The main aim of the Leucémies de l’Enfant et l’Adolescent (LEA) project (Childhood and Adolescent Leukaemia) is to study the determinants (medical, socioeconomic, behavioural and environmental) of medium- and long-term outcomes of patients treated for childhood acute leukaemia (AL). The LEA study began in 2004 and is based on a French multicentric prospective cohort. Included are children treated for AL since January 1980 (incident and prevalent cases), surviving at month 24 for myeloblastic AL and lymphoblastic AL grafted in first complete remission or at month 48 for lymphoblastic AL not grafted in first complete remission. Information is collected during specific medical visits and notably includes the following data: socioeconomic data, AL history, physical late effects (such as fertility, cardiac function and metabolic syndrome) and quality of life. Data are collected every 2 years until the patient is 20 years old and has had a 10-year follow-up duration from diagnosis or last relapse. Thereafter, assessments are planned every 4 years. In active centres in 2013, eligible patients number more than 3000. The cohort has already included 2385 survivors, with rate of exhaustiveness of almost 80%. Data access can be requested from principal coordinators and must be approved by the steering committee.
Recent genome analyses suggest that integrative and conjugative elements (ICEs) are widespread in bacterial genomes and therefore play an essential role in horizontal transfer. However, only a few of these elements are precisely characterized and correctly delineated within sequenced bacterial genomes. Even though previous analysis showed the presence of ICEs in some species of Streptococci, the global prevalence and diversity of ICEs was not analyzed in this genus. In this study, we searched for ICEs in the completely sequenced genomes of 124 strains belonging to 27 streptococcal species. These exhaustive analyses revealed 105 putative ICEs and 26 slightly decayed elements whose limits were assessed and whose insertion site was identified. These ICEs were grouped in seven distinct unrelated or distantly related families, according to their conjugation modules. Integration of these streptococcal ICEs is catalyzed either by a site-specific tyrosine integrase, a low-specificity tyrosine integrase, a site-specific single serine integrase, a triplet of site-specific serine integrases or a DDE transposase. Analysis of their integration site led to the detection of 18 target-genes for streptococcal ICE insertion including eight that had not been identified previously (ftsK, guaA, lysS, mutT, rpmG, rpsI, traG, and ebfC). It also suggests that all specificities have evolved to minimize the impact of the insertion on the host. This overall analysis of streptococcal ICEs emphasizes their prevalence and diversity and demonstrates that exchanges or acquisitions of conjugation and recombination modules are frequent.
integrative and conjugative elements; T4SS; integrase; integration site; Streptococcus
In mammals, multigenerational environmental effects have been documented by either epidemiological studies in human or animal experiments in rodents. Whether such phenomena also occur in birds for more than one generation is still an open question. The objective of this study was to investigate if a methionine deficiency experienced by a mother (G0) could affect her grand-offspring phenotypes (G2 hybrid mule ducks and G2 purebred Muscovy ducks), through their Muscovy sons (G1). Muscovy drakes are used for the production of mule ducks, which are sterile offspring of female common duck (Anas platyrhynchos) and Muscovy drakes (Cairina moschata). In France, mule ducks are bred mainly for the production of “foie gras”, which stems from hepatic steatosis under two weeks of force-feeding (FF). Two groups of female Muscovy ducks received either a methionine deficient diet or a control diet. Their sons were mated to Muscovy or to common duck females to produce Muscovy or Mule ducks, respectively. Several traits were measured in the G2 progenies, concerning growth, feed efficiency during FF, body composition after FF, and quality of foie gras and magret.
In the G2 mule duck progeny, grand-maternal methionine deficiency (GMMD) decreased 4, 8, and 12 week body weights but increased weight gain and feed efficiency during FF, and abdominal fat weight. The plasmatic glucose and triglyceride contents at the end of FF were higher in the methionine deficient group. In the G2 purebred Muscovy progeny, GMMD tended to decrease 4 week body weight in both sexes, and decreased weight gain between the ages of 4 and 12 weeks, 12 week body weight, and body weight at the end of FF in male offspring only. GMMD tended to increase liver weight and increased the carcass proportion of liver in both sexes.
Altogether, these results show that the mother’s diet is able to affect traits linked to growth and to lipid metabolism in the offspring of her sons, in Muscovy ducks. Whether this transmission through the father of information induced in the grand-mother by the environment is epigenetic remains to be demonstrated.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-015-0303-z) contains supplementary material, which is available to authorized users.
Environment; Diet; Methionine; Duck; Multigenerational; Epigenetics
In this randomized-control trial, conducted at a free clinic in France for predominately immigrant populations without healthcare, we demonstrate that simultaneous HIV/HBV/HCV point-of-care rapid testing improves screening outcomes. Increased awareness of infection status likely helped link these patients to care.
Background. In Europe and the United States, more than two thirds of individuals infected with hepatitis B virus (HBV) or hepatitis C virus (HCV) and 15%–30% of human immunodeficiency virus (HIV)-positive individuals are unaware of their infection status. Simultaneous HIV-, HBV-, and HCV-rapid tests could help improve infection awareness and linkage-to-care in particularly vulnerable populations.
Methods. The OptiScreen III study was a single-center, randomized, control trial conducted at a free clinic (“Médecins du Monde”, Paris, France). Participants were randomized 1:1 to receive 1 of 2 interventions testing for HIV, HBV, and HCV: standard serology-based testing (S-arm) or point-of-care rapid testing (RT-arm). The main study endpoints were the proportion of participants who became aware of their HIV, HBV, and HCV status and who were linked to care when testing positive.
Results. A total of 324 individuals, representing mainly African immigrants, were included. In the S-arm, 115 of 162 (71.0%) participants performed a blood draw and 104 of 162 (64.2%) retrieved their test result. In comparison, 159 of 162 (98.2%) of participants randomized to the RT-arm obtained their results (P < .001). Of the 38 (11.7%) participants testing positive (HIV, n = 7; HBV, n = 23; HCV, n = 8), 15 of 18 (83.3%) in the S-arm and 18 of 20 (90.0%) in the RT-arm were linked-to-care (P = .7). In post hoc analysis assuming the same disease prevalence in those without obtaining test results, difference in linkage-to-care was more pronounced (S-arm = 60.0% vs RT-arm = 90.0%; P = .04).
Conclusions. In a highly at-risk population for chronic viral infections, the simultaneous use of HIV, HBV, and HCV point-of-care tests clearly improves the “cascade of screening” and quite possibly linkage-to-care.
HIV; linkage-to-care; point-of-care rapid test; screening; viral hepatitis
To understand the mechanisms of action of (R)-roscovitine and (S)-CR8, two related pharmacological inhibitors of cyclin-dependent kinases (CDKs), we applied a variety of ‘-omics’ techniques to the human neuroblastoma SH-SY5Y and IMR32 cell lines:  kinase interaction assays,  affinity competition on immobilized broad-spectrum kinase inhibitors,  affinity chromatography on immobilized (R)-roscovitine and (S)-CR8,  whole genome transcriptomics analysis and specific quantitative PCR studies,  global quantitative proteomics approach and Western blot analysis of selected proteins. Altogether the results show that the major direct targets of these two molecules belong to the CDKs (1, 2, 5, 7, 9, 12), DYRKs, CLKs, CK1s families. By inhibiting CDK7, CDK9 and CDK12, these inhibitors transiently reduce RNA polymerase 2 activity, which results in down-regulation of a large set of genes. Global transcriptomics and proteomics analysis converge to a central role of MYC transcription factors down-regulation. Indeed CDK inhibitors trigger rapid and massive down-regulation of MYCN expression in MYCN amplified neuroblastoma cells as well as in nude mice xenografted IMR32 cells. Inhibition of casein kinase 1 may also contribute to the antitumoral activity of (R)-roscovitine and (S)-CR8. This dual mechanism of action may be crucial in the use of these kinase inhibitors for the treatment of MYC-dependent cancers, in particular neuroblastoma where MYCN amplification is a strong predictor factor for high-risk disease.
cyclin-dependent kinase; CDK; casein kinase 1; CK1; kinase inhibitor; roscovitine; CR8; c-Myc; MYCN; neuroblastoma; medulloblastoma; interactomics; transcriptomics; proteomics
Immune and inflammatory responses require leukocytes to migrate within and through the vasculature, a process that is facilitated by their capacity to switch to a polarized morphology with asymmetric distribution of receptors. We report that neutrophil polarization within activated venules served to organize a protruding domain that engaged activated platelets present in the bloodstream. The selectin ligand PSGL-1 transduced signals emanating from these interactions, resulting in redistribution of receptors that drive neutrophil migration. Consequently, neutrophils unable to polarize or to transduce signals through PSGL-1 displayed aberrant crawling, and blockade of this domain protected mice against thrombo-inflammatory injury. These results reveal that recruited neutrophils scan for activated platelets, and suggest that their bipolarity allows integration of signals present at both the endothelium and the circulation before inflammation proceeds.
While the number of solved 3D protein structures continues to grow rapidly, the structural rules that distinguish protein-protein interactions between different structural families are still not clear. Here, we classify and analyse the secondary structural features and promiscuity of a comprehensive non-redundant set of domain family binding sites (DFBSs) and hetero domain-domain interactions (DDIs) extracted from our updated KBDOCK resource. We have partitioned 4001 DFBSs into five classes using their propensities for three types of secondary structural elements (“α” for helices, “β” for strands, and “γ” for irregular structure) and we have analysed how frequently these classes occur in DDIs. Our results show that β elements are not highly represented in DFBSs compared to α and γ elements. At the DDI level, all classes of binding sites tend to preferentially bind to the same class of binding sites and α/β contacts are significantly disfavored. Very few DFBSs are promiscuous: 80% of them interact with just one Pfam domain. About 50% of our Pfam domains bear only one single-partner DFBS and are therefore monogamous in their interactions with other domains. Conversely, promiscuous Pfam domains bear several DFBSs among which one or two are promiscuous, thereby multiplying the promiscuity of the concerned protein.
protein secondary structure; protein domain; protein binding sites; protein-protein interactions; domain-domain interactions; interaction promiscuity
Integrating Nurse Practitioners into primary care teams is a process that involves significant challenges. To be successful, nurse practitioner integration into primary care teams requires, among other things, a redefinition of professional boundaries, in particular those of medicine and nursing, a coherent model of inter- and intra- professional collaboration, and team-based work processes that make the best use of the subsidiarity principle. There have been numerous studies on nurse practitioner integration, and the literature provides a comprehensive list of barriers to, and facilitators of, integration. However, this literature is much less prolific in discussing the operational level implications of those barriers and facilitators and in offering practical recommendations.
In the context of a large-scale research project on the introduction of nurse practitioners in Quebec (Canada) we relied on a logic-analysis approach based, on the one hand on a realist review of the literature and, on the other hand, on qualitative case-studies in 6 primary healthcare teams in rural and urban area of Quebec.
Five core themes that need to be taken into account when integrating nurse practitioners into primary care teams were identified. Those themes are: planning, role definition, practice model, collaboration, and team support.
The present paper has two objectives: to present the methods used to develop the themes, and to discuss an integrative model of nurse practitioner integration support centered around these themes.
It concludes with a discussion of how this framework contributes to existing knowledge and some ideas for future avenues of study.
Collaboration; Delivery of health care; Integrating process; Logic evaluation; Nurse practitioners; Practice model; Primary health care; Role definition; Team support
Mice lacking the small GTPase Rap1b exhibit enhanced neutrophil recruitment to inflamed lungs and susceptibility to endotoxin shock via enhance PI3K-Akt activation.
Neutrophils are the first line of cellular defense in response to infections and inflammatory injuries. However, neutrophil activation and accumulation into tissues trigger tissue damage due to release of a plethora of toxic oxidants and proteases, a cause of acute lung injury (ALI). Despite its clinical importance, the molecular regulation of neutrophil migration is poorly understood. The small GTPase Rap1b is generally viewed as a positive regulator of immune cell functions by controlling bidirectional integrin signaling. However, we found that Rap1b-deficient mice exhibited enhanced neutrophil recruitment to inflamed lungs and enhanced susceptibility to endotoxin shock. Unexpectedly, Rap1b deficiency promoted the transcellular route of diapedesis through endothelial cell. Increased transcellular migration of Rap1b-deficient neutrophils in vitro was selectively mediated by enhanced PI3K-Akt activation and invadopodia-like protrusions. Akt inhibition in vivo suppressed excessive Rap1b-deficient neutrophil migration and associated endotoxin shock. The inhibitory action of Rap1b on PI3K signaling may be mediated by activation of phosphatase SHP-1. Thus, this study reveals an unexpected role for Rap1b as a key suppressor of neutrophil migration and lung inflammation.
We compared the blood thixotropic/shear-thinning properties and the red blood cells’ (RBC) rheological properties between a group of patients with sickle cell anaemia (SS) and healthy individuals (AA). Blood thixotropy was determined by measuring blood viscosity with a capillary viscometer using a “loop” protocol: the shear rate started at 1 s−1 and increased progressively to 922 s−1 and then re-decreased to the initial shear rate. Measurements were performed at native haematocrit for the two groups and at 25% and 40% haematocrit for the AA and SS individuals, respectively. RBC deformability was determined by ektacytometry and RBC aggregation properties by laser backscatter versus time. AA at native haematocrit had higher blood thixotropic index than SS at native haematocrit and AA at 25% haematocrit. At 40% haematocrit, SS had higher blood thixotropic index than AA. While RBC deformability and aggregation were lower in SS than in AA, the strength of RBC aggregates was higher in the former population. Our results showed that 1) anaemia is the main modulator of blood thixtropy and 2) the low RBC deformability and high RBC aggregates strength cause higher blood thixotropy in SS patients than in AA individuals at 40% haematocrit, which could impact blood flow in certain vascular compartments.
The pathophysiology of neutrophilic dermatoses (NDs) and autoimmune connective tissue diseases (AICTDs) is incompletely understood. The association between NDs and AICTDs is rare; recently, however, a distinctive subset of cutaneous lupus erythematosus (LE, the prototypical AICTD) with neutrophilic histological features has been proposed to be included in the spectrum of lupus. The aim of our study was to test the validity of such a classification. We conducted a monocentric retrospective study of 7028 AICTDs patients. Among these 7028 patients, a skin biopsy was performed in 932 cases with mainly neutrophilic infiltrate on histology in 9 cases. Combining our 9 cases and an exhaustive literature review, pyoderma gangrenosum, Sweet syndrome (n = 49), Sweet-like ND (n = 13), neutrophilic urticarial dermatosis (n = 6), palisaded neutrophilic granulomatous dermatitis (n = 12), and histiocytoid neutrophilic dermatitis (n = 2) were likely to occur both in AICTDs and autoinflammatory diseases. Other NDs were specifically encountered in AICTDs: bullous LE (n = 71), amicrobial pustulosis of the folds (n = 28), autoimmunity-related ND (n = 24), ND resembling erythema gyratum repens (n = 1), and neutrophilic annular erythema (n = 1). The improvement of AICTDS neutrophilic lesions under neutrophil targeting therapy suggests possible common physiopathological pathways between NDs and AICTDs.
Intellectual disability (ID) is a clinical sign reflecting diverse neurodevelopmental disorders that are genetically and phenotypically heterogeneous. Just recently, partial or complete deletion of methyl-CpG-binding domain 5 (MBD5) gene has been implicated as causative in the phenotype associated with 2q23.1 microdeletion syndrome. In the course of systematic whole-genome screening of individuals with unexplained ID by array-based comparative genomic hybridization, we identified de novo intragenic deletions of MBD5 in three patients leading, as previously documented, to haploinsufficiency of MBD5. In addition, we described a patient with an unreported de novo MBD5 intragenic duplication. Reverse transcriptase-PCR and sequencing analyses showed the presence of numerous aberrant transcripts leading to premature termination codon. To further elucidate the involvement of MBD5 in ID, we sequenced ten coding, five non-coding exons and an evolutionary conserved region in intron 2, in a selected cohort of 78 subjects with a phenotype reminiscent of 2q23.1 microdeletion syndrome. Besides variants most often inherited from an healthy parent, we identified for the first time a de novo nonsense mutation associated with a much more damaging phenotype. Taken together, these results extend the mutation spectrum in MBD5 gene and contribute to refine the associated phenotype of neurodevelopmental disorder.
MBD5; nonsense mutation; intragenic duplication; intellectual disability
Role clarity is a crucial issue for effective interprofessional collaboration. Poorly defined roles can become a source of conflict in clinical teams and reduce the effectiveness of care and services delivered to the population. Our objective in this paper is to outline processes for clarifying professional roles when a new role is introduced into clinical teams, that of the primary healthcare nurse practitioner (PHCNP). To support our empirical analysis we used the Canadian National Interprofessional Competency Framework, which defines the essential components for role clarification among professionals. A qualitative multiple-case study was conducted on six cases in which the PHCNP role was introduced into primary care teams. Data collection included 34 semistructured interviews with key informants involved in the implementation of the PHCNP role. Our results revealed that the best performing primary care teams were those that used a variety of organizational and individual strategies to carry out role clarification processes. From this study, we conclude that role clarification is both an organizational process to be developed and a competency that each member of the primary care team must mobilize to ensure effective interprofessional collaboration.
The information provided by pharmaceutical sales representatives has been shown to influence prescribing. To enable safe prescribing, medicines information must include harm as well as benefits. Regulation supports this aim, but relative effectiveness of different approaches is not known. The United States (US) and France directly regulate drug promotion; Canada relies on industry self-regulation. France has the strictest information standards.
This is a prospective cohort study in Montreal, Vancouver, Sacramento and Toulouse. We recruited random samples of primary care physicians from May 2009 to June 2010 to report on consecutive sales visits. The primary outcome measure was “minimally adequate safety information” (mention of at least one indication, serious adverse event, common adverse event, and contraindication, and no unqualified safety claims or unapproved indications).
Two hundred and fifty-five physicians reported on 1,692 drug-specific promotions. “Minimally adequate safety information” did not differ: 1.7 % of promotions; range 0.9–3.0 % per site. Sales representatives provided some vs. no information on harm more often in Toulouse than in Montreal and Vancouver: 61 % vs. 34 %, OR = 4.0; 95 % CI 2.8–5.6, or Sacramento (39 %), OR = 2.4; 95 % CI 1.7–3.6. Serious adverse events were rarely mentioned (5–6 % of promotions in all four sites), although 45 % of promotions were for drugs with US Food and Drug Administration (FDA) “black box” warnings of serious risks. Nevertheless, physicians judged the quality of scientific information to be good or excellent in 901 (54 %) of promotions, and indicated readiness to prescribe 64 % of the time.
“Minimally adequate safety information” did not differ in the US and Canadian sites, despite regulatory differences. In Toulouse, consistent with stricter standards, more harm information was provided. However, in all sites, physicians were rarely informed about serious adverse events, raising questions about whether current approaches to regulation of sales representatives adequately protect patient health.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-013-2411-7) contains supplementary material, which is available to authorized users.
health policy; patient safety; primary care; health services research
To study the link between climatic variables and the incidence of leishmaniasis a study was conducted in Cayenne, French Guiana. Patients infected between January 1994 and December 2010. Meteorological data were studied in relation to the incidence of leishmaniasis using an ARIMA model. In the final model, the infections were negatively correlated with rainfall (with a 2-month lag) and with the number of days with rainfall > 50 mm (lags of 4 and 7 months). The variables that were positively correlated were temperature and the Multivariate El Niño Southern Oscillation Index with lags of 8 and 4 months, respectively. Significantly greater correlations were observed in March for rainfall and in November for the Multivariate El Niño/Southern Oscillation Index. Climate thus seems to be a non-negligible explanatory variable for the fluctuations of leishmaniasis. A decrease in rainfall is linked to increased cases 2 months later. This easily perceptible point could lead to an interesting prevention message.
[18F]-fluorodeoxyglucose (FDG) has been suggested for the clinical and experimental imaging of inflammatory atherosclerotic lesions. Significant FDG uptake in brown adipose tissue (BAT) has been observed both in humans and mice. The objective of the present study was to investigate the influence of periaortic BAT on apolipoprotein E-deficient (apoE−/−) mouse atherosclerotic lesion imaging with FDG.
ApoE−/− mice (36±2 weeks-old) were injected with FDG (12±2 MBq). Control animals (Group A, n = 7) were injected conscious and kept awake at room temperature (24°C) throughout the accumulation period. In order to minimize tracer activity in periaortic BAT, Group B (n = 7) and C (n = 6) animals were injected under anaesthesia at 37°C and Group C animals were additionally pre-treated with propranolol. PET/CT acquisitions were performed prior to animal euthanasia and ex vivo analysis of FDG biodistribution.
Autoradiographic imaging indicated higher FDG uptake in atherosclerotic lesions than in the normal aortic wall (all groups, P<0.05) and the blood (all groups, P<0.01) which correlated with macrophage infiltration (R = 0.47; P<0.001). However, periaortic BAT uptake was either significantly higher (Group A, P<0.05) or similar (Group B and C, P = NS) to that observed in atherosclerotic lesions and was shown to correlate with in vivo quantified aortic FDG activity.
Periaortic BAT FDG uptake was identified as a confounding factor while using FDG for the non-invasive imaging of mouse atherosclerotic lesions.
The aim of this study was to investigate the reproducibility of intra- and inter-observer interpretation of [18F]choline positron emission tomography/computed tomography examinations in patients suffering from biochemically recurrent prostate cancer following curative treatment.
A total of 60 patients with biochemical recurrence after curative treatment were included in this bicentric study. The interpretations were based on a systematic analysis of several anatomic regions and all the four nuclear medicine physicians used identical result consoles. The examinations were interpreted with no knowledge of the patients' clinical context. Two months later, a second interpretation of all these examinations was performed using the same method, in random order.
To evaluate local recurrences, when the prostate is in place, the results showed moderate inter- and intra-observer reproducibility: concordance of all 4 physicians has a Fleiss' kappa coefficient of 0.553 with a confidence interval of (0.425 to 0.693). For patients who had had a prostatectomy, there was excellent concordance for the negative examinations. For the lymphatic basin, inter- and intra-observer reproducibility was excellent with a Fleiss' kappa coefficient of 0.892 with a confidence interval of (0.788 to 0.975). The lymphatic sub-group analysis was also good. For the lymphatic groups in the right or left hemi-pelves, all Fleiss' kappa and Cohen's kappa coefficients are varying from 0.760 to 1 with narrow confidence intervals from (0.536 to 0.984) to (1 to 1) in favour of good/excellent inter-observer reproducibility. To evaluate bone metastasis, inter-observer reproducibility was good with a Fleiss' kappa coefficient of 0.703 and a confidence interval of (0.407 to 0.881).
Our study is at time the only one on the reproducibility of interpretation of [18F]choline positron emission tomography/computed tomography examinations, which is a key examination for the treatment of patients suffering biochemical recurrence of prostate cancer. Interpretation of the [18F]choline positron emission tomography/computed tomography examination is not so useful at prostate level in patients not previously treated with prostatectomy but has a great interest on patients treated by prostatectomy. It showed good concordance in the interpretation of sub-diaphragmatic lymphatic recurrences as well as in bone metastasis.
18F; choline positron emission tomography; Computed tomography; Prostate cancer; Biochemical recurrence; Inter- and intra-observer reproducibility
Genomic instability is a major hallmark of cancer. To maintain genomic integrity, cells are equipped with dedicated sensors to monitor DNA repair or to force damaged cells into death programs. The tumor suppressor p53 is central in this process. Here, we report that the ubiquitous transcription factor Upstream Stimulatory factor 1 (USF1) coordinates p53 function in making proper cell fate decisions. USF1 stabilizes the p53 protein and promotes a transient cell cycle arrest, in the presence of DNA damage. Thus, cell proliferation is maintained inappropriately in Usf1 KO mice and in USF1-deficient melanoma cells challenged by genotoxic stress. We further demonstrate that the loss of USF1 compromises p53 stability by enhancing p53-MDM2 complex formation and MDM2-mediated degradation of p53. In USF1-deficient cells, the level of p53 can be restored by the re-expression of full-length USF1 protein similarly to what is observed using Nutlin-3, a specific inhibitor that prevents p53-MDM2 interaction. Consistent with a new function for USF1, a USF1 truncated protein lacking its DNA-binding and transactivation domains can also restore the induction and activity of p53. These findings establish that p53 function requires the ubiquitous stress sensor USF1 for appropriate cell fate decisions in response to DNA-damage. They underscore the new role of USF1 and give new clues of how p53 loss of function can occur in any cell type. Finally, these findings are of clinical relevance because they provide new therapeutic prospects in stabilizing and reactivating the p53 pathway.
Cancer is a complex disease that is characterized by the sequential accumulation of genetic mutations. Exposure to environmental agents, such as solar ultraviolet, induces such alterations and thus contributes to the development of genomic instability. The tumor suppressor p53 has a central role in orchestrating cellular responses to genotoxic stress. In response to DNA-damage, p53 is stabilized and activated to direct cell fate decisions. Cells in which p53 stabilization is compromised become more vulnerable to mutagenic agents and hence the mutation rate increases, which promotes tumor development. Stabilization of p53 is thus a critical step towards cancer prevention. Using a genetic approach, we demonstrate that the ubiquitous transcription factor Upstream Stimulatory factor 1 (USF1) is required for immediate p53 stabilization and appropriate cell fate decisions following genotoxic stress. Furthermore, we show that this involves a novel function of USF1 that underscores its critical role as a stress sensor. The loss of USF1 expression should thus be considered as a potential initiator of tumorigenesis in the context of environmental insults.
Hematopoiesis is regulated by components of the microenvironment, so-called niche. Here, we show that p190-B GTPase Activating Protein (p190-B) deletion in mice causes hematopoietic failure during ontogeny, in p190-B−/− fetal liver and bones, and in p190-B+/− adult bones and spleen. These defects are non-cell autonomous, since we previously showed that transplantation of p190-B−/− hematopoietic cells into wild-type hosts leads to normal hematopoiesis. Coculture of mesenchymal stem/progenitor cells (MSC) and wild-type bone marrow cells reveals that p190-B−/− MSCs are dysfunctional in supporting hematopoiesis due to impaired Wnt signaling. Furthermore, p190-B loss causes alteration in bone marrow niche composition, including abnormal CFU-fibroblast, CFU-adipocyte and CFU-osteoblast numbers. This is due to altered MSC lineage fate specification to osteoblast and adipocyte lineages. Thus, p190-B organizes a functional mesenchymal/microenvironment for normal hematopoiesis during development.
mesenchymal stem cell; p190-B RhoGAP; hematopoiesis; microenvironment; Wnt3a
To gain a deeper understanding of how primary care (PC) practices belonging to different models manage resources to provide high-quality care.
Multiple-case study embedded in a cross-sectional study of a random sample of 37 practices.
Three regions of Quebec.
Health care professionals and staff of 5 PC practices.
Five cases showing above-average results on quality-of-care indicators were purposefully selected to contrast on region, practice size, and PC model. Data were collected using an organizational questionnaire; the Team Climate Inventory, which was completed by health care professionals and staff; and 33 individual interviews. Detailed case histories were written and thematic analysis was performed.
The core common feature of these practices was their ongoing effort to make trade-offs to deliver services that met their vision of high-quality care. These compromises involved the same 3 areas, but to varying degrees depending on clinic characteristics: developing a shared vision of high-quality care; aligning resource use with that vision; and balancing professional aspirations and population needs. The leadership of the physician lead was crucial. The external environment was perceived as a source of pressure and dilemmas rather than as a source of support in these matters.
Irrespective of their models, PC practices’ pursuit of high-quality care is based on a vision in which accessibility is a key component, balanced by appropriate management of available resources and of external environment expectations. Current PC reforms often create tensions rather than support PC practices in their pursuit of high-quality care.
Aged; Anemia, Sickle Cell; blood; drug therapy; Antisickling Agents; therapeutic use; Erythrocyte Deformability; Female; Humans; Hydroxyurea; therapeutic use; Logistic Models; Male; Middle Aged; Multivariate Analysis; Osteonecrosis; blood; Risk Assessment; Risk Factors; Young Adult
A decreased global autonomic nervous system (ANS) activity and increased sympathetic activation in patients with sickle cell anemia (SCA) seem to worsen the clinical severity and could play a role in the pathophysiology of the disease, notably by triggering vaso-occlusive crises. Because exercise challenges the ANS activity in the general population, we sought to determine whether a short (<15 min) and progressive moderate exercise session conducted until the first ventilatory threshold had an effect on the ANS activity of a group of SCA patients and a group of healthy individuals (CONT group). Temporal and spectral analyses of the nocturnal heart rate variability were performed before and on the 3 nights following the exercise session. Standard deviation of all normal RR intervals (SDNN), total power, low frequencies (LF) and high frequencies powers (HF) were lower but LF/HF was higher in SCA patients than in the CONT group. Moderate exercise did not modify ANS activity in both groups. In addition, no adverse clinical events occurred during the entire protocol. These results imply that this kind of short and moderate exercise is not detrimental for SCA patients.