Human natural killer cells promote cross-presentation of tumor cell-derived antigens by dendritic cells.

Dendritic cells (DCs) cross-present antigen (Ag) to initiate T-cell immunity against most infections and tumors. Natural killer (NK) cells are innate cytolytic lymphocytes that have emerged as key modulators of multiple DC functions. Here, we show that human NK cells promote cross-presentation of tumor cell-derived Ag by DC leading to Ag-specific CD8(+) T-cell activation. Surprisingly, cytotoxic function of NK cells was not required. Instead, we highlight a critical and nonredundant role for IFN-γ and TNF-α production by NK cells to enhance cross-presentation by DC using two different Ag models. Importantly, we observed that NK cells promote cell-associated Ag cross-presentation selectively by monocytes-derived DC (Mo-DC) and CD34-derived CD11b(neg) CD141(high) DC subsets but not by myeloid CD11b(+) DC. Moreover, we demonstrate that triggering NK cell activation by monoclonal antibodies (mAbs)-coated tumor cells leads to efficient DC cross-presentation, supporting the concept that NK cells can contribute to therapeutic mAbs efficiency by inducing downstream adaptive immunity. Taken together, our findings point toward a novel role of human NK cells bridging innate and adaptive immunity through selective induction of cell-associated Ag cross-presentation by CD141(high) DC, a process that could be exploited to better harness Ag-specific cellular immunity in immunotherapy.

Aberrant drainage of the umbilical vein into the coronary sinus without ductus venosus agenesis.

We describe a case series of 4 fetuses with ectopic connections of the ductus venosus to the coronary sinus detected prospectively between August 2011 and February 2012 in 2 congenital cardiologic centers. An enlarged coronary sinus alerted the sonographer. Fetal echocardiography showed ectopic connection of the ductus venosus in an enlarged coronary sinus in all 4 cases. To our knowledge, this anatomic form of ectopic umbilical vein drainage has not previously been reported. The infants were doing well. This venous variant should be considered in cases of isolated coronary sinus dilatation after elimination of a left superior vena cava and a totally anomalous pulmonary vein connection.

Effect of natural iron fertilization on carbon sequestration in the Southern Ocean.

The availability of iron limits primary productivity and the associated uptake of carbon over large areas of the ocean. Iron thus plays an important role in the carbon cycle, and changes in its supply to the surface ocean may have had a significant effect on atmospheric carbon dioxide concentrations over glacial-interglacial cycles. To date, the role of iron in carbon cycling has largely been assessed using short-term iron-addition experiments. It is difficult, however, to reliably assess the magnitude of carbon export to the ocean interior using such methods, and the short observational periods preclude extrapolation of the results to longer timescales. Here we report observations of a phytoplankton bloom induced by natural iron fertilization--an approach that offers the opportunity to overcome some of the limitations of short-term experiments. We found that a large phytoplankton bloom over the Kerguelen plateau in the Southern Ocean was sustained by the supply of iron and major nutrients to surface waters from iron-rich deep water below. The efficiency of fertilization, defined as the ratio of the carbon export to the amount of iron supplied, was at least ten times higher than previous estimates from short-term blooms induced by iron-addition experiments. This result sheds new light on the effect of long-term fertilization by iron and macronutrients on carbon sequestration, suggesting that changes in iron supply from below--as invoked in some palaeoclimatic and future climate change scenarios--may have a more significant effect on atmospheric carbon dioxide concentrations than previously thought.

TLR3 and Rig-like receptor on myeloid dendritic cells and Rig-like receptor on human NK cells are both mandatory for production of IFN-gamma in response to double-stranded RNA.

Cross-talk between NK cells and dendritic cells (DCs) is critical for the potent therapeutic response to dsRNA, but the receptors involved remained controversial. We show in this paper that two dsRNAs, polyadenylic-polyuridylic acid and polyinosinic-polycytidylic acid [poly(I:C)], similarly engaged human TLR3, whereas only poly(I:C) triggered human RIG-I and MDA5. Both dsRNA enhanced NK cell activation within PBMCs but only poly(I:C) induced IFN-gamma. Although myeloid DCs (mDCs) were required for NK cell activation, induction of cytolytic potential and IFN-gamma production did not require contact with mDCs but was dependent on type I IFN and IL-12, respectively. Poly(I:C) but not polyadenylic-polyuridylic acid synergized with mDC-derived IL-12 for IFN-gamma production by acting directly on NK cells. Finally, the requirement of both TLR3 and Rig-like receptor (RLR) on mDCs and RLRs but not TLR3 on NK cells for IFN-gamma production was demonstrated using TLR3- and Cardif-deficient mice and human RIG-I-specific activator. Thus, we report the requirement of cotriggering TLR3 and RLR on mDCs and RLRs on NK cells for a pathogen product to induce potent innate cell activation.

Local aromatase excess with recruitment of unusual promoters of CYP19A1 gene in prepubertal patients with gynecomastia.

OBJECTIVES: Gynecomastia may be due to aromatase excess in several diseases such as obesity and cancer. Aromatase excess syndrome (AEXS) is an autosomal dominant disorder caused by overexpression of CYP19A1. Germinal mutations occurring in AEXS include various genomic rearrangements including duplication, deletion, and inversion identified in the upstream region of CYP19A1. Aromatase overexpression caused by a CYP19A1 somatic mutation has been rarely described. METHODS: Breast adipose tissue biopsies or surgical specimens were obtained from 19 subjects with gynecomastia. Aromatase quantification was performed by digital PCR and CYP19A1 sequencing by RACE PCR products. RESULTS: We observed localized aromatase overexpression (>10 fold greater than normal) in breast adipose tissue from three prepubertal males with gynecomastia out of the 19 cases. One carried a chromosomal rearrangement between CYP19A1 and DMXL2, consistent with AEXS. In the 2 others, the first exon of CYP19A1 contained 11 different tissue-specific promoter subtypes, specifically I.4 or I.3 normally expressed by adipose tissue, but also the placental I.2 promoter and the more ubiquitous I.7 which is usually expressed in breast cancer, uterine, and endothelial tissues. No differences in clinical or biochemical characteristics were observed between these 3 subjects and 16 others without aromatase overexpression. CONCLUSIONS: We describe two cases of aromatase overexpression in breast adipose tissue associated with nonspecific promoter recruitment. Further investigations are necessary to understand the mechanisms involved in aberrant promoter selection.

Outcomes following prenatal diagnosis of isolated persistent left superior vena cava.

BACKGROUND: Prenatal diagnosis of persistent left superior vena cava is increasing, but little is known about outcomes of infants with prenatally diagnosed isolated persistent left superior vena cava. OBJECTIVE: To assess the outcomes of infants with isolated persistent left superior vena cava diagnosed prenatally compared with infants with associated malformations. METHODS: All cases of persistent left superior vena cava confirmed by specialized fetal echocardiography in pregnant women were included from a single-centre prospective registry. Unfavourable outcome was defined as termination of pregnancy, in utero death, postnatal death or severe genetic syndrome missed prenatally. RESULTS: A total of 256 infants were included: 113 cases (44.1%) with isolated persistent left superior vena cava and 143 cases (55.9%) with associated malformations; respectively, 111 (98.2%) and 101 (70.6%) had a live birth. The median postnatal clinical follow-up was 3.6 years. Five-year postnatal survival with good outcome was estimated at: 100% (95% confidence interval 90.7% to 100%) in infants with isolated persistent left superior vena cava; 91.0% (74.0% to 98.1%) in infants with associated cardiac anomalies; 87.5% (51.8% to 97.3%) in infants with associated extracardiac anomalies; 81.0% (52.6 to 94.6%) in infants with both cardiac and extracardiac anomalies; and 78.9% (36.7% to 95.9%) in infants with non-structural anomalies. All genetic findings and syndromes were detected in fetuses or infants with non-isolated persistent left superior vena cava. CONCLUSION: Infants with isolated persistent left superior vena cava have good short-term outcomes postnatally, but persistent left superior vena cava is frequently associated with other malformations that have an effect on outcomes, which should be thoroughly searched for prenatally.

A NEW COCCIDIAN (APICOMPLEXA: EIMERIIDAE) IN THE CRITICALLY ENDANGERED CENTRAL AMERICAN RIVER TURTLE (DERMATEMYS MAWII) IN BELIZE.

As part of a biannual health examination, coprological samples from 3-mo-old Central American river turtles, Dermatemys mawii (Gray, 1847) in a breeding program in Belize, Central America, revealed a previously undescribed coccidian (Apicomplexa) in 17 of 46 (37%) samples. Of 3 positive fecal samples transported to the University of Florida, coccidian oocysts were observed in 1 sample. Sporulated oocysts were measured and described, and using polymerase chain reaction (PCR), an approximately 400-base pair (bp) region of both the small subunit (18S) ribosomal RNA gene and 1,200-bp region of the internal transcribed spacer (ITS) gene were amplified in all 3 samples and their products were sequenced. For comparative value, the same PCR reactions and amplifications were performed on a fecal sample containing oocysts of Eimeria mitraria obtained from a red-eared slider, Trachemys scripta elegans. Results indicated a new eimerian in D. mawii, Eimeria grayi n. sp.

Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling.

In mouse embryonic stem cells (mESCs), chemical blockade of Gsk3α/ß and Mek1/2 (2i) instructs a self-renewing ground state whose endogenous inducers are unknown. Here we show that the axon guidance cue Netrin-1 promotes naive pluripotency by triggering profound signalling, transcriptomic and epigenetic changes in mESCs. Furthermore, we demonstrate that Netrin-1 can substitute for blockade of Gsk3α/ß and Mek1/2 to sustain self-renewal of mESCs in combination with leukaemia inhibitory factor and regulates the formation of the mouse pluripotent blastocyst. Mechanistically, we reveal how Netrin-1 and the balance of its receptors Neo1 and Unc5B co-regulate Wnt and MAPK pathways in both mouse and human ESCs. Netrin-1 induces Fak kinase to inactivate Gsk3α/ß and stabilize ß-catenin while increasing the phosphatase activity of a Ppp2r2c-containing Pp2a complex to reduce Erk1/2 activity. Collectively, this work identifies Netrin-1 as a regulator of pluripotency and reveals that it mediates different effects in mESCs depending on its receptor dosage, opening perspectives for balancing self-renewal and lineage commitment.

A key process of the nonstationary relationship between ENSO and the Western Pacific teleconnection pattern.

Recent studies have discovered an intriguing nonstationary relationship between El Ninõ-Southern Oscillation (ENSO) and the Western Pacific (WP) teleconnection pattern, one of the most prominent winter atmospheric circulation patterns in the North Pacific, with a regime-dependent interdecadal modulation of significant and insignificant correlations. However, the physical process underlying the observed nonstationary ENSO-WP relationship is a puzzle and remains to be elucidated, which is also essential for clarifying the still-debated nontrivial issue on whether the WP is directly forced by ENSO or by midlatitude storm tracks-driven intrinsic processes. Based on empirical orthogonal function (EOF) analysis of the upper-tropospheric teleconnection patterns and associated Rossby wave sources (RWS), we show that the nonstationarity in question is due to the regime-dependent constructive or destructive interference in meridional overturning circulation between the two leading EOFs of RWS best correlated with ENSO and WP, respectively. The observed insignificant correlation between ENSO and the WP after the 1988 regime shift can be explained by interrupted teleconnection between the tropics and high latitudes due to the collapse of the subtropical bridge pillar in the jet entrance region, consequence of the destructive interference. This suggested interference mechanism related to the regime-dependent upper-level RWS fields has significant implications for resolving the puzzle that hinders better understanding of decadal regime behaviors of the climate system in the North Pacific.

Autocrine Adenosine Regulates Tumor Polyfunctional CD73+CD4+ Effector T Cells Devoid of Immune Checkpoints.

The production of CD73-derived adenosine (Ado) by Tregs has been proposed as a resistance mechanism to anti-PD-1 therapy in murine tumor models. We reported that human Tregs express the ectonucleotidase CD39, which generates AMP from ATP, but do not express the AMPase CD73. In contrast, CD73 defined a subset of effector CD4+ T cells (Teffs) enriched in polyfunctional Th1.17 cells characterized by expression of CXCR3, CCR6, and MDR1, and production of IL17A/IFNγ/IL22/GM-CSF. CD39+ Tregs selectively targeted CD73+ Teffs through cooperative degradation of ATP into Ado inhibiting and restricting the ability of CD73+ Teffs to secrete IL17A. CD73+ Teffs infiltrating breast and ovarian tumors were functionally blunted by Tregs expressing upregulated levels of CD39 and ATPase activity. Moreover, tumor-infiltrating CD73+ Teffs failed to express inhibitory immune checkpoints, suggesting that CD73 might be selected under pressure from immune checkpoint blockade therapy and thus may represent a nonredundant target for restoring antitumor immunity.Significance: Polyfunctional CD73+ T-cell effectors lacking other immune checkpoints are selectively targeted by CD39 overexpressing Tregs that dominate the breast tumor environment. Cancer Res; 78(13); 3604-18. ©2018 AACR.

Methylglyoxal impairs the insulin signaling pathways independently of the formation of intracellular reactive oxygen species.

Nonenzymatic glycation is increased in diabetes and leads to elevated levels of advanced glycation end products (AGEs), which link hyperglycemia to the induction of insulin resistance. In hyperglycemic conditions, intracellularly formed alpha-ketoaldehydes, such as methylglyoxal, are an essential source of intracellular AGEs, and the abnormal accumulation of methylglyoxal is related to the development of diabetes complications in various tissues and organs. We have previously shown in skeletal muscle that AGEs induce insulin resistance at the level of metabolic responses. Therefore, it was important to extend our work to intermediates of the biosynthetic pathway leading to AGEs. Hence, we asked the question whether the reactive alpha-ketoaldehyde methylglyoxal has deleterious effects on insulin action similar to AGEs. We analyzed the impact of methylglyoxal on insulin-induced signaling in L6 muscle cells. We demonstrate that a short exposure to methylglyoxal induces an inhibition of insulin-stimulated phosphorylation of protein kinase B and extracellular-regulated kinase 1/2, without affecting insulin receptor tyrosine phosphorylation. Importantly, these deleterious effects of methylglyoxal are independent of reactive oxygen species produced by methylglyoxal but appear to be the direct consequence of an impairment of insulin-induced insulin receptor substrate-1 tyrosine phosphorylation subsequent to the binding of methylglyoxal to these proteins. Our data suggest that an increase in intracellular methylglyoxal content hampers a key molecule, thereby leading to inhibition of insulin-induced signaling. By such a mechanism, methylglyoxal may not only induce the debilitating complications of diabetes but may also contribute to the pathophysiology of diabetes in general.

Molecular characterization of Clostridium difficile clinical isolates in a geriatric hospital.

The discriminatory potential of a combination of various typing methods was evaluated on a set of 21 Clostridium difficile isolates obtained from symptomatic patients hospitalized in a geriatric unit and 7 non-toxigenic isolates from the same hospital. Isolates were firstly serotyped and toxinotyped. Of the 28 isolates, 19 belonged to serogroup A. PCR-ribotyping and PCR-RFLP on the fliC and slpA genes were then applied to these 19 isolates. The results suggest that the combination of PCR-ribotyping with PCR-RFLP analysis of slpA could be more discriminatory and suitable for studying C. difficile epidemiology.

Prevalence of Toxocara spp., Toxascaris leonina and ancylostomidae in public parks and beaches in different climate zones of Costa Rica.

This epidemiological study was conducted in different regions of Costa Rica to determine the prevalence of the developmental stages of potential zoonotic intestinal helminths of dogs and cats in public places. Samples were collected within three main climate zones including rural and urban areas during both the rainy and the dry season. Faecal and environmental samples were taken from 69 parks and beaches. Of the faecal samples 3% contained Toxascaris spp. eggs, 7% Toxocara spp. eggs and 55% contained ancylostomidae eggs. Of the soil samples, 2% contained ancylostomidae eggs and 0.8% contained ascarid eggs. Significant differences in the presence of parasites were found in faecal samples of dry, moist and wet climate zones and between the dry and rainy seasons. Significant differences in the presence of eggs and larvae were also found in the grass samples in the dry, the moist and the wet climate zones and between the different seasons. No significant differences were found between rural and urban areas.

Seroprevalence of varicella in the French population.

OBJECTIVES: To assess the age-specific seroprevalence of varicella in the French population and to explore age-adjusted differences according to gender and geographic region. METHODS: Data were obtained from 1257 randomly selected, frozen serum samples, from subjects 1-30 years of age, that were sent to the Pasteur-Cerba laboratory in November 2003 to January 2004 for the following clinical indications: allergies, respiratory infections, herpes virus infections excluding varicella and endocrinologic tests. IgG concentrations were tested with an indirect enzyme immunoassay. Statistical analyses included use of locally weighted, scatterplot smoothers. RESULTS: Age-specific seroprevalence of varicella increased by >6-fold between 1 and 8 years of age, ie, from 15.0% (95% confidence interval, 8.6-23.5%) for subjects 1-2 years of age to 89.0% (95% confidence interval, 81.0-94.3%) for those 7-8 years of age. The smoothed curve of age-specific seroprevalence suggested that the steepest rate of increase occurred between 1 and 8 years of age, followed by a considerable slowing in the rate of increase, reaching a prevalence of approximately 95% by age 30. Varicella seroprevalence rates were similar for the samples referred for the 4 clinical indications, as follows: allergies, 76.2%; respiratory infections, 74.0%; herpes virus infections excluding varicella, 73.3%; endocrinologic tests, 73.7% (P = 0.84). CONCLUSIONS: Most varicella-zoster virus infections occur during early childhood. Seroprevalence rates reach approximately 50% by 4 years of age and approximately 90% by 8 years. Therefore, the best strategy to reduce the prevalence of wild-type varicella-zoster virus in the French population would be to immunize children 12-18 months of age, as is currently performed in the United States.

Virus overrides the propensity of human CD40L-activated plasmacytoid dendritic cells to produce Th2 mediators through synergistic induction of IFN-{gamma} and Th1 chemokine production.

Depending on the activation status, plasmacytoid dendritic cells (PDC) and myeloid DC have the ability to induce CD4 T cell development toward T helper cell type 1 (Th1) or Th2 pathways. Thus, we tested whether different activation signals could also have an impact on the profile of chemokines produced by human PDC. Signals that induce human PDC to promote a type 1 response (i.e., viruses) and a type 2 response [i.e., CD40 ligand (CD40L)] also induced PDC isolated from tonsils to secrete chemokines preferentially attracting Th1 cells [such as interferon-gamma (IFN-gamma)-inducible protein (IP)-10/CXC chemokine ligand 10 (CXCL10) and macrophage inflammatory protein-1beta/CC chemokine ligand 4 (CCL4)] or Th2 cells (such as thymus and activation-regulated chemokine/CCL17 and monocyte-derived chemokine/CCL22), respectively. Activated natural killer cells were preferentially recruited by supernatants of virus-activated PDC, and supernatants of CD40L-activated PDC attracted memory CD4(+) T cells, particularly the CD4(+)CD45RO(+)CD25(+) T cells described for their regulatory activities. It is striking that CD40L and virus synergized to trigger the production of IFN-gamma by PDC, which induces another Th1-attracting chemokine monokine-induced by IFN-gamma/CXCL9 and cooperates with endogenous type I IFN for IP-10/CXCL10 production. In conclusion, our studies reveal that PDC participate in the selective recruitment of effector cells of innate and adaptive immune responses and that virus converts the CD40L-induced Th2 chemokine patterns of PDC into a potent Th1 mediator profile through an autocrine loop of IFN-gamma.

Risk of malaria among French adult travellers.

BACKGROUND: Imported malaria remains an important, but often unrecognised, health problem in Europe. Little information exists on the incidence of imported malaria with respect to exposure. This study aimed to estimate the incidence of malaria in a cohort of travellers with respect to protection measures. METHOD: In all 13,017 participants enrolled in a French general population cohort (SU.VI.MAX cohort) and followed-up over 8 years were investigated. All participants received a retrospective questionnaire about travel to malaria-endemic countries relating to countries visited, duration of stay, use of protection measures and chemoprophylaxis. Malaria cases was confirmed from medical records. RESULTS: Data were obtained for 752 individuals who made 1,393 trips to malaria-endemic areas. This sample was predominantly middle-class and high-risk groups such as migrants were not represented. Mechanical protection was used in 589 trips (42.3%) and chemoprophylaxis in 1,017 trips (73.0%). This was appropriate for the zone in 615 trips (44.0%) and adequate compliance was reported in the case of 497 trips (35.6%). Appropriate chemoprophylaxis and physical protection measures were used in 21.7% of the trips. Six laboratory-confirmed cases of imported malaria yielded an estimated incidence density of 148 cases/month of exposure/10,000 travellers. In five cases, appropriate protection measures had not been taken. CONCLUSION: Appropriate chemoprophylaxis and physical protection measures against malaria infection are used by less than one-quarter of a sample of predominantly middle-class travellers from France to endemic areas. More intense education measures need to be implemented to reduce the risk of imported malaria.

A novel regulation of PD-1 ligands on mesenchymal stromal cells through MMP-mediated proteolytic cleavage.

Whether fibroblasts regulate immune response is a crucial issue in the modulation of inflammatory responses. Herein, we demonstrate that foreskin fibroblasts (FFs) potently inhibit CD3+ T cell proliferation through a mechanism involving early apoptosis of activated T cells. Using blocking antibodies, we demonstrate that the inhibition of T cell proliferation occurs through cell-to-cell interactions implicating PD-1 receptor expressed on T cells and its ligands, PD-L1 and PD-L2, on fibroblasts. Dual PD-1 ligand neutralization is required to abrogate (i) binding of the PD-1-Fc fusion protein, (ii) early apoptosis of T cells, and (iii) inhibition of T cell proliferation. Of utmost importance, we provide the first evidence that PD-1 ligand expression is regulated through proteolytic cleavage by endogenous matrix metalloproteinases (MMPs) without transcriptional alteration during culture-time. Using (i) different purified enzymatic activities, (ii) MMP-specific inhibitors, and (iii) recombinant human MMP-9 and MMP-13, we demonstrated that in contrast to CD80/CD86, PD-L1 was selectively cleaved by MMP-13, while PD-L2 was sensitive to broader MMP activities. Their cleavage by exogenous MMP-9 and MMP-13 with loss of PD-1 binding domain resulted in the reversion of apoptotic signals on mitogen-activated CD3+ T cells. We suggest that MMP-dependent cleavage of PD-1 ligands on fibroblasts may limit their immunosuppressive capacity and thus contribute to the exacerbation of inflammation in tissues. In contrast, carcinoma-associated fibroblasts appear PD-1 ligand-depleted through MMP activity that may impair physical deletion of exhausted defective memory T cells through apoptosis and facilitate their regulatory functions. These observations should be considered when using the powerful PD-1/PD-L1 blocking immunotherapies.

Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance.

The generation of induced pluripotent stem (iPS) cells holds great promise in regenerative medicine. The use of the transcription factors Oct4, Sox2, Klf4 and c-Myc for reprogramming is extensively documented, but comparatively little is known about soluble molecules promoting reprogramming. Here we identify the secreted cue Netrin-1 and its receptor DCC, described for their respective survival/death functions in normal and oncogenic contexts, as reprogramming modulators. In various somatic cells, we found that reprogramming is accompanied by a transient transcriptional repression of Netrin-1 mediated by an Mbd3/Mta1/Chd4-containing NuRD complex. Mechanistically, Netrin-1 imbalance induces apoptosis mediated by the receptor DCC in a p53-independent manner. Correction of the Netrin-1/DCC equilibrium constrains apoptosis and improves reprogramming efficiency. Our work also sheds light on Netrin-1's function in protecting embryonic stem cells from apoptosis mediated by its receptor UNC5b, and shows that the treatment with recombinant Netrin-1 improves the generation of mouse and human iPS cells.

Economic evaluation of a combined DTPa, hepatitis B, polio, Hib vaccine. Potential impact of the introduction of Infanrix-Hexa in the French childhood immunisation schedule.

A new hexavalent combination vaccine, Infanrix-HEXA, including a recombinant hepatitis B vaccine in addition to the vaccines for diphtheria, tetanus, pertussis, poliomyelitis, and Haemophilus influenzae type B, has recently become available in France. The objectives of this study were to: (1) estimate the break-even price of Infanrix-Hexa for the National Sickness Fund; (2) evaluate its potential impact on vaccine coverage for hepatitis B and the corresponding budget impact. The public price of Infanrix-HEXA associated with a break-even point would be 53.77 euro. Our analyses suggested that other estimates based on a societal perspective including opportunity and indirect costs remained close to this value. The annual additional reimbursed cost of protecting an infant against the risk of hepatitis B would be 28.20 euro per child, or about 21 million euro for an annual cohort of 760,000 births (total cost, 35 million euro). The number of infants protected against hepatitis B could increase from 230,000 in the current situation to about 600,000.

[Cost of colorectal cancer in France in 1999]. / Coût du cancer colorectal en France en 1999.

AIM: Due to high incidence and disease severity, colorectal cancer is a major public health concern in western countries. Few studies have been devoted to estimating its cost in France. The aim of this study was to analyze the direct (medical) and indirect (short-term disability, long-term disability, premature death) costs of colorectal cancer in France. METHODS: This cost-of-illness study was based on data available for 1999. Two evaluation perspectives were considered: French social security system (medical care + daily allowances + disability allowances) and the society (medical care + production losses). Sources of data used in this analysis were: PMSI (hospital care), EPPM-IMS study (ambulatory care) and the GAZEL cohort (short-term disability). RESULTS: Direct costs of colorectal cancer in France amounted in 1999 to more than 469.7 million euros, of which 98% were induced by hospitalisation (on an outpatient or an inpatient basis). Indirect costs represented in 1999 for the French social security system an amount of 85.9 million, of which 71% were due to disability allowances. Taking into account the society's point of view, indirect costs corresponded to production losses of 528.1 million. Total costs of colorectal cancer amounted 555.5 million for the social security system and 997 million for the society. CONCLUSION: These results confirm the high economic burden of colorectal cancer for the French social security system and for the society in general.