC mutants of the PY motif showed a five- to sixfold higher basal Isc compared with control cells and responded to stimulation by aldosterone (10(-6) M) or vasopressin (10(-9) M) with a further increase in Isc. The rates of the initial increases in Isc after aldosterone or vasopressin stimulation were comparable in cells transduced with wild-type and mutant ENaCs, but reversal of the effects of aldosterone and vasopressin was slower in cells that expressed the ENaC mutants. The conserved sensitivity of ENaC mutants to stimulation by aldosterone and vasopressin together with the prolonged activity at the cell surface likely contribute to the increased Na+ absorption in the distal nephron of patients with Liddle's syndrome.

Field testing of arsenic in groundwater samples of Bangladesh using a test kit based on lyophilized bioreporter bacteria.

A test kit based on living, lyophilized bacterial bioreporters emitting bioluminescence as a response to arsenite and arsenate was applied during a field campaign in six villages across Bangladesh. Bioreporter field measurements of arsenic in groundwater from tube wells were in satisfying agreement with the results of spectroscopic analyses of the same samples conducted in the lab. The practicability of the bioreporter test in terms of logistics and material requirements, suitability for high sample throughput, and waste disposal was much better than that of two commercial chemical test kits that were included as references. The campaigns furthermore demonstrated large local heterogeneity of arsenic in groundwater, underscoring the use of well switching as an effective remedy to avoid high arsenic exposure.

Decreased well-being after job loss : testing omitted causes

Job loss is widely known to lead to a substantial decrease in workers' subjective well-being. Functionalist theories explain this fact by arguing that the fundamental needs that work fulfills are absent during unemployment. Recent evidence from longitudinal studies however contradicts this approach, showing that workers who find a new job do not fully regain their former level of well-being upon reemployment. Therefore other mechanisms must be at work. We suggest that changes in social or economic domains of workers' lives - triggered by job displacement - lead to the observed changes in well-being. Drawing on a unique data set from a survey of workers displaced by plant closure in Switzerland after the financial crisis of 2008, our analysis confirms the previous result that finding a job after displacement does not completely restore workers' pre-displacement level of well-being. The factors that best explain this outcome are changes in social domains, notably changes in workers' job - related social status and their relationships to friends. This result provides valuable insights about the long lasting scars job displacement leaves on workers' lives.

Profiling of 19-norandrosterone sulfate and glucuronide in human urine: implications in athlete's drug testing.

19-Norandrosterone (19-NA) as its glucuronide derivative is the target metabolite in anti-doping testing to reveal an abuse of nandrolone or nandrolone prohormone. To provide further evidence of a doping with these steroids, the sulfoconjugate form of 19-norandrosterone in human urine might be monitored as well. In the present study, the profiling of sulfate and glucuronide derivatives of 19-norandrosterone together with 19-noretiocholanolone (19-NE) were assessed in the spot urines of 8 male subjects, collected after administration of 19-nor-4-androstenedione (100mg). An LC/MS/MS assay was employed for the direct quantification of sulfoconjugates, whereas a standard GC/MS method was applied for the assessment of glucuroconjugates in urine specimens. Although the 19-NA glucuronide derivative was always the most prominent at the excretion peak, inter-individual variability of the excretion patterns was observed for both conjugate forms of 19-NA and 19-NE. The ratio between the glucuro- and sulfoconjugate derivatives of 19-NA and 19-NE could not discriminate the endogenous versus the exogenous origin of the parent compound. However, after ingestion of 100mg 19-nor-4-androstenedione, it was observed in the urine specimens that the sulfate conjugates of 19-NA was detectable over a longer period of time with respect to the other metabolites. These findings indicate that more interest shall be given to this type of conjugation to deter a potential doping with norsteroids.

Reduced learning ability as a consequence of evolutionary adaptation to nutritional stress in Drosophila melanogaster

1. Dietary conditions affect cognitive abilities of many species, but it is unclear to what extent this physiological effect translates into an evolutionary relationship. 2. A reduction of competitive ability under nutritional stress has been reported as a correlated response to selection for learning ability in Drosophila melanogaster. Here we test whether the reverse holds as well, i.e. whether an evolutionary adaptation to poor food conditions leads to a decrease in learning capacities. 3. Populations of D. melanogaster were: (i) not subject to selection (control), (ii) selected for improved learning ability, (iii) selected for survival and fast development on poor food, or (iv) subject to both selection regimes. 4. There was no detectable response to selection for learning ability. 5. Selection on poor food led to higher survival, faster development and smaller adult size as a direct response, and to reduced learning ability as a correlated response. This study supports the hypothesis that adaptation to poor nutrition is likely to trade off with the evolution of improved learning ability.

Organisational PSM Antecedents. Do HRM Practices Matter? Testing the Mediating Role of Job Satisfaction and Organisational Commitment

The present study aims to identify organisational antecedents of public service motivation (PSM). Numerous research has been devoted to the identification of socio-demographic PSM antecedents, or to its outcomes. However, organisational antecedents are understudied thus far. In order to fill this research gap, we question whether human resources management practices, whether intrinsic or extrinsic ones, might be related to PSM. Drawing on person-environment fit theoretical assumptions, we depart from the idea that PSM may be developed or sustained by HRM practices, which might contribute to create an environment allowing public employees to fulfill their needs or personal aspirations. Based upon a survey in an important Swiss municipality (N = 859), our findings surprisingly highlight that extrinsic HRM practices are significantly related to PSM, whereas intrinsic ones are not. Furthermore, when taking into account work-related outcomes, such as job satisfaction and organisational commitment, there is evidence of full mediation effects towards extrinsic HRM practices from organisational commitment. Astonishingly, neither job satisfaction nor intrinsic HRM practices are significantly related to PSM.

Anti-doping testing at the 2008 European football championship.

Big sports events like the 2008 European Football Championship are a challenge for anti-doping activities, particularly when the sports event is hosted by two different countries and there are two laboratories accredited by the World Anti-Doping Agency. This challenges the logistics of sample collection as well as the chemical analyses, which must be carried out timeously. The following paper discusses the handling of whereabouts information for each athlete and the therapeutic use exemption system, experiences in sample collection and transportation of blood and urine samples, and the results of the chemical analysis in two different accredited laboratories. An overview of the analytical results of blood profiling and growth hormone testing in comparison with the distribution of the normal population is also presented.

Bénéfices de l'utilisation d'un test VIH rapide à la permanence PMU-FLON [Benefits of using rapid HIV testing at the PMU-FLON walk-in clinic in Lausanne].

Lab tests are frequently used in primary care to guide patient care. This is particularly the case when a severe disorder, or one that will affect patients' initial care, needs to be excluded rapidly. At the PMU-FLON walk-in clinic the use of HIV testing as recommended by the Swiss Office of Public Health was hampered by the delay in obtaining test results. This led us to introduce rapid HIV testing which provides results within 30 minutes. Following the first 250 tests the authors discuss the results as well as the benefits of rapid HIV testing in an urban walk-in clinic.

Discriminant validity and test-retest reliability of a self-administered Internet-based questionnaire testing doctors' knowledge in evidence-based medicine.

Aims and objectives  This study aimed to determine the discriminant validity and the test-retest reliability of a questionnaire testing the impact of evidence-based medicine (EBM) training on doctors' knowledge and skills. Methods  Questionnaires were sent electronically to all doctors working as residents and chief residents in two French speaking hospital networks in Switzerland. Participants completed the questionnaire twice, within a 4-week interval. The discriminant validity was examined in comparing doctors' performance according to their reported EBM previous training. Proportion of agreement between both sessions of the questionnaire, Cohen's kappa and 'uniform kappa' determined its test-retest reliability. Results  The participation rate was 9.8%/7.1% to first/second session. Performance increased according to the level of doctors' previous training in EBM. The observed proportion of agreement between both sessions was over 70% for 14/19 questions, and the 'uniform kappa' was superior to 0.60 for 15/19 questions. Conclusion  The discriminant validity and test-retest reliability of the questionnaire were satisfying. The low participation rate did not prevent the study from achieving its aims.

Sudden death: ethical and legal problems of post-mortem forensic genetic testing for hereditary cardiac diseases.

Hereditary non-structural diseases such as catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT, and the Brugada syndrome as well as structural disease such as hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) cause a significant percentage of sudden cardiac deaths in the young. In these cases, genetic testing can be useful and does not require proxy consent if it is carried out at the request of judicial authorities as part of a forensic death investigation. Mutations in several genes are implicated in arrhythmic syndromes, including SCN5A, KCNQ1, KCNH2, RyR2, and genes causing HCM. If the victim's test is positive, this information is important for relatives who might be themselves at risk of carrying the disease-causing mutation. There is no consensus about how professionals should proceed in this context. This article discusses the ethical and legal arguments in favour of and against three options: genetic testing of the deceased victim only; counselling of relatives before testing the victim; counselling restricted to relatives of victims who tested positive for mutations of serious and preventable diseases. Legal cases are mentioned that pertain to the duty of geneticists and other physicians to warn relatives. Although the claim for a legal duty is tenuous, recent publications and guidelines suggest that geneticists and others involved in the multidisciplinary approach of sudden death (SD) cases may, nevertheless, have an ethical duty to inform relatives of SD victims. Several practical problems remain pertaining to the costs of testing, the counselling and to the need to obtain permission of judicial authorities.

Chronic potassium depletion increases adrenal progesterone production that is necessary for efficient renal retention of potassium.

Modern dietary habits are characterized by high-sodium and low-potassium intakes, each of which was correlated with a higher risk for hypertension. In this study, we examined whether long-term variations in the intake of sodium and potassium induce lasting changes in the plasma concentration of circulating steroids by developing a mathematical model of steroidogenesis in mice. One finding of this model was that mice increase their plasma progesterone levels specifically in response to potassium depletion. This prediction was confirmed by measurements in both male mice and men. Further investigation showed that progesterone regulates renal potassium handling both in males and females under potassium restriction, independent of its role in reproduction. The increase in progesterone production by male mice was time dependent and correlated with decreased urinary potassium content. The progesterone-dependent ability to efficiently retain potassium was because of an RU486 (a progesterone receptor antagonist)-sensitive stimulation of the colonic hydrogen, potassium-ATPase (known as the non-gastric or hydrogen, potassium-ATPase type 2) in the kidney. Thus, in males, a specific progesterone concentration profile induced by chronic potassium restriction regulates potassium balance.

Testing for potential contextual bias effects during the verification stage of the ACE-V methodology when conducting fingerprint comparisons

This study was conducted to assess if fingerprint specialists could be influenced by extraneous contextual information during a verification process. Participants were separated into three groups: a control group (no contextual information was given), a low bias group (minimal contextual information was given in the form of a report prompting conclusions), and a high bias group (an internationally recognized fingerprint expert provided conclusions and case information to deceive this group into believing that it was his case and conclusions). A similar experiment was later conducted with laypersons. The results showed that fingerprint experts were influenced by contextual information during fingerprint comparisons, but not towards making errors. Instead, fingerprint experts under the biasing conditions provided significantly fewer definitive and erroneous conclusions than the control group. In contrast, the novice participants were more influenced by the bias conditions and did tend to make incorrect judgments, especially when prompted towards an incorrect response by the bias prompt.

Aptitude à la conduite, pathologies psychiatriques et psychotropes chez la personne âgée [Driving ability, mental illness and psychotropic medication in the elderly].

Fitness to drive in elderly drivers is most commonly discussed with a focus on cognitive impairment. Therefore, this article is focussing on mental illness and the use of psychotropic drugs in elderly drivers, which can both interfere with fitness to drive. Based on a detailed literature review and on clinical judgement, we propose signposts and "red flags" to judge the individual risks. Health professionals dealing with elderly patients should in particular be aware of the dangers related to cumulative risks and need to inform the patients appropriately. For medico-legal reasons the information provided to patients must be written down in the medical record. Individual counselling is important as fitness to drive is a complex topic.