Trophic specialization influences the rate of environmental niche evolution in damselfishes (Pomacentridae).

The rate of environmental niche evolution describes the capability of species to explore the available environmental space and is known to vary among species owing to lineage-specific factors. Trophic specialization is a main force driving species evolution and is responsible for classical examples of adaptive radiations in fishes. We investigate the effect of trophic specialization on the rate of environmental niche evolution in the damselfish, Pomacentridae, which is an important family of tropical reef fishes. First, phylogenetic niche conservatism is not detected in the family using a standard test of phylogenetic signal, and we demonstrate that the environmental niches of damselfishes that differ in trophic specialization are not equivalent while they still overlap at their mean values. Second, we estimate the relative rates of niche evolution on the phylogenetic tree and show the heterogeneity among rates of environmental niche evolution of the three trophic groups. We suggest that behavioural characteristics related to trophic specialization can constrain the evolution of the environmental niche and lead to conserved niches in specialist lineages. Our results show the extent of influence of several traits on the evolution of the environmental niche and shed new light on the evolution of damselfishes, which is a key lineage in current efforts to conserve biodiversity in coral reefs.

Cost-effectiveness of pharmacotherapies for nicotine dependence in primary care settings: a multinational comparison.

OBJECTIVE: To estimate the incremental cost-effectiveness of the first-line pharmacotherapies (nicotine gum, patch, spray, inhaler, and bupropion) for smoking cessation across six Western countries-Canada, France, Spain, Switzerland, the United States, and the United Kingdom. DESIGN AND STUDY POPULATION: A Markov-chain cohort model to simulate two cohorts of smokers: (1) a reference cohort given brief cessation counselling by a general practitioner (GP); (2) a treatment cohort given counselling plus pharmacotherapy. Effectiveness expressed as odds ratios for quitting associated with pharmacotherapies. Costs based on the additional physician time required and retail prices of the medications. INTERVENTIONS: Addition of each first-line pharmacotherapy to GP cessation counselling. MAIN OUTCOME MEASURES: Cost per life-year saved associated with pharmacotherapies. RESULTS: The cost per life-year saved for counselling only ranged from US190 dollars in Spain to 773 dollars in the UK for men, and from 288 dollars in Spain to 1168 dollars in the UK for women. The incremental cost per life-year saved for gum ranged from 2230 dollars for men in Spain to 7643 dollars for women in the US; for patch from 1758 dollars for men in Spain to 5131 dollars for women in the UK; for spray from 1935 dollars for men in Spain to 7969 dollars for women in the US; for inhaler from 3480 dollars for men in Switzerland to 8700 dollars for women in France; and for bupropion from 792 dollars for men in Canada to 2922 dollars for women in the US. In sensitivity analysis, changes in discount rate, treatment effectiveness, and natural quit rate had the strongest influences on cost-effectiveness. CONCLUSIONS: The cost-effectiveness of the pharmacotherapies varied significantly across the six study countries, however, in each case, the results would be considered favourable as compared to other common preventive pharmacotherapies.

Cost-effectiveness analysis of the first-line therapies for nicotine dependence.

BACKGROUND: Nicotine dependence is the major obstacle for smokers who want to quit. Guidelines have identified five effective first-line therapies, four nicotine replacement therapies (NRTs)--gum, patch, nasal spray and inhaler--and bupropion. Studying the extent to which these various treatments are cost-effective requires additional research. OBJECTIVES: To determine cost-effectiveness (CE) ratios of pharmacotherapies for nicotine dependence provided by general practitioners (GPs) during routine visits as an adjunct to cessation counselling. METHODS: We used a Markov model to generate two cohorts of one-pack-a-day smokers: (1) the reference cohort received only cessation counselling from a GP during routine office visits; (2) the second cohort received the same counselling plus an offer to use a pharmacological treatment to help them quit smoking. The effectiveness of adjunctive therapy was expressed in terms of the resultant differential in mortality rate between the two cohorts. Data on the effectiveness of therapies came from meta-analyses, and we used odds ratio for quitting as the measure of effectiveness. The costs of pharmacotherapies were based on the cost of the additional time spent by GPs offering, prescribing and following-up treatment, and on the retail prices of the therapies. We used the third-party-payer perspective. Results are expressed as the incremental cost per life-year saved. RESULTS: The cost per life-year saved for only counselling ranged from Euro 385 to Euro 622 for men and from Euro 468 to Euro 796 for women. The CE ratios for the five pharmacological treatments varied from Euro 1768 to Euro 6879 for men, and from Euro 2146 to Euro 8799 for women. Significant variations in CE ratios among the five treatments were primarily due to differences in retail prices. The most cost-effective treatments were bupropion and the patch, and, then, in descending order, the spray, the inhaler and, lastly, gum. Differences in CE between men and women across treatments were due to the shape of their respective mortality curve. The lowest CE ratio in men was for the 45- to 49-year-old group and for women in the 50- to 54-year-old group. Sensitivity analysis showed that changes in treatment efficacy produced effects only for less-well proven treatments (spray, inhaler, and bupropion) and revealed a strong influence of the discount rate and natural quit rate on the CE of pharmacological treatments. CONCLUSION: The CE of first-line treatments for nicotine dependence varied widely with age and sex and was sensitive to the assumption for the natural quit rate. Bupropion and the nicotine patch were the two most cost-effective treatments.

Cost-effectiveness analysis of a European primary-care physician training in smoking cessation counseling.

BACKGROUND: Physician training in smoking cessation counseling has been shown to be effective as a means to increase quit success. We assessed the cost-effectiveness ratio of a smoking cessation counseling training programme. Its effectiveness was previously demonstrated in a cluster randomized, control trial performed in two Swiss university outpatients clinics, in which residents were randomized to receive training in smoking interventions or a control educational intervention. DESIGN AND METHODS: We used a Markov simulation model for effectiveness analysis. This model incorporates the intervention efficacy, the natural quit rate, and the lifetime probability of relapse after 1-year abstinence. We used previously published results in addition to hospital service and outpatient clinic cost data. The time horizon was 1 year, and we opted for a third-party payer perspective. RESULTS: The incremental cost of the intervention amounted to US$2.58 per consultation by a smoker, translating into a cost per life-year saved of US$25.4 for men and 35.2 for women. One-way sensitivity analyses yielded a range of US$4.0-107.1 in men and US$9.7-148.6 in women. Variations in the quit rate of the control intervention, the length of training effectiveness, and the discount rate yielded moderately large effects on the outcome. Variations in the natural cessation rate, the lifetime probability of relapse, the cost of physician training, the counseling time, the cost per hour of physician time, and the cost of the booklets had little effect on the cost-effectiveness ratio. CONCLUSIONS: Training residents in smoking cessation counseling is a very cost-effective intervention and may be more efficient than currently accepted tobacco control interventions.

Resting metabolic rate and protein turnover in apparently healthy elderly Gambian men.

Body composition, resting energy expenditure (REE), and whole body protein metabolism were studied in 26 young and 28 elderly Gambian men matched for body mass index during the dry season in a rural village in The Gambia. REE was measured by indirect calorimetry (hood system) in the fasting state and after five successive meals. Rates of whole body nitrogen flux, protein synthesis, and protein breakdown were determined in the fed state from the level of isotopic enrichment of urinary ammonia over a period of 12 h after a single oral dose of [15N]glycine. Expressed in absolute value, REE was significantly lower in the elderly compared with the young group (3.21 +/- 0.07 vs. 4.04 +/- 0.07 kJ/min, P < 0.001) and when adjusted to body weight (3.29 +/- 0.05 vs. 3.96 +/- 0.05 kJ/min, P < 0.0001) and fat-free mass (FFM; 3.38 +/- 0.01 vs. 3.87 +/- 0.01 kJ/min, P < 0.0001). The rate of protein synthesis averaged 207 +/- 13 g protein/day in the elderly and 230 +/- 13 g protein/day in the young group, whereas protein breakdown averaged 184 +/- 13 g protein/day in the elderly and 203 +/- 13 g protein/day in the young group (nonsignificant). When values were adjusted for body weight or FFM, they did not reveal any difference between the two groups. It is concluded that the reduced REE adjusted for body composition observed in elderly Gambian men is not explained by a decrease in protein turnover.

Phenotypic heterogeneity of antigen-specific CD4 cells under different conditions of antigen persistence and antigen load

RESUME Nous n'avons pas de connaissance précise des facteurs à l'origine de l'hétérogénéité phénotypique des cellules T CD4 mémoires. Une troisième population phénotypique des cellules T CD4 mémoires, caractérisée par les marqueurs CD45RA+CCR7- a été identifiée dans cette étude. Cette population présente un état de différentiation avancée, comme en témoigne son histoire de réplication, ainsi que sa capacité de prolifération homéostatique. Les réponses des cellules T CD4 mémoires à différentes conditions de persistance et charge antigénique ont trois patterns phénotypiques différents, caractérisés par les marqueurs CD45RA et CCR7. La réponse CD4 mono -phénotypique CD45RA-CCR7+ ou CD45RA- CCR7- est associée à des conditions d'élimination de l'antigène (telle la réponse CD4 tétanos spécifique) ou à des conditions de persistance antigénique et de virémie élevée (telle la réponse HIV chronique ou la primo-infection CMV) respectivement. D'autre part, les réponses T CD4 multi -phénotypiques CD45RA-CCR7+ sont associées à des conditions d'exposition antigénique prolongée et de faible virémie (telles les infections CMV, EBV et HSV ou les infections HIV chez les long term non progressons). La réponse mono -phénotypique CD45RA- CCR7+ est propre aux cellules T CD4 secrétant de IL2, définies également comme centrales mémoires, la réponse CD45RA- CCR7- aux cellules T CD4 secrétant de l'IFNγ et finalement la réponse mufti-phénotypique aux cellules T CD4 secrétant à la fois de l'IL2 et de l' IFNγ. En conclusion, ces résultats témoignent d'une régulation de l'hétérogénéité phénotypique par l'exposition et la charge antigénique. ABSTRACT The factors responsible for the phenotypic heterogeneity of memory CD4 T cells are unclear. In the present study, we have identified a third population of memory CD4 T cells characterized as CD45RA+CCRT that, based on its replication history and the homeostatic proliferative capacity, was at an advanced stage of differentiation. Three different phenotypic patterns of memory CD4 T cell responses were delineated under different conditions of antigen (Ag) persistence and load using CD45RA and CCR7 as markers of memory T cells. Mono-phenotypic CD45RA'CCR7+ or CD45RA'CCR7' CD4 T cell responses were associated with conditions of Ag clearance (tetanus toxoid-specific CD4 T cell response) or Ag persistence and high load (chronic HIV-1 and primary CMV infections), respectively. Multi-phenotypic CD45RA CCR7+, CD45RA'CCRT and CD45RA+CCRT CD4 T cell responses were associated with protracted Ag exposure and low load (chronic CMV, EBV and HSV infections and HIV-1 infection in long-term nonprogressors). The mono-phenotypic CD45RA'CCR7+ response was typical of central memory (TCM) IL-2-secreting CD4 T cells, the mono-phenotypic CD45RA CCRT response of effector memory (TEM) IFN-γ -secreting CD4 T cells and the multi-phenotypic response of both IL-2- and IFN-γ -secreting cells. The present results indicate that the heterogeneity of different Ag-specific CD4 T cell responses is regulated by Ag exposure and Ag load.

Heterogeneity of atherosclerotic plaque phenotypes and composition in four different arterial beds: an intravascular ultrasound virtual histology study

Purpose: The purpose of this study was to compare the plaque morphology between coronary and peripheral arteries using intravascular ultrasound (IVUS). Methods: IVUS was performed in 68 patients with coronary and 93 with peripheral artery lesions (29 carotid, 50 renal, and 14 iliac). Plaques were classified as fibroatheroma (VH-FA) (further subclassified as thin-capped [VH-TCFA] and thick-capped [VH-ThCFA]), fibrocalcific plaque (VH-FC) and pathological intimal thickening (VH-PIT). Results: Plaque rupture (13% of coronary, 7% of carotid, 6% of renal, and 7% of iliac arteries; P=NS) and VH-TCFA (37% of coronary, 24% of carotid, 16% of renal, and 7% of iliac arteries; P=0.02) was observed in all arteries. Compared to coronary arteries, VH-FA was less frequently observed in renal (P<0.001) and iliac arteries (P<0.006), while VH-PIT and VH-FC were prevalent in both of these peripheral arteries. Lesions with positive remodeling demonstrated more characteristics of VH-FA in coronary, carotid, and renal arteries compared to those with intermediate/negative remodeling (all P<0.01). There was positive relationship between RI and percent necrotic core area in all four arteries. Conclusions: Atherosclerotic plaque phenotypes were heterogeneous among four different arteries. In contrast, the associations of remodeling mode with plaque phenotype and composition were similar among the various arterial beds.

Acute endotoxemia inhibits microvascular nitric oxide-dependent vasodilation in humans.

Nitric oxide (NO) is crucial for the microvascular homeostasis, but its role played in the microvascular alterations during sepsis remains controversial. We investigated NO-dependent vasodilation in the skin microcirculation and plasma levels of asymmetric dimethylarginine (ADMA), a potent endogenous inhibitor of the NO synthases, in a human model of sepsis. In this double-blind, randomized, crossover study, microvascular NO-dependent (local thermal hyperemia) and NO-independent vasodilation (post-occlusive reactive hyperemia) assessed by laser Doppler imaging, plasma levels of ADMA, and l-arginine were measured in seven healthy obese volunteers, immediately before and 4 h after either a i.v. bolus injection of Escherichia coli endotoxin (LPS; 2 ng/kg) or normal saline (placebo) on two different visits at least 2 weeks apart. LPS caused the expected systemic effects, including increases in heart rate (+43%, P < 0.001), cardiac output (+16%, P < 0.01), and rectal temperature (+1.4°C, P < 0.001), without change in arterial blood pressure. LPS affected neither baseline skin blood flow nor post-occlusive reactive hyperemia but decreased the NO-dependent local thermal hyperemia response, l-arginine, and, to a lesser extent, ADMA plasma levels. The changes in NO-dependent vasodilation were not correlated with the corresponding changes in the plasma levels of ADMA, l-arginine, or the l-arginine/ADMA ratio. Our results show for the first time that experimental endotoxemia in humans causes a specific decrease in endothelial NO-dependent vasodilation in the microcirculation, which cannot be explained by a change in ADMA levels. Microvascular NO deficiency might be responsible for the heterogeneity of tissue perfusion observed in sepsis and could be a therapeutic target.

Identification of C7orf11 (TTDN1) gene mutations and genetic heterogeneity in nonphotosensitive trichothiodystrophy.

We have identified C7orf11, which localizes to the nucleus and is expressed in fetal hair follicles, as the first disease gene for nonphotosensitive trichothiodystrophy (TTD). C7orf11 maps to chromosome 7p14, and the disease locus has been designated "TTDN1" (TTD nonphotosensitive 1). Mutations were found in patients with Amish brittle-hair syndrome and in other nonphotosensititive TTD cases with mental retardation and decreased fertility but not in patients with Sabinas syndrome or Pollitt syndrome. Therefore, genetic heterogeneity in nonphotosensitive TTD is a feature similar to that observed in photosensitive TTD, which is caused by mutations in transcription factor II H (TFIIH) subunit genes. Comparative immunofluorescence analysis, however, suggests that C7orf11 does not influence TFIIH directly. Given the absence of cutaneous photosensitivity in the patients with C7orf11 mutations, together with the protein's nuclear localization, C7orf11 may be involved in transcription but not DNA repair.

Methicillin-susceptible Staphylococcus aureus clonal complex 398: high prevalence and geographical heterogeneity in bone and joint infection and nasal carriage.

The prevalence of clonal complex (CC) 398 methicillin-susceptible Staphylococcus aureus (MSSA) was unexpectedly high among bone and joint infections (BJIs) and nasal-colonizing isolates in France, with surprising geographical heterogeneity. With none of the major, most-known staphylococcal virulence genes, MSSA CC398 BJI was associated with lower biological inflammatory syndrome and lower treatment failure rates.

Reduction of small infrarenal abdominal aortic aneurysm expansion rate by statins.

BACKGROUND: To evaluate the effect of statins on the annual expansion rate (ER) of small infrarenal abdominal aortic aneurysms (AAA). PATIENTS AND METHODS: All patients under regular surveillance for small AAA between January 2000 and September 2007, in the Department of Angiology, Lausanne University Hospital, were included. Inclusion criteria were baseline abdominal aortic diameter between 25 and 55 mm, at least two measurements of AAA diameter and a minimum follow up of 6 months. Patients with Marfan disease, infectious or inflammatory AAA, and patients with prior AAA repair were excluded. The influence of statin use and other factors on ER were examined by bivariate and multivariate analysis. RESULTS: Among 589 patients who underwent an abdominal aorta evaluation, 94 patients (89 % men, mean age 69.1 years) were finally included in the analysis. Baseline AAA size was 39.9 ± 7.7 mm (mean±SE) and 48.7 ± 8.4 mm at end of follow-up. Patients had a regular aneurysm size assessment during 38.5 ± 27.7 months. Mean ER was 3.59 mm/y (± 2.81). The 50 patients who were treated with statin during the study period had a lower ER compared to the 44 controls (2.91 vs 4.37 mm/year, p = 0.01). CONCLUSIONS: This study confirms the considerable individual variations in the AAA expansion rate, and emphasizes the need for regular aortic diameter assessments. In this study, patients treated with statin demonstrate a significant decrease in the ER compared to controls. This finding need to be evaluated in prospective interventional studies powered to demonstrate the potential benefit of statin treatment.

Stochastic demography and the neutral substitution rate in class-structured populations.

The neutral rate of allelic substitution is analyzed for a class-structured population subject to a stationary stochastic demographic process. The substitution rate is shown to be generally equal to the effective mutation rate, and under overlapping generations it can be expressed as the effective mutation rate in newborns when measured in units of average generation time. With uniform mutation rate across classes the substitution rate reduces to the mutation rate.