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Dendritic cells are professional APCs that play a central role in the initiation of immune responses. The limited ex vivo availability of dendritic cells inspires the widespread use of bone marrow-derived dendritic cells as an alternative in research. However, the functional characteristics of bone marrow-derived dendritic cells are incompletely understood. Therefore, we compared functional and phenotypic characteristics of rat bone marrow-derived dendritic cells generated with GM-CSF/IL-4 or FLT3 ligand bone marrow-derived dendritic cells. A comparison of surface markers revealed that FLT3 ligand-bone marrow-derived dendritic cells expressed signal regulatory protein α, CD103, and CD4 and baseline levels of MHC class II, CD40, and CD86, which were highly up-regulated upon stimulation. Conversely, GM-CSF/IL-4-bone marrow-derived dendritic cells constitutively expressed signal regulatory protein α, CD11c, and CD11b but only mildly up-regulated MHC class II, CD40, or CD86 following stimulation. Expression of dendritic cell-associated core transcripts was restricted to FLT3 ligand-bone marrow-derived dendritic cells . GM-CSF/IL-4-bone marrow-derived dendritic cells were superior at phagocytosis but were outperformed by FLT3 ligand-bone marrow-derived dendritic cells at antigen presentation and T cell stimulation in vitro. Stimulated GM-CSF/IL-4-bone marrow-derived dendritic cells secreted more TNF, CCL5, CCL20, and NO, whereas FLT3 ligand-bone marrow-derived dendritic cells secreted more IL-6 and IL-12. Finally, whereas GM-CSF/IL-4-bone marrow-derived dendritic cell culture supernatants added to resting T cell cultures promoted forkhead box p3(+) regulatory T cell populations, FLT3 ligand-bone marrow-derived dendritic cell culture supernatants drove Th17 differentiation. We conclude that rat GM-CSF/IL-4-bone marrow-derived dendritic cells and FLT3 ligand-bone marrow-derived dendritic cells are functionally distinct. Our data support the current rationale that FLT3 ligand-bone marrow-derived dendritic cells mostly resemble classic dendritic cells but comprise additional minor subpopulations, whereas GM-CSF/IL-4-bone marrow-derived dendritic cells resemble monocyte-derived inflammatory dendritic cells (iNOS-positive monocyte-derived cells)., (© Society for Leukocyte Biology.)

Background: Ιn multiple sclerosis (MS), axonal damage leads to permanent neurological disabilities and the spreading of the autoimmune response to axonal antigens is implicated in disease progression. Experimental autoimmune encephalomyelitis (EAE) provides an animal model that mimics MS. Using different EAE models, we investigated the pathophysiological basis of epitope spreading to neurofascin, a protein localized at the node of Ranvier and its regulation by non-MHC genes., Methods: We used two different EAE models in DA rat; one which is induced with myelin oligodendrocyte glycoprotein (MOG) which leads to disease characterized by profound demyelination, and the second which is induced with myelin basic protein (MBP) peptide 63-88 which results in severe central nervous system (CNS) inflammation but little or no demyelination. We determined anti-neurofascin antibody levels during the course of disease. Furthermore, the anti-neurofascin IgG response was correlated with clinical parameters in 333 (DAxPVG.1AV1) x DA rats on which we performed linkage analysis to determine if epitope spreading to neurofascin was affected by non-MHC genes., Results: Spreading of the antibody response to neurofascin occurred in demyelinating MOG-induced EAE but not in EAE induced with MBP peptide 63-88. Anti-neurofascin IgG levels correlated with disease severity in (DAxPVG.1AV1) x DA rats, and a genomic region on chromosome 3 was found to influence this response., Conclusions: Inter-molecular epitope spreading to neurofascin correlates with disease severity in MOG-EAE is dependent on extensive demyelination and is influenced by non-MHC genes. The findings presented here may shed light on factors involved in the severity of MS and its genetics.

Background: Prefilled syringes are the standard in developed countries but logistic and financial barriers prevent their widespread use in developing countries. The current study evaluated use of a compact, prefilled, autodisable device (CPAD) to deliver pentavalent vaccine by field actors in Senegal and Vietnam., Methods: We conducted a logistic, programmatic, and anthropological study that included a) interviews of immunization staff at different health system levels and parents attending immunization sessions; b) observation of immunization sessions including CPAD use on oranges; and c) document review., Results: Respondents perceived that the CPAD would improve safety by being non-reusable and preventing needle and vaccine exposure during preparation. Preparation was considered simple and may reduce immunization time for staff and caretakers. CPAD impact on cold storage requirements depended on the current pentavalent vaccine being used; in both countries, CPAD would reduce the weight and volume of materials and safety boxes thereby potentially improving outreach strategies and waste disposal. CPAD also would reduce stock outages by bundling vaccine and syringes and reduce wastage by using a non-breakable plastic presentation. Respondents also cited potential challenges including ability to distinguish between CPAD and other pharmaceuticals delivered via a similar mechanism (such as contraceptives), safety, and concerns related to design and ease of administration (such as activation, ease of delivery, and needle diameter and length)., Conclusions: Compared to current pentavalent vaccine presentations in Vietnam and Senegal, CPAD technology will address some of the main barriers to vaccination, such as supply chain issues and safety concerns among health workers and families. Most of the challenges we identified can be addressed with health worker training, minor design modifications, and health messaging targeting parents and communities. Potentially the largest remaining barrier is the marginal increase in pentavalent cost--if any--from CPAD use, which we did not assess in our study.

Ovarian carcinoma is the leading cause of death from gynecologic cancer in the developed world and is characterized by acquired chemoresistance leading to an overall 5-year survival rate of about 30 %. We previously showed that Bcl-xL and Mcl-1 cooperatively protect platinum-resistant ovarian cancer cells from apoptosis. Despite BH3-mimetics represent promising drugs to target Bcl-xL, anti-Mcl-1 strategies are still in pre-clinical studies and required new investigations. Calcium is a universal second messenger and dysregulation of calcium signal is often observed during carcinogenesis. As change in cytosolic free calcium concentration [Ca(2+)]i is known to control the fate of the cell by regulating Bcl-2 family members, we wonder if calcium signal could impact on Mcl-1 expression and if its pharmacological inhibition could be useful to sensitize ovarian carcinoma cells to anti-Bcl-xL strategies. We therefore studied the effect of different calcium signals inhibitors in ovarian carcinoma cell lines SKOV3 and IGROV1-R10 and analysed their effects on proliferation and Mcl-1 expression. We also exposed these cells to these inhibitors in combination with anti-Bcl-xL strategies (siRNA or BH3-mimetic: ABT-737). We found that calcium signaling regulates Mcl-1 through translational events and a calmodulin-mediated pathway. BAPTA-AM and calmodulin inhibitor combination with ABT-737 leads to apoptosis, a process that is reversed by Mcl-1 enforced expression. As Mcl-1 represents a crucial hurdle to the success of chemotherapy, these results could open to new area of investigation using calcium modulators to directly or indirectly target Mcl-1 and thus efficiently sensitize ovarian carcinoma cells to anti-Bcl-xL strategies.

Ovarian cancers are addicted to Bcl-xL and Mcl-1, antiapoptotic members of the Bcl-2 family. Bcl-xL can be inhibited by the BH3-mimetic ABT-737. In vitro, ABT-737 can induce apoptosis of cancer cells, and its activity is potentiated by Mcl-1 inactivation. Herein, we assessed the sensitivity of human ovarian tumor nodes to ABT-737 when combined with carboplatin, which can indirectly inhibit Mcl-1. Fresh samples from 25 patients with high-grade serous ovarian cancer (HGSOC) who were chemo-naïve and had undergone surgery were prospectively exposed ex vivo to ABT-737 ± carboplatin. The treatment effect was studied on sliced tumor nodes by assessment of cleaved-caspase 3 immunostaining. We also studied the association between baseline Bcl-2 family protein expression (via immunohistochemistry) and the response of nodes to treatment. ABT-737 induced apoptosis as a single agent but its efficacy was not improved by the addition of carboplatin. Bim was frequently expressed (20/25) and its absence or low expression was associated with the absence of response to ABT-737, p value = 0.019 by Fisher's test and sensitivity = 93%, (95% confidence interval, 66-100). Moreover, we observed that in tumors in which Bim was expressed, a low expression of phospho-Erk1/2 or Mcl-1 improved the proportion of responses. This pilot study showed that ABT-737 has promise as monotherapy for HGSOC in a specific subgroup of tumors. Bim, Mcl-1, and phospho-Erk1/2 appeared to be relevant biomarkers that could be used for the selection of patients in the design of clinical trials using Navitoclax (an orally available compound related to ABT-737)., (© 2014 UICC.)

Apoptosis control defects such as the deregulation of Bcl-2 family member expression are frequently involved in chemoresistance. In ovarian carcinoma, we previously demonstrated that Bcl-xL and Mcl-1 cooperate to protect cancer cells against apoptosis and their concomitant inhibition leads to massive apoptosis even in the absence of chemotherapy. Whereas Bcl-xL inhibitors are now available, Mcl-1 inhibition, required to sensitize cells to Bcl-xL-targeting strategies, remains problematic. In this context, we designed and synthesized oligopyridines potentially targeting the Mcl-1 hydrophobic pocket, evaluated their capacity to inhibit Mcl-1 in live cells, and implemented a functional screening assay to evaluate their ability to sensitize ovarian carcinoma cells to Bcl-xL-targeting strategies. We established structure-activity relationships and focused our attention on MR29072, named Pyridoclax. Surface plasmon resonance assay demonstrated that pyridoclax directly binds to Mcl-1. Without cytotoxic activity when administered as a single agent, pyridoclax induced apoptosis in combination with Bcl-xL-targeting siRNA or with ABT-737 in ovarian, lung, and mesothelioma cancer cells.

Multiple myeloma is due to the proliferation of malignant plasma cells which increase the number of osteoclasts leading to trabecular and cortical bone osteolysis. The 5T2MM murine model reproduces the human disease and microcomputed tomography is a precise tool to investigate bone loss. Bisphosphonates (zoledronic acid or pamidronate) are used in preventing osteolysis. However, loss of cortical bone in not possible to quantify by histomorphometry on histological sections or microCT images. Osteolysis was studied in mice grafted with the 5THL subline to see if one drug was more active after 10 weeks. Mice were distributed into 4 groups: control, untreated, treated with pamidronate or with zoledronic acid. The left femurs were embedded undecalcified and sectioned at 7 μm. The right tibias and femurs were analyzed by microCT and trabecular morphometric parameters were obtained. Cortical bone osteolysis was analyzed by developing a new algorithm to unwrap microCT sections of the cortices, allowing measurement of the number of perforations, porosity and mean perforation area. The bisphosphonates had no significant effect on the tumor growth as evidence by the absence of effect on the M-protein level. Cortical perforations were evidenced on histological sections and their number seemed to be reduced by both bisphosphonates. MicroCT was used to quantify the trabecular bone: a bone loss was evidenced in the untreated myeloma group and both bisphosphonates appeared equal to preserve trabecular mass. However, the number and size of cortical perforations cannot be determined on 3D models. Unwrapping microCT images provided flat images allowing a precise determination of cortical perforations. Pamidronate did not reduce the number and size of cortical perforations but significantly reduced porosity. Zoledronic acid appeared significantly superior and considerably reduced all parameters. Unwrapping microCT image is a new method allowing the measurement of cortical perforations in bone malignancies, a parameter that cannot be measured correctly on 2D histological sections., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

Porous structures are becoming more and more important in biology and material science because they help in reducing the density of the grafted material. For biomaterials, porosity also increases the accessibility of cells and vessels inside the grafted area. However, descriptors of porosity are scanty. We have used a series of biomaterials with different types of porosity (created by various porogens: fibers, beads …). Blocks were studied by microcomputed tomography for the measurement of 3D porosity. 2D sections were re-sliced to analyze the microarchitecture of the pores and were transferred to image analysis programs: star volumes, interconnectivity index, Minkowski-Bouligand and Kolmogorov fractal dimensions were determined. Lacunarity and succolarity, two recently described fractal dimensions, were also computed. These parameters provided a precise description of porosity and pores' characteristics. Non-linear relationships were found between several descriptors e.g. succolarity and star volume of the material. A linear correlation was found between lacunarity and succolarity. These techniques appear suitable in the study of biomaterials usable as bone substitutes., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: The authors had for aim to assess the prevalence of hepatitis B co-infection in a cohort of HIV-infected patients, routinely followed-up at the Day Care Unit of the Bobo Dioulasso Sanou Souro University Hospital, Burkina Faso., Patients and Methods: The Elisa technique was used to dose HBs antigen (AgHBs), antibodies anti-HBs and anti-HBc in all the patients followed by the biological laboratory, from October to December 2008., Results: The AgHBs prevalence was 12.7% [CI at 95%: 10.7-15.0%] and men were slightly more likely to be positive for AgHBs than women (16.5% [12.0-21.9%] versus 11.6% [9.4-14.1%]; P=0.047); 83.3% of the patients [80.8-85.6%] were positive for hepatitis B core antibody, and 32.6% [29.7-35.6%] for hepatitis B surface antibody; 29.9% of the patients [27.1-32.8%] had a complete profile of former hepatitis B infection, 41.3% [38.2-44.4%] expressed core antibodies only; 13.8% [11.7-16.0%] had a negative serological test, and 2.3% [1.5-3.4%] presented a vaccinal immunity., Conclusion: These results stress the usefulness of screening for hepatitis B in all HIV-infected patients, along with the initial biological tests. This would help adapt HIV treatment to co-infected patients and to build an expanded program of vaccination for non-immune patients., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Ovarian cancer is the leading cause of death from gynecological cancer. The anti-apoptotic protein Bcl-x(L) is frequently overexpressed in ovarian carcinoma which correlates with chemotherapy resistance. It has been demonstrated that Bcl-x(L) cooperates with another anti-apoptotic protein, Mcl-1, to protect ovarian cancer cells against apoptosis, and that their concomitant inhibition induces massive cell death. Here, we examined the interest of ABT-737, a potent BH3-mimetic molecule targeting Bcl-x(L), both alone and in combination with Mcl-1 modulators, in ovarian cancer cell lines. As a single agent, ABT-737 was ineffective at promoting cell death in the four cell lines we tested in vitro. However, the specific inhibition of Mcl-1 by siRNA dramatically increased the sensitivity of chemoresistant cells to ABT-737. Platinum compounds also sensitize to ABT-737 by dose-dependently decreasing Mcl-1 expression or by increasing the expression of pro-apoptotic BH3-only proteins Noxa and, to a lower extent, Bim. Furthermore, we demonstrated that Noxa accumulation was involved in apoptosis occurring in response to the combination of ABT-737 and platinum compounds, since cells were protected from apoptosis by its silencing. Moreover, the combination was also highly cytotoxic ex vivo in sliced SKOV3 tumor nodes. However we observed in these slices a strong basal expression of Noxa and apoptotic cell death in response to ABT-737 alone. Therefore, we have revealed that the modulation of the Mcl-1/Noxa axis by platinum compounds results in a strong sensitization of chemoresistant ovarian carcinoma cells to ABT-737, which could constitute a promising therapeutic in these cancers.

PMMA (poly(methyl methacrylate)) is widely used to prepare orthopedic cements. They are in direct contact with cells and body fluids. PMMA, despite its hydrophobic nature, can absorb ~2% w/w water. We have evaluated by vertical interference microscopy if water absorption can produce a significant swelling in different types of PMMA blocks: pure, with a plasticizer, with a cross-linker, and in two types of commercial bone cements. Graphite rods which do not swell in water were used as internal standard. Hardness, indentation modulus, plastic, and elastic works were determined by nanoindentation under a 25mN fixed force. Vertical interference microscopy was used to image the polymer in the dry state and hydrated states (after 24 h in distilled water). On the surface of the polished polymers (before and after hydration), we measured roughness by the fractal dimension, the swelling in the vertical and the lateral directions. For each polymer block, four images were obtained and values were averaged. Comparison and standardization of the images in the dry and hydrated states were done with Matlab software. The average value measured on the graphite rod between the two images (dried and hydrated) was used for standardization of the images which were visualized in 3D. After grinding, a small retraction was noticeable between the surface of the rod and the polymers. A retraction ring was also visible around the graphite rod. After hydration, only the pure PMMA and bone cements had a significant swelling in the vertical direction. The presence of polymer beads in the cements limited the swelling in the lateral direction. Swelling parameters correlated with the nanoindentation data. PMMA can swell by absorbing a small amount of water and this induces a swelling that varies with the polymer composition and particle inclusions.

Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (B(a)P) are widely distributed environmental contaminants, known as potent ligands of the aryl hydrocarbon receptor (AhR). These chemicals trigger an early and transient increase of intracellular calcium concentration ([Ca(2+)](i)), required for AhR-related effects of PAHs. The mechanisms involved in this calcium mobilization were investigated in the present study. We demonstrated that B(a)P-mediated [Ca(2+)](i) induction was prevented in endothelial HMEC-1 cells by counteracting β2-adrenoreceptor (β2ADR) activity using pharmacological antagonists, anti-β2ADR antibodies, or siRNA-mediated knockdown of β2ADR expression; by contrast, it was strongly potentiated by β2ADR overexpression in human kidney HEK293 cells. B(a)P was shown, moreover, to directly bind to β2ADR, as assessed by in vitro binding assays and molecular modeling. Pharmacological inhibition and/or siRNA-mediated silencing of various signaling actors acting downstream of β2ADR in a sequential manner, such as G protein, adenylyl cyclase, Epac-1 protein, and inositol 1,4,5-trisphosphate (IP(3))/IP(3) receptor, were next demonstrated to prevent B(a)P-induced calcium signal. Inhibition or knockdown of these signaling elements, as well as the use of chemical β-blockers, were finally shown to counteract B(a)P-mediated induction of cytochrome P-450 1B1, a prototypical AhR target gene. Taken together, our results show that B(a)P binds directly to β2ADR and consequently utilizes β2ADR machinery to mobilize [Ca(2+)](i), through activation of a G protein/adenylyl cyclase/cAMP/Epac-1/IP(3) pathway. This β2ADR-dependent signaling pathway activated by PAHs may likely be crucial for PAH-mediated up-regulation of AhR target genes, thus suggesting a contribution of β2ADR to the health-threatening effects of these environmental pollutants.

Papillary fibroelastomas are cardiac benign tumours. Among the benign cardiac tumor, papillary fibroelastomas are reported second after myxomas. Most often diagnosed incidentally, papillary fibroelastomas may embolize to cerebral circulation. Valvular locations are predominant; location in left atrium is rare. In this paper, we present a case of papillary fibroelastoma located in left atrium with symptoms of cerebral embolization. Transoesophageal echocardiography diagnosed a mobile mass. The patient was treated with surgical resection without further embolic complication.

Unlabelled: Neonatal morbidity and mortality is a real concern in our context. Several factors including the organization of the reference contribute to it. Our work was aimed at studying the conditions of newborns transfer of the towards the service of pediatrics of teaching hospital Gabriel Touré., Material and Methods: Our study proceeded from October 15th, 2006 to January 15th, 2007 in the unit of neonatology of the service of Pediatrics of the CHU of the Hospital Gabriel Touré. It was a cross sectional and descriptive study. All the newborns referred by a health structure were included., Results: We included 760 referred newborns out of 1072 neonatal admissions which means a frequency of reference of 71%. In 91.6% of the cases, the newborn were referred on the very day of their birth. Prematurity (29%), perinatal anoxia (24%), respiratory distress (13.9%) were the main reasons for reference. In no case, the service of pediatrics was contacted in advance by the referring health agent. More than half of the cases (58.6%), the public transport was used. Ambulance car transported 17.4% of the newborns. All the newborns came held in the arms of a member of their family. The referring agent was a physician in 70.3% of cases. Hypothermia was found for all the newborns (759/760) when being received. More half of the newborns (56.4%) had a small weight at birth and the quarter (25.8%) was resuscited. Lethality was 32%. Mother illiteracy, small weight at birth, the outborn birth were factors related to neonatal mortality., Conclusion: In our context, the reduction of neonatal morbidity and mortality has to go through an improvement of the reference system.

Chemoresistance of ovarian carcinoma has been associated previously to the absence of Bcl-x(L) expression downregulation in response to cisplatin. Among BH3-mimetic molecules constituting promising anticancer agents able to inhibit the activity of antiapoptotic Bcl-2 family proteins, we evaluated the effect of one of them, HA14-1, on various ovarian carcinoma cell lines. In response to HA14-1, the cisplatin-resistant IGROV1-R10 cell line underwent massive cell death, whereas other cell lines presented a partial response (IGROV1, SKOV3, and A2780) or did not respond to this molecule (OAW42 and OAW42-R). However, the expression of HA14-1 targets (Bcl-2 and Bcl-x(L)) did not correlate to these different responses. In contrast, cell death was associated with the disappearance of Mcl-1 after exposure to HA14-1. We showed that, in the HA14-1 nonresponsive cell lines (SKOV3 and OAW42), small interfering RNA-mediated Mcl-1 downregulation allowed HA14-1-induced massive apoptosis in the absence of chemotherapy. Furthermore, cisplatin-induced Mcl-1 downregulation was also able to sensitize highly chemoresistant SKOV3 cells to HA14-1. Taken together, these results show that Bcl-x(L) and Mcl-1 are able to cooperate to protect ovarian carcinoma cells against oncogenic stress or chemotherapy-induced apoptosis and suggest that the development of multitargeted strategies directed against these two antiapoptotic proteins may constitute a major challenge for the therapeutic care of chemoresistant ovarian carcinomas. BH3-mimetic compounds represent promising tools for this purpose either on their own (direct or indirect pan-inhibitors) or in combination with new drugs aiming to inactivate Mcl-1.

Mitral valve repair is a better therapeutic alternative than valve replacement for rheumatic valve disease in children. Repair procedures are especially well suited to developing countries where heart prostheses and life-long anti-coagulation therapy are largely unaffordable. The purpose of this study was to evaluate medium-term outcome of mitral valve repair in children in Senegal. A retrospective review was conducted in a cohort of 100 patients who underwent mitral valve repair for rheumatic mitral lesions over the 8-year period from 1999 to 2007. Mean age was 12 +/- 5 years (range, 7 to 17 years). The most common symptom of valve disease was dysypnea (stage IV in 26 cases and stage III in 74). Valve lesions were complex with anterior leaflet prolapse in 62 cases, posterior leaflet restriction in 35, commissural fusion in 30, and fusion of chordaes in 54. Repair procedures consisted of transfer and shortening of chordaes in 73 cases in association with commissurotomy in 22 cases and cleft closure in 17. Ring annuloplasty was performed in 84 patients. Hospital mortality was 2%. Postoperative morbidity was characterized by residual mitral regurgitation in four cases. Mean follow-up was 5 years. No late deaths were observed. Outcome was satisfactory in 84 patients with low-grade mitral regurgitation (grade I-II). Reduction of left ventricle diameter was statistically significant during systole and diastole, i.e., from 29.5 +/- 6.2 mm to 33.1 +/- 5.3 mm (p<0.05) and from 47.1 +/- 8.6 mm to 50.5 +/- 9.4 mm (p<0.05) respectively. Improvement in cardiac function was not significant, i.e., from 63.3 +/- 4.8% to 62 +/- 6.4% (p = 0.99). Mitral valve repair was successful in stabilizing myocardial function and remodeling the left ventricle. Outcome is dependent on careful patient selection and evaluation of lesions. Middle-term outcome is encouraging.

Aims: CCL1 is a chemokine thought to contribute to cardiovascular diseases and recently reported to be regulated by the pro-atherogenic lipoprotein(a) (Lp(a)) and the ligand-activated aryl hydrocarbon receptor (AhR). The present study was designed to investigate molecular regulatory pathways involved in Lp(a)-mediated induction of CCL1., Main Methods: CCL1 regulation was studied in Lp(a)-exposed human primary macrophages using mainly quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay and electrophoretic mobility shift assay (EMSA)., Key Findings: Using the AhR antagonist alpha-napthtoflavone, the translational inhibitor cycloheximide and anti-tumor necrosis factor alpha (TNFalpha) neutralizing antibodies, we demonstrated that Lp(a)-mediated mRNA induction of CCL1 occurs in an AhR-independent manner and requires de novo protein synthesis of TNFalpha. Involvement of this cytokine was further underlined by the fact that it increased expression and secretion of CCL1 by itself in macrophages. DNA binding activity of NF-kappaB, a well-known molecular effector of TNFalpha, was moreover activated by Lp(a) in a TNFalpha-dependent manner and the use of the NF-kappaB inhibitor Bay 11-7082 blocked Lp(a)-triggered CCL1 induction. In addition, Lp(a) induced binding of NF-kappaB to a NF-kappaB consensus element on CCL1 promoter as assessed by EMSA. Co-exposure to Lp(a) and the AhR ligand benzo(a)pyrene was finally shown to superinduce CCL1 expression in human macrophages, supporting the conclusion that Lp(a) and AhR ligands act on CCL1 through independent ways., Significance: These data suggest that Lp(a)-triggered induction of CCL1 expression is mediated by TNFalpha and subsequent activation of NF-kappaB, without AhR involvement.

Compressive pnemopericardium is an uncommon cause of shock after blunt trauma. The purpose of this report is to describe a case of air tamponnade observed during management of a patient with thoraco-abominal injuries in Dakar, Senegal. Diagnosis was suspected based on chest x-rays and subsequently confirmed by CT-scan. Clinical features included shock syndrome, small heart sign, and constant deterioration under assisted ventilation. Despite initial improvement after needle aspiration, the patient died due to probable recurrence of air tamponnade. Based on their review of the literature, the authors discuss the physiopathology of air tamponande and emergency treatment by needle aspiration that must be followed by surgery for creation of a pericardial window.

Objectives: The purpose of this study is to illustrate a rare vascular malformation and to make a literature review., Patient: Klippel-Trenaunay's syndrome is a congenital disorder which characterized by capillary malformation, varicosities and bony or soft tissue hypertrophy. This disease is subject to significant morbidity like bleeding, deep vein thrombosis, embolic complications and in some cases enlargement of limb that may require amputation. Our case study was a young woman of twenty years suffering since birth, from a painful, heaviness and enlarged left lower limb that reached 2.5 cm. The distal hypertrophy at the big toe which the site of a botriomycoma (telengectasic granuloma). The inner side of the thigh was also the site of small port-wine stains and varicose of the great saphenous vein. Vascular Doppler ultrasound, skeletal computed tomography and angio-MRI of the limb indicated a klippel-Trenaunay disease. A surgical abstention was decided. The patient underwent only to resection of the toe's botriomycoma followed by an elastic contention associated with "a heel pad compensation" and an anti platelet therapy to prevent deep vein thrombosis and embolic complications., Conclusion: The syndrome of Klippel-Trenaunay is a rare vascular malformation. The basic pathology can not be corrected. The treatment's aims are to control varicose veins, to prevent complications and to preserve aesthetic and functional prognosis of the leg.

Although centipede bits can cause severe symptoms, they are seldom reported since outcome is generally favorable. The purpose of this report is to describe a case of centipede envenomation causing severe and prolonged symptoms in a woman with sickle cell trait.

The objectives of this study were to study the prevalence of oral traumatisms and their relationship to epileptic seizures in Senegalese children. This study was undertaken in the Children's National Hospital of Dakar and deal with children with epilepsy. Sotf tissues and the teeth traumatisms that have occurred during epileptic seizures were recorded. We have also studied the relationship between the frequency of the seizures and the oral soft and hard tissues traumatisms. One hundred and eight children aged from 5 to 15 years with 67 boys and 41 girls with an average age of 8.16+/-2.86 years were enrolled. Several types of epileptic seizures were observed during which 44.5% of the children presented oral traumatisms of soft tissues (27.8%) and the teeth (16.7%). There is no significant relationship between the number of seizures and the frequency of the dental traumatisms (p = 0.352). The tooth fractures are the lesions most frequently noticed and are observed in 24.4% of the children. The traumatisms of the maxillary central incisors account for 38% of the traumatisms, followed by the canines (2.7%) and the molars (1.9%). The lower central incisors are the least affected. The traumatisms of soft tissues were observed in 27.8% of the children: the lips are more often affected (44%), followed by the tongue (30%), the association between lip and tongue (18%) and the cheeks (8%). There is no significant relationship between the number of seizures and the frequency of the traumatisms of soft tissues (p = 0.35).

In order to identify molecular targets of environmental polycyclic aromatic hydrocarbons (PAHs), we have analysed regulation of integrin (ITG) expression in PAH-exposed human macrophages. Among ITG subunits, beta7 ITG was found to be markedly up-regulated at both mRNA and protein levels in response to the prototypical PAH benzo(a)pyrene (BP). Knock-down of the transcription factor c-maf, known to control beta7 ITG expression, markedly impaired BP-mediated beta7 ITG induction. Moreover, chromatin immunoprecipitation and electrophoretic mobility shift assays showed BP-triggered binding of c-maf to a specific maf-responsive element found in beta7 ITG promoter. Such a binding, and also beta7 ITG induction, were however abolished in response to chemical inhibition of the aryl hydrocarbon receptor (AhR), to which PAHs bind. Taken together, these data establish beta7 ITG as a new molecular target of PAHs, whose up-regulation by these environmental contaminants most likely requires activation of co-operative pathways involving both AhR and c-maf.

Polycyclic aromatic hydrocarbons (PAHs) are widely distributed immunotoxic environmental contaminants well known to regulate expression of pro-inflammatory cytokines such as interleukine-1beta and tumor necrosis factor-alpha. In the present study, we demonstrated that the chemokine CCL1, notably involved in cardiovascular diseases and inflammatory or allergic processes, constitutes a new molecular target for PAHs. Indeed, exposure to PAHs such as benzo[a]pyrene (BP) markedly increased mRNA expression and secretion of CCL1 in primary human macrophage cultures. Moreover, intranasal administration of BP to mice enhanced mRNA levels of TCA3, the mouse orthologue of CCL1, in lung. CCL1 induction in cultured human macrophages was fully prevented by targeting the aryl hydrocarbon receptor (AhR) through chemical inhibition or small interfering RNA-mediated down-modulation of its expression. In addition, BP and the potent AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin were found to enhance activity of a CCL1 promoter sequence containing a consensus xenobiotic-responsive element known to specifically interact with AhR. Moreover, 2,3,7,8-tetrachlorodibenzo-p-dioxin triggered AhR binding to this CCL1 promoter element as revealed by chromatin immunoprecipitation experiments and electrophoretic mobility shift assays. In an attempt to further characterize the mechanism of CCL1 induction, we demonstrated that BP was able to induce an early and transient increase of intracellular calcium concentration in human macrophages. Inhibition of this calcium increase, using the calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester or the calcium store-operated channel inhibitor 2-aminoethoxydiphenyl borate, fully blocked CCL1 up-regulation. Taken together, these results bring the first demonstration that PAHs induce expression of the chemokine CCL1 in an AhR- and calcium-dependent manner.

Actinobacillus pleuropneumoniae, the etiological agent of porcine pleuropneumonia, is able to persist on respiratory epithelia, in tonsils, and in the anaerobic environment of encapsulated lung sequesters. We have demonstrated previously that putative HlyX-regulated genes, coding for dimethyl sulfoxide (DMSO) reductase and aspartate ammonia lyase, are upregulated during infection and that deletions in these genes result in attenuation of the organism. The study presented here investigates the role of HlyX, the fumarate nitrate reductase regulator (FNR) homologue of A. pleuropneumoniae. By constructing an isogenic A. pleuropneumoniae hlyX mutant, the HlyX protein is shown to be responsible for upregulated expression of both DMSO reductase and aspartate ammonia lyase (AspA) under anaerobic conditions. In a challenge experiment the A. pleuropneumoniae hlyX mutant is shown to be highly attenuated, unable to persist in healthy lung epithelium and tonsils, and impaired in survival inside sequestered lung tissue. Further, using an A. pleuropneumoniae strain carrying the luxAB genes as transcriptional fusion to aspA on the chromosome, the airway antioxidant glutathione was identified as one factor potentially responsible for inducing HlyX-dependent gene expression of A. pleuropneumoniae in epithelial lining fluid.

Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BP) are toxic environmental contaminants known to enhance production of pro-inflammatory cytokines such as IL-1beta. The present study was designed in order to determine whether TNFalpha, another cytokine acting in inflammation, may also constitute a target for these chemicals. Both TNFalpha mRNA and TNFalpha secretion levels were found to be enhanced in human BP-treated macrophages. Dioxin, a contaminant activating the aryl hydrocarbon receptor (AhR) like PAHs, was also shown to increase TNFalpha expression. BP-mediated TNFalpha induction was however not suppressed by AhR antagonists, making unlikely the involvement of the typical AhR signalling pathway. BP-exposure of macrophages did not enhance NF-kappaB DNA binding activity, but it activated the MAP kinase ERK1/2. In addition, the use of chemical inhibitors of extracellular signal-regulated protein kinase (ERK) activation fully abrogated induction of TNFalpha production in BP-treated macrophages. These data likely indicate that PAHs enhance TNFalpha expression in human macrophages through an ERK-related mechanism. Such a regulation may contribute to confer pro-inflammatory properties to these widely-distributed environmental contaminants.

Bilateral obstruction of the internal jugular veins is rare in the neonatal period and no long-term follow-up has been reported yet. We report two cases. The first developped an extensive thrombosis of superior veina cava related to a central veinous line, the second an unilateral thrombosis of the transverse-sigmoid sinus associated to a constitutional hypoplasia of the contralateral jugular vein. In the latter case, no cause or risk factor was noticeable, except for a forceps delivery. In both cases the clinical course was dominated by the development of a prominent collateral network of cervico-facial veins and by a progressive macrocrania. According to MRImaging, the latter was not related to a dilation of CSF spaces, but to a macro-encephaly, either by inflation of the vascular veinous compartment inside the parenchyma or by genuine brain's overgrowth. Long-term follow-up showed a grossly normal course, both from the neurological and the scholar point of view. However, slight neuropsychological anomalies were noticed, bringing some shade on the prognosis.

The World Health Organization has proposed the syndromic approach for management of sexually transmissible diseases (STD) in countries where diagnostic laboratory tests are not consistently available. The purpose of this study was to evaluate the effectiveness of this approach for treatment of ureteral discharge in Senegal. Twenty seven men presenting ureteral discharge underwent two-week treatment using a combination of cotrimoxazole plus tetracycline for suspected gonococcal and a chlamydial infections. Ureteral samples were collected before and after treatment to detect Neisseria gonorrhoeae by culture and Chlamydia trachomatis by direct immunofluorescence and ELISA. Results demonstrated successful treatment of all patients presenting gonococcal and chlamydial infections i.e. 84.6% of cases. Neither germ was detected in 15.4% of cases. Before treatment, Neisseria gonorrhoeae, Chlamydia trachomatis or both were found respectively in 53.9%, 5.1% and 25.6% of samples respectively. Based on these findings we conclude that the syndromic approach was effective in 84.6% of cases but treatment was in adequation with STD biologically documented only with 25.6% of cases.

Supplementation of exogenous growth hormone (GH) during prepuberty advances onset of spermatogenesis in boars, but the mechanism of action is unknown. The present study is an investigation of the presence and characteristics of testicular growth hormone receptors (GHR). A total of 36 boars were castrated, three boars every 10 days, between the ages of 10 and 120 days. Testicular membrane preparations of 10, 20, 30, 50, 70, 100 and 120-day-old boars were used to determine (125)I-bGH binding and Scatchard analysis. Liver from a 60-kg barrow was used for comparison. Specific (125)I-bGH binding to testicular membrane preparations occurred in all age groups with the exception of 20-day-old boars at levels of 30-40% of liver binding. At 30 days of age the unlabelled bGH at 1.1 ng/tube achieved half maximal inhibition (ID(50)). Results of Scatchard analysis indicated a single class of binding sites. Binding affinity was 2.89 x 10(9) m with a binding capacity of 12 fmole/mg membrane protein. The results from this study suggest that GH may act directly on the cells of the prepubertal boar testis.

Co-infection of Cryptococcal meningitis and syphilis is rare. We report the first case of coinfection with cryptococcus neoformans and treponema pallidum in Dakar. There was a 41 yearold senegalese man with HIV2 infection despite a CD4 count of 50 /mm3. The patient have had the history of precedent genital ulcerations and trush. Finally he died on eigth day of treatment with Fluconazol and Penicillin G.

The aim of this study is to determine the choleretic properties of lyophilized aqueous extract of Tinospora bakis roots. For thus, we have used healthy and cholestatic Wistar rats. After administration of the extract (4 mg/100 g of weight) biliary flow, biliary acids flow, biliary glutathione and glucose concentrations were measured by specific methods. Comparative results between treated rats and non treated rats show: For healthy rats: a significant increase of biliary flow, biliary acids flow in the group of treated rats versus non treated healthy rats. There were no significant difference in the glutathione and glucose concentrations. For cholestatic rats: we noted also significant increase of biliary flow, biliary acids flow and glutathione concentration in the treated rats group. These results suggest that Tinospora bakis has a choleretic effect in vivo which depends on biliary acids and/or glutathione concentration.

Three patients aged 32, 30 and 36 years, had chicken pox then developed acute cerebellar ataxia (for two) and acute polyradiculoneuritis. Cerebrospinal fluid (CSF) protein content was increased and varicella virus serology was positive in both blood and CSF. All three patients improved with aciclovir.

Our survey was concerned with searching for different markers of Hepatitis B virus infection in 267 primary and secondary school children in two Mauritanian sites in the south and south-east of the country. The results showed that for the surveyed subjects, 16.8% were carriers of HBs antigen, 21% of anti-HBs antibodies, 50.2% of anti-HBc antibodies and 45.4% of anti-HBe antibodies. Furthermore, 28.9% of the carriers of HBs antigen were also of HBe antigen. In all, 32.2% of the subjects had not been exposed to the Hepatitis B virus. These results confirmed the serious problem posed to public health by Hepatitis B infection and should prompt a programme to combat it.

The nucleotide sequences of HA1 domain of hemagglutinin of clinical H1N1 influenza viruses, isolated during recent outbreaks of respiratory problems in pig farms of Quebec, was determined. The viruses A/Sw/Quebec/3291/90 (SwQc3291) and A/Sw/Quebec/1747/90 (SwQc1747), associated with chronic respiratory disease, showed close similarity for their deduced aa sequences. When compared with the published data of A/Sw/Quebec/5393/91 (SwQc91), the variations observed included Cb and Ca antigenic sites in SwQc3291 and Sb and Ca sites in SwQc1747 isolates. These variants were antigenically related to SwQc91 virus associated with chronic respiratory disease, but differed from the more classical A/Sw/Quebec/192/81 (SwQc81) strain. In contrast, A/Sw/Quebec/1192/86 (SwQc1192) isolate, associated with acute respiratory influenza, showed maximum number of differences including Ca, Cb, Sa and Sb antigenic sites. The latter, as well as the SwQc81 strain, were antigenically distinct from SwQc91 virus on the basis of its cross-reactivity to MAbs directed against the HA glycoprotein. Estimation of genetic distances and phylogenic tree analysis showed that SwQc1747 and SwQc3291 were closely related, but these viruses along with SwQc1192 were considerably divergent from SwQc91 virus.

The effects of exogenous growth hormone (GH) and FSH on development of the testes in intact prepubertal boars was investigated. Twenty-four boars received one of four daily treatments from 8 through 40 days of age: 1) 90 micrograms porcine (p) GH/kg body weight (BW), 2) 100 micrograms pFSH/kg BW, 3) GH + FSH, or 4) vehicle only (control). Plasma testosterone levels, measured at 10-day intervals, were similar among groups of boars throughout the study. Body weights among groups were similar during treatment, and testicular weight between treatment groups did not differ at castration (100 days of age). However, total length of the seminiferous tubule per testis in FSH-treated boars was 59% greater than in GH-treated animals (2705 vs. 1704 m; p < 0.05). Diameter of the tubule in GH-treated boars was 58% greater than in FSH-treated boars (p = 0.03). Relative mass of spermatocytes and spermatids in GH-treated animals exceeded that in controls by 2.5-fold and that in FSH boars by 75-fold (p = 0.05). There were no differences in effects of GH + FSH treatment as compared to control treatment; none of the treatments affected any interstitial tissue parameter measured. These results suggest that exogenous FSH had a mitogenic effect on Sertoli cells while delaying tubular maturity, whereas exogenous GH promoted tubular and Sertoli cell maturation, defined as increased Sertoli cell size, lumen formation, and onset of spermatogenesis.

Binding of leprosy sera to peripheral nerve from different species (mouse, guinea pig and rabbit) was evaluated by ELISA. A majority of sera, whatever the clinical form of leprosy, bind to these antigens. Absorption with Mycobacterium bovis BCG demonstrated that these antibodies recognize cross-reactive epitopes between peripheral nerve and mycobacteria. In immunoblot analysis, both leprosy patient sera and a monoclonal antibody directed at the 65 kDa heat shock protein of M. leprae were shown to react with a heat-shock 67-68 kDa sciatic nerve protein. Binding of the monoclonal antibody to this sciatic nerve antigen was prevented by incubation with lepromatous patient sera, showing that some peripheral nerve epitopes recognized by patient antibodies are shared by the 65 kDa heat shock protein of M. leprae.

Endemic goitre and its response to orally administered iodized oil has been studied in seven villages 25-30 km south of Velingara, Eastern Casamance, Senegal. In 502 adults aged greater than 15 years goitre prevalence was 62% with 18.2% having goitre grade 2 or 3. Mean free T4 (FT4) was 11.9 +/- 3.5 (SD) pmol/l and iodine deficiency was confirmed by noting median urinary I of 0.079 mumol/l (14.9 mumol I/mol creatinine) with elevated free T3 (FT3)/FT4 ratios. Serum selenium concentrations were normal. The response to 480 mg of oral iodized oil assessed at 6 and 12 months was characterized by a 35.8% increase in FT4, a 25% decrease in FT3 and a 50% decrease in TSH (all p less than 0.01) at 12 months associated with a significant decrease in goitre size measured in 70 persons when compared to 65 controls not receiving iodine. Urinary iodine rose from 0.071 mumol/l to 0.189 mumol/l (p less than 0.01) during this time and no adverse effects on thyroid antibodies (anti-thyroid peroxidase and anti-thyroglobulin) were observed. A variation in goitre prevalence between villages was noted which, in such a small geographical area, suggests that etiological factors in addition to iodine deficiency may be important in goitre pathogenesis. Oral iodized oil administration is an effective treatment for iodine deficiency goitre in the short term.

The epidemiologic data and surgical results of 253 cataract extractions performed in a new department of Ophthalmology in Eastern Senegal were reviewed. 87 per cent have been operated without hospitalization, with restricted follow up. The complication rate was low, showing that this kind of surgery was suitable to local socio-economical conditions.

The 1986-87 outbreak of paralytic poliomyelitis in Senegal, with 676 reported cases, provided an opportunity to evaluate the efficacy of an enhanced-potency inactivated poliovirus vaccine (N-IPV) in the Kolda region, where this vaccine has been used since 1980. 89 cases, confirmed to have poliomyelitis with residual paralysis, were enrolled in a case-control study, up to 5 matched controls being obtained for each case. The clinical efficacy for one dose of N-IPV was 36% (95% confidence interval 0%, 67%) and for two doses was 89% (95% CI 62%, 97%).

We have evaluated the cardiac risk for 212 patients who underwent internal carotid surgery (245 operations). The mean age at the time of operation was of 63 +/- 8 years. A complete pre-operative cardiac assessment was performed splitting the patients in two groups: one considered as having a coronary heart disease (CHD) and the other as "healthy heart" (HH). The peri-operative cardiac morbidity and mortality rate were low (CHD group: 16.88%; HH group: 2.22%). At a 2 years follow-up we notice 31% of cardiac problems in the CHD group (with a mortality rate of 5.7%) for 3.9% in the HH group (with a mortality rate of 3.9%). The 4 years follow-up gives similar results.

Of 43 tracheo-bronchial ruptures, 19 patients presented with disruption of the laryngo-tracheal junction which would appear to be a very specific anatomical lesion. The disruptions were secondary to blunt cervical trauma in 11 cases and strangulation in 8 cases. The disruption was complete in 14 cases and incomplete in 5. The lesion is very complex and involved the retraction of the lower part of the trachea into the mediastinum (14 cases), fracture of the cricoid ring (9 cases), bilateral recurrent nerve tears (14 cases), unilateral (4 cases) and retraction of the laryngeal mucosa with exposure of the cricoid cartilage in all cases. According to the complexity of the lesion, the treatment was: laryngo-tracheal resection and end-to-end anastomosis with treatment of the vocal cord palsy in 13 patients; simple end-to-end anastomosis in 4 patients who had an unilateral vocal cord palsy; 2 patients with a partial disruption were treated medically with endoscopic stenting and laser photocoagulation. All had restoration of airway patency and recovery of voice. The results contrast with the failures and reoperations reported in the literature and underline the necessity of complete evaluation and treatment of these complex lesions.

The evolution of CT signs of small, deep infarcts of the cerebral hemispheres in thirty adults, in the first five weeks, has been retrospectively studied. The relevant literature has been reviewed and an attempt has been made to present a synthesis, accompanied by a commentary. It is impossible now to give the frequency of each type of evolution, but the main data are as follows: The shortest delay of visibility of an hypodense area is about 17 to 19 h, but at 27 h the densities may still be normal. The evolution of the hypodense area is also variable: after a minimum attenuation is reached--at approximately 72 h--there is a risk of "fogging effect", which reduces the visibility of ischemic lesions; it could be seen from the end of the 1st week to the beginning of the 4th, but its frequency and its duration have yet to be better determined. In our series, contrast enhancement has been found in the gray matter of the basal ganglia between the 8th and the 22nd days--but according to some observations recorded in the literature, it may be found from the second to the twenty sixth day--and there was no obvious contrast enhancement in the white matter. The significance of the evolving CT signs is discussed in connection with the clinical applications, principally in the management of these patients, and with the attempts to correlate the clinical and CT findings.