Lead in the marine environment: concentrations and effects on invertebrates.

Lead (Pb) is a non-essential metal naturally present in the environment and often complexed with other elements (e.g., copper, selenium, zinc). This metal has been used since ancient Egypt and its extraction has grown in the last centuries. It has been used until recently as a fuel additive and is currently used in the production of vehicle batteries, paint, and plumbing. Marine ecosystems are sinks of terrestrial contaminations; consequently, lead is detected in oceans and seas. Furthermore, lead is not biodegradable. It remains in soil, atmosphere, and water inducing multiple negative impacts on marine invertebrates (key species in trophic chain) disturbing ecological ecosystems. This review established our knowledge on lead accumulation and its effects on marine invertebrates (Annelida, Cnidaria, Crustacea, Echinodermata, and Mollusca). Lead may affect different stages of development from fertilization to larval development and can also lead to disturbance in reproduction and mortality. Furthermore, we discussed changes in the seawater chemistry due to Ocean Acidification, which can affect the solubility, speciation, and distribution of the lead, increasing potentially its toxicity to marine invertebrates.

Outcomes at 7 and 21 years after surgical treatment of Dupuytren's disease by fasciectomy and open-palm technique.

The goal of this study was to assess the recurrence of Dupuytren's disease and the stability of the functional result after fasciectomy combined with the McCash open-palm technique. From 1989 to 1999, 56 consecutive patients were surgically treated for Dupuytren's disease. In 2003, 40 of these operated patients were reviewed by an independent evaluator; 12 patients were Tubiana stage 1, 16 stage 2, 9 stage 3 and 3 stage 4. Twenty-one of them were reviewed again in 2016 by a second evaluator who was unaware of the clinical results in 2003. The mean follow-up was 7.32 years (range, 4.26 to 12.5 years) at the first review. Recurrence occurred in 7 patients (17.5%) and extension of the disease in 15 (37.5%). Three patients had developed complex regional pain syndrome (CRPS). Mean residual contracture was 19.3°. Average improvement in finger extension was 53°. At the second review, 21 patients were assessed with a mean follow-up of 21.5 years (range, 18.7 to 26.3 years). None of them were re-operated and no extension of the disease was observed. There was no recurrence in patients who had no recurrence in 2003. However, the contracture had worsened in five patients (23.8%), three of whom had a recurrence of the disease in 2003. Mean residual contracture was 31.8°. Recurrence occurs most often in the first few years after surgery. The functional result is stable over time. CRPS and the number of rays operated are the main factors negatively affecting overall improvement of mobility.

Diffusion through colloidal shells under stress.

The permeability of solids has long been associated with a diffusive process involving activated mechanism as originally envisioned by Eyring. Tensile stress can affect the activation energy but definitive experiments of the diffusion rate of species through a stressed solid are lacking. Here we use core-shell (liquid core-solid shell) colloidal particles that are sensitive to osmotic pressure to follow the permeation of encapsulated probes at various stresses. We unambiguously show that the tensile stress applied on colloidal shells linearly reduces the local energy barrier for diffusion.

Role of inflammatory cytokines in the effect of estradiol on atheroma.

1. Although hormonal therapy (HT) may increase the risk of coronary heart disease (CHD) and stroke in postmenopausal women, epidemiological studies (protection in premenopausal women) suggest and experimental studies (prevention of fatty streak development in animals) demonstrate a major atheroprotective action of estradiol (E2). The understanding of the deleterious and beneficial effects of oestrogens is thus required. 2. The immuno-inflammatory system plays a key role in the development of fatty streak deposit as well as in the rupture of the atherosclerotic plaque. Although E2 favours an anti-inflammatory effect in vitro (cultured cells), it rather elicits a pro-inflammatory response in vivo involving several subpopulations of the immuno-inflammatory system, which could contribute to plaque destabilization. The functional role of several cytokines was explored in hypercholesterolemic mice. The atheroprotective effect of E2 was fully maintained in mice deficient in interferon-g or interleukin-12, as well as IL-10. In contrast, the protective effect of estradiol was abolished and even reversed in hypercholesterolemic mice given a neutralizing anti-transforming growth factor-b (TGF-b) antibody. Endothelium is another important target for E2, since it not only potentiates endothelial nitric oxide and prostacyclin production, but also controls trafficking of the populations of the immuno-inflammatory system. 3. To conclude, the respective actions of oestrogens on the cell populations involved in the pathophysiology of atherothrombosis may be influenced, among others, by the timing of HT initiation, the status of the vessel wall and, as recently demonstrated the status of the TGF-b pathway.

Understanding the controversy about hormonal replacement therapy: insights from estrogen effects on experimental and clinical atherosclerosis.

Whereas hormonal replacement/menopause therapy (HRT) in post-menopausal women increases the coronary artery risk, epidemiological studies (protection in pre-menopaused women) suggest and experimental studies (prevention of the development of fatty streaks in animals) demonstrate a major atheroprotective action of estradiol (E2). The understanding of the deleterious and beneficial effects of estrogens is thus required. The immuno-inflammatory system plays a key role in the development of fatty streak deposit as well as in the atherosclerotic plaque rupture. Whereas E2 favors an anti-inflammatory effect in vitro (cultured cells), it rather elicits pro-inflammation in vivo, at the level of several subpopulations of the immuno-inflammatory system, which could contribute to plaque destabilization. Endothelium is another important target for E2, since it stimulates endothelial NO and prostacyclin production, thus promoting beneficial effects of vasorelaxation and platelet aggregation inhibition. Prostacyclin, but not NO, appears to be involved in the atheroprotective effect of E2. Estradiol accelerates also endothelial regrowth, thus favoring vascular healing. Finally, most of these effects of E2 are mediated by estrogen receptor alpha, and are independent of estrogen receptor beta. In summary, a better understanding of the mechanisms of estrogen action is required not only on the normal and atheromatous arteries, but also on innate and adaptive immune responses. This should help cardiovascular disease prevention optimization after menopause. These mouse models should help to screen existing and future Selective Estrogen Receptor Modulators (SERMs).

Understanding the oestrogen action in experimental and clinical atherosclerosis.

Whereas hormone replacement/menopause therapy (HRT) in postmenopausal women increases the coronary artery risk, epidemiological studies (protection in premenopaused women) suggest and experimental studies (prevention of the development of fatty streaks in animals) demonstrate a major atheroprotective action of oestradiol (E2). The understanding of the deleterious and beneficial effects of oestrogens is thus required. The immuno-inflammatory system plays a key role in the development of fatty streak deposit as well as in the rupture of the atherosclerotic plaque. Whereas E2 favours an anti-inflammatory effect in vitro (cultured cells), it rather elicits in vivo a proinflammation at the level of several subpopulations of the immuno-inflammatory system, which could contribute to plaque destabilization. Endothelium is another important target for E2, as it potentiates endothelial NO and prostacyclin production, thus promoting the beneficial effects as vasorelaxation and inhibition of platelet aggregation. Prostacyclin, but not NO, appears to be involved in the atheroprotective effect of E2. E2 also accelerates endothelial regrowth, thus favouring vascular healing. Finally, most of these effects of E2 are mediated by oestrogen receptor alpha, and are independent of oestrogen receptor beta. In summary, a better understanding of the mechanisms of oestrogen action not only on the normal and atheromatous arteries, but also on innate and adaptive immune responses is required and should help to optimize the prevention of cardiovascular disease after menopause. These mouse models should help to screen existing and future selective oestrogen receptor modulators.

Irreversible shear-activated aggregation in non-Brownian suspensions.

We have studied the effect of shear on the stability of suspensions made of non-Brownian solid particles. We demonstrate the existence of an irreversible transition where the solid particles aggregate at remarkably low volume fractions (phi approximately 0.1). This shear-induced aggregation is dramatic and exhibits a very sudden change in the viscosity, which increases sharply after a shear-dependent induction time. We show that this induction time is related exponentially to the shear rate, reflecting the importance of the hydrodynamic forces in reducing the repulsive energy barrier that prevents the particles from aggregating.

[Results of a five-year series of 44 trapeziectomies associated with ligamentoplasty and interposition arthroplasty]. / Résultats à plus de cinq ans d'une série consécutive de 44 trapézectomies avec ligamentoplastie et interposition.

BACKGROUND: Surgical management of trapeziometacarpal joint osteoarthritis remains controversial. There have been few long term studies of trapeziectomy combined with ligamentoplasty and interposition arthroplasty (TLIA). Our results are based on a five year minimum follow-up study. METHODS: We carried out a study of 44 TLIA in 39 consecutive patients. A physical and radiological assessment was undertaken after on average of 6.9 years by a independent observer. RESULTS: A durable physical improvement was obtained in 18 cases in less than six months and in five cases after more than one year. Thereafter there was no secondary deterioration. A standard pain measurement gave an average result of 1.4 on a ten point scale. Pain was independent of displacement of the first metacarpal bone but had a tendency to be greater where associated with scaphotrapezoidal joint osteoarthritis. Strength was improved in 36 cases. The patients were satisfied and considered their grip to be normal in 41 cases. These variables did not change over time. DISCUSSION: TLIA give an excellent result in more than 90% of cases. This remains unchanged seven years after surgery. As opposed to prostheses, there is no secondary deterioration once healing is achieved. Algodystrophy is the main drawback. CONCLUSION: In our opinion, TLIA remains the best available surgical treatment of trapeziometacarpal joint osteoarthristis.

Weak TCR stimulation induces a calcium signal that triggers IL-4 synthesis, stronger TCR stimulation induces MAP kinases that control IFN-gamma production.

Th1 and Th2 cells produce different cytokines and have distinct functions. Th1/Th2 cell differentiation is influenced, among other factors, by the nature of TCR-MHC interactions. However, how the TCR transduces a signal resulting in IFN-gamma or IL-4 production is a matter of debate. For example, some authors reported a loss of calcium signaling pathway in Th2 cells. We used a T cell hybridoma producing IL-4 upon weak TCR stimulation and both IL-4 and IFN-gamma for strong TCR engagement as a model to study how TCR signaling pathways are differentially activated in both conditions of stimulation and how this influences the production of cytokines. We show that: (1) the calcium response is identical following weak and strong TCR stimulation; (2) mitogen-activated protein kinase(MAPK) activation is a gradual phenomenon depending upon the strength of TCR activation; (3) a calcium response, even weak, triggers IL-4 expression; (4) IFN-gamma synthesis requires not only a calcium response but also MAPK activation. The MAPK pathway is dispensable for IL-4 production, although it amplifies IL-4 synthesis upon strong TCR stimulation; (5) TCR-induced IL-4 production also depends on calcium signaling in Th2 cells, while IFN-gamma synthesis is dependent, in addition, on MAPK activation in Th1 cells.

Dendritic cells prime in vivo alloreactive CD4 T lymphocytes toward type 2 cytokine- and TGF-beta-producing cells in the absence of CD8 T cell activation.

The mechanisms that influence the polarization of CD4 T cells specific for allogeneic MHC class II molecules in vivo are still poorly understood. We have examined the pathway of alloreactive CD4 T cell differentiation in a situation in which only CD4 T cells could be activated in vivo. In this report we show that priming of adult mice with allogeneic APC, in the absence of MHC class I-T cell interactions, induces a strong expansion of type 2 cytokine-producing allohelper T cells. These alloantigen-specific CD4 T cells directly recognize native allogeneic MHC class II molecules on APC and secrete, in addition to the prototypic Th2 cytokines IL-4, IL-5, and IL-10, large amounts of TGF-beta. The default Th2-phenotype acquisition is not genetically controlled and occurred both in BALB/c and C57BL/6 mice. CD8 T cells are the principal cell type that controls CD4 T cell differentiation in vivo. Furthermore, we demonstrate that strong Th2 priming can be induced not only with allogeneic splenocytes but also with a low number of bone marrow-derived dendritic cells. Finally, using a passive transfer system, we provide direct evidence that CD8 T cell expansion in situ promotes alloreactive Th1 cell development principally by preventing their default development to the Th2 pathway in a mechanism that is largely IFN-gamma independent. Therefore, this work demonstrates that type 2 cytokine production represents a dominant pathway of alloreactive CD4 T cell differentiation in adult mice, a phenomenon that was initially thought to occur only during the neonatal period.

Lethal host-versus-graft disease and hypereosinophilia in the absence of MHC I-T-cell interactions.

Neonatal injection of semiallogeneic spleen cells in BALB/c mice induces a self-limited state of chimerism that promotes the differentiation of donor-specific CD4 T cells toward the Th2 phenotype. Here we show that injection of spleen cells from beta2-microglobulin-deficient (BALB/c x C57BL/6) F1 mice into BALB/c newborns with a disrupted beta2-microglobulin (beta2m) gene results in a lethal lymphoproliferative disorder associated with uncontrolled Th2 response, long-term persistence of donor B cells, and sustained blood eosinophilia. Autoimmune manifestations are also enhanced and characterized by a severe autoantibody-mediated glomerulonephritis. Histological examination of the spleen shows a hyperplasia of periarteriolar lymphoid sheaths, with accumulation of eosinophils and basophils, and variable degree of fibrosis. Perivascular lymphoid infiltrates with eosinophils are also found in the lung and are correlated with disease severity. Such abnormalities are almost absent using beta2m-sufficient mice. These data demonstrate that induction of lymphoid chimerism in the absence of MHC class I-T-cell interactions results in a lethal form of host-versus-graft disease that represents a unique model of Th2-dependent chronic inflammatory disease associated with an hypereosinophilic syndrome in mice.

Interleukin 4-producing CD4 T cells arise from different precursors depending on the conditions of antigen exposure in vivo.

The precursor origin of T helper (Th) cell subsets in vivo has been difficult to study and remains poorly investigated. We have previously shown that chronic administration of soluble protein antigen induces selective development of antigen-specific CD4 Th2 cells in genetically predisposed mouse strains. To analyze the origin of effector T cells in this model, we designed a competitive polymerase chain reaction-based approach to track public BV-J rearrangement expressed by CD4 T cells specific for hen egg white lysozyme (HEL) in BALB/c mice. We show that public T cell clones are predominantly associated with type 1 or 2 effector Th cells recovered after primary immunization in complete or incomplete Freund's adjuvant, respectively. Conversely, continuous administration of soluble antigen, which induces strong memory Th2 response, is associated with a dose-dependent reduction of public clone size by a mechanism resembling clonal anergy. Thus, soluble HEL-induced Th2 cells do not express the public complementarity determining region 3 motifs characteristic of immunogenic challenge in the presence of adjuvant. These results demonstrate that there are multiple pathways of induction of Th2 responses depending on the condition of antigen exposure in vivo, i.e., clonal immune deviation versus recruitment of a different pool of precursor cells.

Selective activation and expansion of high-affinity CD4+ T cells in resistant mice upon infection with Leishmania major.

Using multimers of MHC class II molecules linked to a peptide derived from the Leishmania LACK antigen, we have compared the fate of parasite-specific CD4+ T cells in resistant and susceptible mice transgenic for the beta chain of a LACK-specific TCR. Activated T cells were readily detected in the draining lymph nodes of infected animals. Although the kinetics of activation and expansion were similar in both strains, T cells from susceptible and resistant mice expressed low- and high-affinity TCR, respectively. As T cells from resistant mice produced more IFN-gamma and less IL-4 than those from susceptible animals, our results suggest that differences in TCR usage between MHC-matched animals may influence the development of the antiparasite immune response.

Experimental autoimmune myasthenia gravis may occur in the context of a polarized Th1- or Th2-type immune response in rats.

Experimental autoimmune myasthenia gravis (EAMG) is a T cell-dependent, Ab-mediated autoimmune disease induced in rats by a single immunization with acetylcholine receptor (AChR). Although polarized Th1 responses have been shown to be crucial for the development of mouse EAMG, the role of Th cell subsets in rat EAMG is not well established. In the present work we show that while the incidence and severity of EAMG are similar in Lewis (LEW) and Brown-Norway (BN) rats, strong differences are revealed in the immune response generated. Ag-specific lymph node cells from LEW rats produced higher amounts of IL-2 and IFN-gamma than BN lymph node cells, but expressed less IL-4 mRNA. IgG1 and IgG2b anti-AChR isotype predominated in BN and LEW rats, respectively, confirming the dichotomy of the immune response observed between the two strains. Furthermore, although IL-12 administration or IFN-gamma neutralization strongly influenced the Th1/Th2 balance in BN rats, it did not affect the disease outcome. These data demonstrate that a Th1-dominated immune response is not necessarily associated with disease severity in EAMG, not only in rats with disparate MHC haplotype but also in the same rat strain, and suggest that in a situation where complement-fixing Ab can be generated as a consequence of either Th1- or Th2-mediated T cell help, deviation of the immune response will not be an adequate strategy to prevent this Ab-mediated autoimmune disease.

Beta 2-microglobulin-dependent T cells are not necessary for alloantigen-induced Th2 responses after neonatal induction of lymphoid chimerism in mice.

We have analyzed the requirement for beta 2-microglobulin (beta 2m)-dependent T cells in the generation of allogeneic Th2 responses in vivo. A neonatal injection of semiallogeneic cells in BALB/c mice induces a state of chimerism that promotes the differentiation of donor-specific CD4+ T cells toward the Th2 phenotype. Polyclonal T-B cell interactions occur in this model between host Th2 and donor B cells, resulting in the production of IgE Abs. IgE production and Th2-priming are critically dependent upon the early production of IL-4. Our data in the present paper demonstrate that: 1) IgE synthesis and the up-regulation of MHC class II and CD23 molecules on B cells are independent of beta 2m expression in the host, 2) no difference in the induction of CD4 alloreactive Th2 cells could be observed between beta 2m-/- and their wild-type control littermates when Th2-priming was measured in adult mice, and 3) the Th2 response and IgE production is induced in the complete absence of beta 2m-dependent T cells both in the host and in the inoculum. Therefore, using a variety of assays, we could not demonstrate diminished responses in mice with a disrupted beta 2m gene in this model of Th2-mediated allogeneic interaction, indicating that beta 2m-dependent NK1.1+ and CD8+ T cells are not required for the generation of alloreactive Th2 responses in vivo.

Regulation of the IL-12 receptor beta2 subunit by soluble antigen and IL-12 in vivo.

Continuous administration of soluble protein antigen to BALB/c mice inhibits the development of Th1 and induces selective differentiation of Th2 cells. Here we show that interleukin (IL)-12, administered together with soluble protein through a mini-osmotic pump implanted subcutaneously, not only prevents the inhibition of Th1 cell development, but stimulates higher interferon (IFN)-gamma production than in mice receiving IL-12 alone. In parallel to co-stimulation of Th1 cell development, co-administration of IL-12 blocks the Th2 response induced by soluble protein. IL-12 administered in adjuvant with antigen or intraperitoneally 2 days after the immunization does not break the inhibition of Th1 but can still decrease the Th2 response induced by pretreatment with soluble protein antigen. In contrast to IL-12, co-administration of IL-2 or IFN-gamma does not affect the diversion to Th2 induced by soluble antigen. Thus IL-12, but not IL-2 nor IFN-gamma, converts in vivo the inhibitory signal for Th1 cell development delivered by soluble antigen into an immunogenic one, while blocking a positive signal for Th2 cell differentiation. A molecular basis for the co-stimulation of Th1 priming and the prevention of Th2 differentiation by IL-12 in vivo is provided by the observation that transcripts encoding the IL-12 receptor beta2 chain, which is required for IL-12 signaling and Th1 cell development, are selectively inhibited by soluble antigen but are enhanced by IL-12 co-administration.