Search

In this study, we focused on evaluating the responses of the cockle, Cerastoderma glaucum to in situ exposures to metals at three sites in the Gulf of Gabes in the coastal zone of Tunisia differing in levels of metal contamination. Firstly, we examined the general physiological state of the organisms. Secondly, we evaluated the bioaccumulation of several metals (Cd, Cu, Zn, Ni) in the cockles. Thirdly, we focused on evaluating histologically changes in gametogenesis and sexual maturity of the organisms. Finally, we determined the expression of seven key genes encoding enzymes or proteins involved in responses to different types of environmental stressors. Results showed a decrease in the general physiological status of the cockles, including a reduced condition index, sex ratios skewed to females (70% and 80% females in the intermediate and the contaminated site, respectively) and greater mortalities in tests under anoxic conditions (i.e., stress on stress test) in cockles collected from the most contaminated site (LT50 = 2.88 days) compared to the cockles from the intermediate site (LT50 = 5 days) and the less contaminated site (LT50 = 6 days). Results for metal bioaccumulation showed that the levels of Cd, Cu, Zn and Ni in cockles were consistent with the contaminant gradient, with the highest levels in cockles from the most contaminated site (1.04; 4.92; 52.76 and 13.81 µg/g dw, respectively), followed by those from the intermediate site (0.34; 2.94; 36.94; 17.40 µg/g dw, respectively) and then the less contaminated site (0.065; 1.27; 21.62 and 5.40 µg/g dw, respectively). Results from the gametogenesis and maturity index showed few differences in the reproductive cycle of cockles collected from the three study sites. There were different patterns of gene expression that were divided into three groups in terms of responses: (1) expression of genes involved in metal detoxification, ATP Binding Cassette Subfamily B Member 1 (ABCB1) and metallothionein MT) and genes for superoxide dismutases (i.e., Mn SOD and CuZn SOD), which did not show any difference in their levels of expression; (2) heat shock protein 70 (HSP70) gene expression, which decreased in cockles according to the pollution gradient, and (3) expression of catalase (CAT) and cytochrome oxidase subunit 1 (COI) genes was threefold and 1000-fold higher in cockles from intermediate and most contaminated sites compared to the less contaminated site. Therefore, changes in overall physiological condition, sex ratios and expression of HSP70, CAT and COI genes may be appropriate biomarkers for in situ studies of the impacts of metals in cockles. However, these biomarkers should be coupled to proteomics studies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Development of Graft Versus Host Disease (GVHD) represents a major impediment in allogeneic hematopoietic stem cell transplantation (HSCT). The observation that the presence of bone marrow and circulating hematogones correlated with reduced GVHD risks prompted us to evaluate whether B-cell progenitors, which provide protection in various autoimmune disease models following activation with the TLR-9 agonist CpG (CpG-proBs), could likewise reduce this allogeneic disorder. In a murine model of GVHD that recapitulates an initial phase of acute GVHD followed by a phase of chronic sclerodermatous GVHD, we found that CpG-proBs, adoptively transferred during the initial phase of disease, reduced the diarrhea score and mostly prevented cutaneous fibrosis. Progenitors migrated to the draining lymph nodes and to the skin where they mainly differentiated into follicular B cells. CpG activation and IFN-γ expression were required for the protective effect, which resulted in reduced CD4 + T-cell-derived production of critical cytokines such as TGF-β, IL-13 and IL-21. Adoptive transfer of CpG-proBs increased the T follicular regulatory to T follicular helper (Tfr/Tfh) ratio. Moreover, CpG-proBs privileged the accumulation of IL-10-positive CD8 + T cells, B cells and dendritic cells in the skin. However, CpG-proBs did not improve survival. Altogether, our findings support the notion that adoptively transferred CpG-proBs exert immunomodulating effect that alleviates symptoms of GVHD but require additional anti-inflammatory strategy to improve survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Agbogan, Gastineau, Tejerina, Karray and Zavala.)

Invariant natural killer T (iNKT) cells expressing the retinoic acid receptor-related orphan receptor γt (RORγt) and producing IL-17 represent a minor subset of CD1d-restricted iNKT cells (iNKT17) in C57BL/6J (B6) mice. We aimed in this study to define the reasons for their low distribution and the sequence of events accompanying their normal thymic development. We found that RORγt+ iNKT cells have higher proliferation potential and a greater propensity to apoptosis than RORγt- iNKT cells. These cells do not likely reside in the thymus indicating that thymus emigration, and higher apoptosis potential, could contribute to RORγt+ iNKT cell reduced thymic distribution. Ontogeny studies suggest that mature HSAlow RORγt+ iNKT cells might develop through developmental stages defined by a differential expression of CCR6 and CD138 during which RORγt expression and IL-17 production capabilities are progressively acquired. Finally, we found that RORγt+ iNKT cells perceive a strong TCR signal that could contribute to their entry into a specific 'Th17 like' developmental program influencing their survival and migration. Overall, our study proposes a hypothetical thymic developmental sequence for iNKT17 cells, which could be of great use to study molecular mechanisms regulating this developmental program., (© The Japanese Society for Immunology. 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Lipoma arborescens is a rare intra-articular benign tumor. It affects mostly the knee and the diagnosis is usually difficult due to resembling symptomatology of osteoarthritis., Cases Presentation: We report herein 3 new cases of lipoma arborescens of the knee in which a patient has synovitis associated. In 2 cases, the discovery was intraoperatively. We also report a tumor relapse 2 years after surgery.

This study assessed the responses of primary cultured haemocytes from the marine gastropod Haliotis tuberculata exposed to the increasing concentrations of industrial effluent (0, 0.5, 1, 10, 15 and 20%) discharged into the Tunisian coastal area. Analyses showed the presence of metals such as cadmium (Cd), chromium (Cr), copper (Cu), manganese (Mn), zinc (Zn), nickel (Ni) and lead (Pb) in the effluent. The effects of this mixture of pollutants on abalone haemocyte parameters were reflected by a significant decrease of cell viability, phagocytotic activity and reactive oxygen species (ROS) production as well as morphological and lysosomal membrane alterations. Thus, these results indicated that our primary culture system represents a suitable in vitro model for monitoring of anthropogenic contaminants in aquatic environments.

Vascular complications of lumbar disc surgery are rare. Few cases have been reported. Arteriovenous fistulas are the most common. They are due to anatomical relationships between the last lumbar vertebrae, the corresponding discs, and the iliac vessels; degenerative lesions of the intervertebral discs facilitate instrumental vessel perforation, and operative difficulty. Computed tomography is particularly accurate for making the diagnosis. Treatment strategies consist in surgery or endovascular management. Percutaneous endovascular treatment using a stent-graft is a reasonable option for treating arteriovenous fistula. We describe the case of a 50-year-old patient who developed an iliocaval arteriovenous fistula following lumbar disc hernia surgery. The lesion was excluded by a stent-graft. The postoperative period was uneventful., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

This study assessed the responses of molecular biomarkers and heavy metal levels in Cerastoderma glaucum exposed for 1 week to two industrial effluents (1%) discharged into the Tunisian coastal area, F1 and F2, produced by different units of production of a phosphate treatment plant. A significant uptake of metals (Cd, Cu, Zn, and Ni) was observed in exposed cockles compared to controls, with an uptake higher for F1 than for F2. A decrease in LT50 (stress on stress test) was also observed after an exposure to the effluent F1. Treatments resulted in different patterns of messenger RNA (mRNA) expression of the different genes tested in this report. Gene transcription monitoring performed on seven genes potentially involved in the tolerance to metal exposure showed that for both exposures, mechanisms are rapidly and synchronically settled down to prevent damage to cellular components, by (1) handling and exporting out metal ions through the up-regulation of ATP-binding cassette xenobiotic transporter (ABCB1) and metallothionein (MT), (2) increasing the mRNA expression of antioxidant enzymes (catalase (CAT), superoxide dismutases, CuZnSOD and MnSOD), (3) protecting and/or repairing proteins through the expression of heat shock protein 70 (HSP70) mRNAs, and (4) increasing ATP production (through the up-regulation of cytochrome c oxidase 1 (CO1)) to provide energy for cells to tolerate stress exposure. The tools developed may be useful both for future control strategies and for the use of the cockle C. glaucum as a sentinel species.

The gametogenic cycle of the Cerastoderma glaucum was analyzed using both qualitative and semi-quantitative methods. The condition index and glycogen concentrations were determined in order to provide information on energy storage. The cockles were collected monthly from a Bayyadha site located 15 km south of Sfax City (Gulf of Gabès) between January 2007 and January 2008. From histological point of view, we applied two approaches: (i) the qualitative method describing the various stages of gamete development for males and females during a cycle of 13 months, and (ii) the semi-quantitative method concerning the estimation of different tissue surfaces. The results showed that there is evidence of three periods of reproduction in this population. A comparison between the surfaces occupied by the three organs showed that the foot and the gonad surfaces are higher than the surface of the adductor muscle. This could suggest that these two organs are more involved in the process of glycogen reserve storage. The results of the glycogen concentrations in the different tissues (gonad, adductor muscle, and "remainders") show that during the second and third periods of reproduction, glycogen was stored in the adductor muscle and in the remainder during sexual rest, and in the gonad during the gametogenesis phases in order to supply the reproductive effort. On the contrary, in the first period of reproduction, the low concentrations of glycogen recorded in the gonad coincided with its high degree of development. This fact could be related to environmental conditions (low temperature and food) recorded during this period.

This study investigates cadmium effects on key messenger RNA (mRNA) expression (MT, MnSOD, CuZnSOD, CAT, ABCB1, HSP70, and CO1) by qPCR in the cockle Cerastoderma glaucum after chronic exposure to two high but environmentally relevant concentrations of CdCl2 (50 μg/L and 5 mg/L) for 12 h to 18 days. Cd accumulation measured in cockles' tissues is significantly higher in both treatment conditions compared to controls and in a dose-dependent manner. Stress on stress tests performed at different times of the experiment clearly demonstrated that exposure to both concentrations of Cd significantly affects cockle survival time in air. Important changes in gene transcription were also highlighted. In particular, MT, HSP70, CAT, and CuZnSOD seem to be relevant biomarkers of Cd exposure because (1) their mRNA levels increase upon exposure and (2) they are highly correlated to Cd accumulation in tissues. Results may be useful for control strategies and for the use of cockles as sentinel organisms.

The Fas receptor ligand FasL regulates immune cell levels by inducing apoptosis of Fas receptor-positive cells. Here, we studied the impact of host FasL on tumor development in mice. Genetically targeting FasL in naïve mice increased myeloid cell populations, but, in marked contrast, it reduced the levels of myeloid-derived suppressor cells (MDSC) in mice bearing Lewis lung carcinoma tumors. Analysis of the MDSC subset distribution revealed that FasL deficiency skewed cell populations toward the M-MDSC subset, which displays a highly immunosuppressive activity. Furthermore, tumor-bearing mice that were FasL-deficient displayed an enhanced proportion of tumor-associated macrophages and regulatory T cells. Overall, the immunosuppressive environment produced by FasL targeting correlated with reduced survival of tumor-bearing mice. These results disclose a new role for FasL in modulating immunosuppressive cells., (©2015 American Association for Cancer Research.)

Neuroinflammation is increasingly recognized as a hallmark of neurodegeneration. Activated central nervous system-resident microglia and infiltrating immune cells contribute to the degeneration of dopaminergic neurons (DNs). However, how the inflammatory process leads to neuron loss and whether blocking this response would be beneficial to disease progression remains largely unknown. CD95 is a mediator of inflammation that has also been proposed as an apoptosis inducer in DNs, but previous studies using ubiquitous deletion of CD95 or CD95L in mouse models of neurodegeneration have generated conflicting results. Here we examine the role of CD95 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP)-induced neurodegeneration using tissue-specific deletion of CD95 or CD95L. We show that DN death is not mediated by CD95-induced apoptosis because deletion of CD95 in DNs does not influence MPTP-induced neurodegeneration. In contrast, deletion of CD95L in peripheral myeloid cells significantly protects against MPTP neurotoxicity and preserves striatal dopamine levels. Systemic pharmacological inhibition of CD95L dampens the peripheral innate response, reduces the accumulation of infiltrating myeloid cells, and efficiently prevents MPTP-induced DN death. Altogether, this study emphasizes the role of the peripheral innate immune response in neurodegeneration and identifies CD95 as potential pharmacological target for neurodegenerative disease., (© 2015 Gao et al.)

Tumor-infiltrating myeloid cells such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) form an important component of the hypoxic tumor microenvironment. Here, we investigated the influence of hypoxia on immune checkpoint receptors (programmed death [PD]-1 and CTLA-4) and their respective ligands (PD-1 ligand 1 [PD-L1], PD-L2, CD80, and CD86) on MDSCs. We demonstrate that MDSCs at the tumor site show a differential expression of PD-L1 as compared with MDSCs from peripheral lymphoid organ (spleen). Hypoxia caused a rapid, dramatic, and selective up-regulation of PD-L1 on splenic MDSCs in tumor-bearing mice. This was not limited to MDSCs, as hypoxia also significantly increased the expression of PD-L1 on macrophages, dendritic cells, and tumor cells. Furthermore, PD-L1 up-regulation under hypoxia was dependent on hypoxia-inducible factor-1α (HIF-1α) but not HIF-2α. Chromatin immunoprecipitation and luciferase reporter assay revealed direct binding of HIF-1α to a transcriptionally active hypoxia-response element (HRE) in the PD-L1 proximal promoter. Blockade of PD-L1 under hypoxia enhanced MDSC-mediated T cell activation and was accompanied by the down-regulation of MDSCs IL-6 and IL-10. Finally, neutralizing antibodies against IL-10 under hypoxia significantly abrogated the suppressive activity of MDSCs. Simultaneous blockade of PD-L1 along with inhibition of HIF-1α may thus represent a novel approach for cancer immunotherapy.

Background: Medicinal products that have been developed and approved for one disease may be the object of additional clinical development in other disease areas or of additional pharmaceutical development for new and different formulations. The newly developed products can be named as repositioned or reformulated products, respectively. Market access of repositioned or reformulated products in Europe and the United States is an interesting object of study as it may provide clarity about which parameters are assessed and considered to bring added value, other than the molecule itself. As such, we aim to evaluate if the added value of repositioned or reformulated medicinal products can be systematically described, quantified, and predicted. As a first step toward investigating the impact of market access on drug research and development trends for repositioned and reformulated products, it is necessary to have consistency in the designations for the case studies evaluated in this project. In an attempt to achieve that consistency, the current study aims to propose harmonized definitions for the repositioning and reformulation strategies and to propose a taxonomy for the medicinal products derived thereof., Methods: A systematic literature review was conducted to collect information on existing cases of repositioning or reformulation. A search strategy was developed by defining the search objectives, targeted data sources, search keywords, and inclusion/exclusion criteria for the retrieved documents., Results: A total of 505 publications were retrieved through a search of the main data sources. The screenings and the ad hoc search led to a total of 56 publications to be used for the case study data extraction. In total, 87 repositioning and/or reformulation cases were found described in the literature, 23 of which presented different definitions and/or classifications by different authors., Conclusion: Given the disparity and inconsistency of terminologies and classifications in the literature, a harmonized nomenclature for drug repositioning, reformulation, and combination cases will allow for a robust analysis of the added value and market access conditions attributed for each strategy and case type as assessed by regulators and payors in Europe and the United States. After evaluation of the existing terminologies and given the absence of clear and consistent definitions for drug reformulation and repositioning in the literature, we propose a global terminology and taxonomy in order to cover all of the previously unclear definitions and classifications for repositioned and reformulated products.

In T-cell-mediated autoimmune diseases of the CNS, apoptosis of Fas(+) T cells by FasL contributes to resolution of disease. However, the apoptosis-inducing cell population still remains to be identified. To address the role of astrocytic FasL in the regulation of T-cell apoptosis in experimental autoimmune encephalomyelitis, we immunized C57BL/6 glial fibrillary acid protein (GFAP)-Cre FasL(fl/fl) mice selectively lacking FasL in astrocytes with MOG(35-55) peptide. GFAP-Cre FasL(fl/fl) mice were unable to resolve EAE and suffered from persisting demyelination and paralysis, while FasL(fl/fl) control mice recovered. In contrast to FasL(fl/fl) mice, GFAP-Cre FasL(fl/fl) mice failed to induce apoptosis of Fas(+) activated CD4(+) T cells and to increase numbers of Foxp3(+) Treg cells beyond day 15 post immunization, the time point of maximal clinical disease in control mice. The persistence of activated and GM-CSF-producing CD4(+) T cells in GFAP-Cre FasL(fl/fl) mice also resulted in an increased IL-17, IFN-γ, TNF, and GM-CSF mRNA expression in the CNS. In vitro, FasL(+) but not FasL(-) astrocytes induced caspase-3 expression and apoptosis of activated T cells. In conclusion, FasL expression of astrocytes plays an important role in the control and elimination of autoimmune T cells from the CNS, thereby determining recovery from EAE., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Glaucoma, the most frequent optic neuropathy, is a leading cause of blindness worldwide. Death of retinal ganglion cells (RGCs) occurs in all forms of glaucoma and accounts for the loss of vision, however the molecular mechanisms that cause RGC loss remain unclear. The pro-apoptotic molecule, Fas ligand, is a transmembrane protein that can be cleaved from the cell surface by metalloproteinases to release a soluble protein with antagonistic activity. Previous studies documented that constitutive ocular expression of FasL maintained immune privilege and prevented neoangeogenesis. We now show that FasL also plays a major role in retinal neurotoxicity. Importantly, in both TNFα triggered RGC death and a spontaneous model of glaucoma, gene-targeted mice that express only full-length FasL exhibit accelerated RGC death. By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma.

Injury to the central nervous system initiates an uncontrolled inflammatory response that results in both tissue repair and destruction. Here, we showed that, in rodents and humans, injury to the spinal cord triggered surface expression of CD95 ligand (CD95L, FasL) on peripheral blood myeloid cells. CD95L stimulation of CD95 on these cells activated phosphoinositide 3-kinase (PI3K) and metalloproteinase-9 (MMP-9) via recruitment and activation of Syk kinase, ultimately leading to increased migration. Exclusive CD95L deletion in myeloid cells greatly decreased the number of neutrophils and macrophages infiltrating the injured spinal cord or the inflamed peritoneum after thioglycollate injection. Importantly, deletion of myeloid CD95L, but not of CD95 on neural cells, led to functional recovery of spinal injured animals. Our results indicate that CD95L acts on peripheral myeloid cells to induce tissue damage. Thus, neutralization of CD95L should be considered as a means to create a controlled beneficial inflammatory response., (Copyright 2010 Elsevier Inc. All rights reserved.)

Mice with mutations in the gene encoding Fas ligand (FasL) develop lymphoproliferation and systemic autoimmune diseases. However, the cellular subset responsible for the prevention of autoimmunity in FasL-deficient mice remains undetermined. Here, we show that mice with FasL loss on either B or T cells had identical life span as littermates, and both genotypes developed signs of autoimmunity. In addition, we show that T cell-dependent death was vital for the elimination of aberrant T cells and for controlling the numbers of B cells and dendritic cells that dampen autoimmune responses. Furthermore, we show that the loss of FasL on T cells affected the follicular dentritic cell network in the germinal centers, leading to an impaired recall response to exogenous antigen. These results disclose the distinct roles of cellular subsets in FasL-dependent control of autoimmunity and provide further insight into the role of FasL in humoral immunity.

Background: Breast carcinoma is a disease with a tremendous heterogeneity in its clinical behavior. Newer prognostic factors and predictors of response to therapy are needed. The aim of this study was to evaluate the expression of HER-2, estrogen receptor (ER) and progesterone receptors (PR) in breast carcinoma and to compare it with other prognostic parameters such as histological type and grade, tumor size, patients' age, and lymph node metastases., Patients and Methods: This is a retrospective study conducted in the department of pathology at Sfax University Hospital. Confirmed 155 Cases of breast carcinoma were reviewed in the period between January 2000 and December 2004. We used immunohistochemistry to evaluate the expression of HER-2, ER, and PR receptor and Chi-square and Fisher exact test to correlate immunohistochemical findings with prognostic parameters for breast carcinoma such as patients' age, tumor size, histological type, histological grade and lymph node status., Results: The mean age of patients was 51.5 years, ranging from 22 to 89 years. 80 (51.6%) of the patients were below 50 years. The percentage of expression of HER-2, ER and PR was 26, 59.4, and 52.3%, respectively. HER-2 was over-expressed (3+) in 18.1% of the cases, was inversely related to ER expression (p = 0.00) and to PR expression (p = 0.048). This over-expression was also associated with a high tumor grade with marginal significance (p = 0.072). A negative correlation was noted between ER and PR expression and SBR grade (p = 0.000) and ER and age (p = 0.002)., Conclusion: HER-2 over-expression was observed in 18.1% of Tunisian breast carcinoma affecting female patients. This group presents apparently an aggressive form of breast carcinoma with high histological grade and negative ER.

The cytoplasmic domain of Fas ligand is sufficient to costimulate CD8(+) T cells by driving Fas ligand recruitment into lipid rafts and association with select Src homology 3-containing proteins, activating PI3K and MAPK pathways, mediating nuclear translocation of the transcription factors NFAT and AP-1, and enhancing IFN-gamma production and Ag-specific CD8(+) T cell proliferation. We now show that Fas ligand molecules lacking amino acids 45-54 in the proline-rich region of the cytoplasmic domain fail to costimulate but serve as effective death inducers. Death induction and costimulation by Fas ligand are therefore clearly separable functions. Further, upon Fas ligand-mediated costimulation, casein kinase I phosphorylates Fas ligand, in which two conserved casein kinase I binding sites regulate NFAT activation and costimulation. These results help resolve how one molecule can serve as a double-edged immunomodulator by directing discrete biological consequences.

A 54-year-old man was seen with a fracture of the left femur. Plain radiographs revealed a 40-mm lytic centromedullary lesion. Magnetic resonance T1- and T2-weighted sequences showed high and low signals. After stabilization of the fracture, the tumor was removed followed by reconstruction with a vascularized fibula. The pathological examination demonstrated proliferation of non atypical CD34 and CD31 positive epithelioid cells with few lumens, accompanied by abundant fibrous stroma, sometimes masking tumor cells. Satisfactory motion was achieved with no recurrence at 20 months follow-up. Bone hemangioendothelioma can simulate metastasis and must be distinguished by immunohistochemistry. Prognosis is a subject of debate as the tumor is considered to exhibit intermediate malignancy by some authors while other consider it to be a malignant tumor.

The subcellular localization of cerium and lanthanum in the intestinal mucosa was studied after oral administration of cerium chloride or lanthanum chloride or lanthanum chloride followed 30 minutes after of cerium chloride to young adults Wistar rats. Two methods of observation and microanalysis were used. The transmission electron microscopy revealed the presence of dense electron granulations in the lysosmes of the duodenum enterocyte, when these elements were administrated simultaneously. The ion mass microanalysis permits to detect the presence of La and Ce as bright points outlining the intestinal villi. These points correspond to the lysosomes containing the granulations previously described. These granulations are formed by the cerium and the lanthanum associated to the phosphor and forming probably insoluble salts of Ce/La phosphate.

To investigate the in vivo function of Fas ligand (FasL), we produced a mouse strain with a FasL gene flanked by loxP sequences. Mice with homozygous floxed FasL gene showed no obvious abnormalities. However, germline deletion of the FasL gene, obtained after mating with mice expressing ubiquitous Cre recombinase, resulted in an unexpectedly severe phenotype. FasL(-/-) mice exhibited an extreme splenomegaly and lymphadenopathy associated with lymphocytic infiltration into multiple organs and autoimmune disease. This severe phenotype led to the premature death at 4 mo of age of >50% of the homozygous mice. It stands in sharp contrast with the milder disease observed in gld (generalized lymphoproliferative disease) mice, indicating that the FasL allele of these mice encodes a protein still able to bind, albeit at a very low level, the Fas receptor.

The authors present a rare case of univertebral hydatidosis, and report encouraging results 12 years after radical resection of the involved vertebra. They stress the importance of computed tomography and especially magnetic resonance for monitoring early recurrence. A two-staged anterior and posterior approach, although difficult, seems to offer a very good prognosis in case of univertebral localisation.

Stickler syndrome, also called hereditary arthro-ophthalmopathy is a dominant disorder, with poly-epiphyseal dysplasia resulting in early osteoarthritis. It usually includes bilateral myopia, that changes little during the follow up period, but can lead to retinal detachment. Children with Stickler syndrome can show facial dysmorphism that may improve with age, but severe anomalies may exist such as Pierre Robin sequence. Our case, a woman, 20-year-old, presents chronic polyarthritis which is an unusual feature of this disease. The diagnosis of Stickler's syndrome is based on polyepiphyseal dysplasia in skeletal radiography and bilateral myopia. Otherwise, this patient has no facial dysmorphism.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that consumes NAD in response to DNA strand breaks. Its excessive activation seems particularly deleterious to pancreatic beta-cells, as exemplified by the complete resistance of PARP-1-deficient mice to the toxic diabetes induced by streptozotocin. Because of the possible implication of this enzyme in type 1 diabetes, many human trials using nicotinamide, an inhibitor of PARP-1, have been conducted either in patients recently diagnosed or in subjects highly predisposed to this disease. To analyze the role of this enzyme in murine type 1 diabetes, we introgressed a disrupted PARP-1 allele onto the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain. We showed that these mice were protected neither from spontaneous nor from cyclophosphamide-accelerated diabetes. Surprisingly they were also highly sensitive to the diabetes induced by a single high dose of streptozotocin, standing in sharp contrast with C57BL/6 mice that bear the same inactivated PARP-1 allele. Our results suggest that NOD mice are characterized not only by their immune dysfunction but also by a peculiarity of their islets leading to a PARP-1-independent mechanism of streptozotocin-induced beta-cell death.

Purpose of the Study: Treating hip trauma victims who develop nonunion of the femoral neck remains a challenge in orthopedic surgery. We studied the clinical and radiological outcome after Pauwels osteotomy for valgisation., Material and Methods: This retrospective series included 41 patients (25 men and 16 women), mean age 44.5 years. Initial treatment was surgical in 21 cases and had been insufficient in 91%. Nonunion (subcapital in 53%, transcervical in 40% and basicervical in 7%) had persisted for 16 months. A tight nonunion was present in 65.9% of the cases and the femoral head appeared normal in 70%. Femoral osteotomy was performed for simple valgisation in 78% of the cases with a mean 31.5 degrees correction (range 15 degrees to 50 degrees ). A nail or screwed plate was used for fixation. Results were analyzed at a mean 76 months post-surgery., Results: Bone healing was achieved in 98% of the cases. The only failure was related to inappropriate surgical technique. Necrosis was observed in 16 cases. The functional outcome was very good or good in 82% of the patients., Conclusion: Osteotomy for valgisation remains a very good salvage procedure for nonunion of the femoral neck following hip trauma. It can be used for elderly subjects even in the presence of early stage or partial necrosis.

We report the results of a prospective Tunisian study using primary chemotherapy followed by conservative surgery in primitive limb osteosarcoma. From January 1988 to January 1998, 56 patients affected by limb osteosarcoma entered in a prospective study of neoadjuvant chemotherapy with the T10 protocol before surgery with a conservative intent. Initial work-up include: clinical exam with tumor measurements, chest and limb X-rays, limb CT-scan or MRI, chest CT-scan, bone scintigraphy and hematological and renal biological exams. Patients receive pre- and post-operative chemotherapy according to the T10 modified protocol. Fifty-six patients (33 M/23 F) with a mean age of 19 years (8 to 28) are included. Mean clinical and radiological tumor size is around 14 cm. Main histologic type is classic osteosarcoma (50% of cases) and 10 patients (9%) presented with initial metastasis; 42 patients on 56 receive the whole pre-operative protocol. Treatment is well tolerated excluding 18 episodes of mucositis, 29 of leucopenia (< grade 3), 7 of thrombopenia (< grade 3), 4 of cutaneous toxicity, 2 of pulmonary toxicity and 3 of nausea-vomiting. We observe 36% of good histological responders and 64% of bad responders to primary chemotherapy, 27 patients on 49 operated (53%) have a conservative surgery and 18 (47%) a radical surgery. With a median follow-up of 51 months (8 to 128), 29 patients remain alive free of disease (15/17 GR and 14/30 BR), 2 are alive with disease, 2 died by toxicity, 14 died by progressive disease and 9 are lost to follow-up with evolutive disease. Five year disease-free survival is 55% for the 46 non metastatic patients. In univariate analysis, seric alkaline phosphatase level (p = 0.0014) and histological response to chemotherapy (p = 0.0218) are significant factors for prognosis.

Purpose of the Study: The aim of this study was to emphasize the importance of the distraction osteogenesis technique in the treatment of post-osteomyelitis nonunion. We report 12 cases., Patients and Methods: Mean patient age was 9.5 years. There were 7 cases of nonunion of the femur and 5 involving the tibia. Nonunion was associated with 5.9 cm shortening in 10 cases, 8.4 cm circumferential bone defect in 1 case, shortening and bone defects in 6 cases, and shortening and joint deformities in 2 cases., Results: Consolidation was obtained in 11 cases with an average delay of 11.6 months. Infection was eradicated in 75 per cent of the cases. Average residual shortening was 0.4 cm. Joint deformities and axial deviations were corrected at the same time in all cases., Discussion: The advantages of the Ilizarov technique are well known for the treatment of such deformities and musculoskeletal system disorders subsequent to osteomyelitis: nonunion, infection, shortening, joint deformities and malunion.

The authors report the results of a retrospective study of 36 cases of tibiotalar arthrodesis performed in 22 men and 14 women with an average age of 32 years. All patients were reviewed with an average of 8.5 years follow-up. The predominating etiologies were ankle osteoarthritis (15 cases) and neurologic deformities of the foot (13 cases). Arthrodesis was performed using the Meary technique in 60% of cases, using the Charnley technique in 20% and the Crawford-Adams technique or with clamps in the other cases. Fusion was obtained in 97% of cases. Long-term results were assessed using Duquennoy et al.'s scoring system. They were very good or good in 58% of cases, fair in 31% and poor in 11%. The study of distal repercussions of tibiotalar arthrodesis shows progressive deterioration of the subtalar joint in 70% of cases and appearance or increase of degenerative changes in 75% of cases. The final results of the procedure depend on this deterioration; the latter is related with the arthrodesis position. Midtalar joint is a compensation joint showing hypermobility in 40% of cases. Degenerative changes were limited and asymptomatic in 80% of cases. Based on the findings in this study and on the literature, we conclude that the foot should be fixed at 90 degrees or with less than 5 degrees of equinus, with 5 degrees of valgus and 10 to 15 degrees of external rotation.

The distal end of the radius is one of the sites commonly affected by giant-cell tumor of bone; it poses problems of reconstruction after resection of the distal radius. The authors present a retrospective study of 5 giant cells tumors treated by resection-arthrodesis of the wrist. These tumors were seen in 3 men and 2 women. From the radiological point of view, all tumors were extensive and lytic lesions centered in the epiphysis and involving the metaphysis; the wrist joint was respected. From the histological point of view, the tumors were grade I in 3 cases and grade II in 2 cases. With a mean follow up of 8 years, the results were considered good in 3 cases, fair in 1 case and poor in 1 case. A high incidence of bone complications was noted: delayed union (up to 11 months) and fracture of the graft, which occurred in 3 patients.

The authors report 10 segmental fractures of the femoral head associated with a dislocation of the hip. Using PIPKIN's classification, they noted 1 type I, 7 type II and 2 type III fractures. The initial treatment of the hip dislocation was conservative in all cases. Failure of reduction was noted in 6 cases and was complicated by fracture of the femoral neck in 2 cases. The attitude regarding the head fragment was: conservative in 5 cases, the reduction was considered satisfactory in 4 cases and poor in 1 case; surgical in the other 5 cases: screw fixation in 1 case, excision of the fragment in 1 case and prosthetic replacement of the femoral head in 3 cases. After a mean follow-up of 5 years, functional results were satisfactory in the majority of cases. The radiological assessment showed malunion without osteoarthrosis in one case and avascular necrosis of the femoral head in three cases. The authors propose a treatment policy based upon their experience and a review of the literature.

In response to viruses, monocytes and B cells produce TNF alpha. Therefore, we investigated TNF alpha gene expression and protein secretion in a human monocytic cell line, THP-1, and a Burkitt's lymphoma B-cell line, Namalwa, in response to hepatitis B virus (HBV). Stimulation by phorbol myristate acetate (PMA) (100 ng/ml for 48 h) induced TNF alpha secretion in THP-1 and Namalwa cells (100 to 300 pg/ml). In THP cells, the optimum response (> 2000 pg/ml) was obtained in the presence of a second mitogenic signal such as lipopolysaccharide (LPS) (10 microg/ml for 24 h). In our activation conditions, Northern blot analysis revealed a marked accumulation of TNF alpha mRNA species at 1.7 kb in both cell lines. When PMA- or PMA+LPS-stimulated THP-1 cells were exposed to HBV, TNF alpha protein and mRNA significantly decreased (> 50%). In contrast, HBV exposure of PMA-activated Namalwa cells resulted in strongly increased TNF alpha protein secretion (1 ng/ml). In this case, HBV induced TNF alpha mRNA accumulation that consisted of two types: a regular 1.7 kb and two novel high molecular weight (HMW) species at 3.7 and 4.3 kb. Exposure of stimulated THP-1 and Namalwa cells to HBV resulted in HBs and pre-S1 antigen production in the supernatants. In addition, HMW HBV DNA forms were detected in both cell lines, but with distinct HindIII restriction patterns. These findings indicate that TNF alpha gene expression may be differently regulated by HBV in activated human macrophages and B cells, and thus TNF alpha may be involved in the pathogenesis of HBV.

Previous studies showed that the gp120 envelope protein of HIV-1 is able to crosslink membrane IgM on normal human B cells and to induce their activation in a V(H)3 immunoglobulin gene-family-specific manner. Because this V(H) gene family is the largest in the human repertoire, this superantigen (SAg) property is thought to have deleterious consequences for the host, including a progressive decline of B cells with progression of the HIV-1-induced disease. Here, we have identified the sequence motifs on gp120 involved in SAg binding to normal Igs. We show that this SAg-binding activity is present in gp120s from highly divergent isolates of HIV-1 belonging to clades derived from various geographical origins, and that carbohydrate residues are not essential for its expression. The SAg-binding site is formed by protein sequences from two regions of the gp120 molecule. The core motif is a discontinuous epitope spanning the V4 variable domain and the amino-terminal region flanking the C4 constant domain. The most critical residues appear to be Leu395-Asp397 and Ile425-Gln427. Residues from the C2 constant domain (positions 252-272) also seem to play an accessory role in SAg binding of gp120 to normal human Igs. These findings are important in the design of a successful gp120-based vaccine against HIV-1.

The authors report two cases of rare localization of intra muscular myxoma: one in the buttock, and the other in the lumbar area. The first case, a 58 years old woman had a four month history of a mass in the buttock. Computed tomography revealed the presence of a solid tumor. Diagnosis was based on histological examination. After surgical treatment no recurrence was observed after fourteen months. The second case was a 54 years old woman who presented a sciatica with back pain and neurological signs. The symptoms didn't response to medical treatment. Computed tomography showed an enlarged and-cystic lumbar lesion extending to the first sacral hole, with bone erosion of L3 and L4 articular apophysis and spinous process. Needle biopsy and surgical excision of the tumor were performed. Total neurological recovery was observed and no recurrence was observed after three years. The authors reminded the characteristics of this rare and benign soft tissue tumor and specified the place of magnetic resonance imaging (MRI) to establish the diagnosis which was still confirmed by histological examination of an open biopsy. Clinical follow-up revealed exceptional recurrence and no metastasis.

The purpose of the study was to clarify the clinico pathological features of periosteal ganglion. The authors present a case of an unusual diaphyseal bony tumor in a 27 years old man. The diagnosis of diaphyseal periosteal ganglion cyst was made on roentgenographic appearance, presence of mucoid material and histologic evidence of a synovial type cellular lining. The patient was successfully treated with excision. The follow-up examination showed no recurrence one year after surgery. The radiological differential diagnosis were considered and possible pathogenes for a periosteal ganglion was discussed. Periosteal ganglia must be considered as a cause of cortical erosions. This lesion may radiologically mimic other periosteal lesions. Treatment with excision is successful in most cases.

Angiomyolipoma is a benign kidney tumour. Its extrarenal, retroperitoneal site is exceptional. The authors report a case and emphasise the value of ultrasonography and computed tomography in the diagnosis of these tumours with a marked fatty component, without neglecting the contribution of arteriography which can be useful in the diagnosis of the origin of very large retroperitoneal tumours.

This paper presents a short study of 17 cases of tuberculosis of the greater trochanter seen during a period of 19 years at the National Orthopaedic Institute in Tunis. The onset of the infection is slow with patients presenting at a mean of 7 years after initial symptoms. The diagnosis is confirmed by biopsy and culture of the organism. Management is based on treatment with antituberculous drugs, although surgical excision of the lesion is sometimes required. Successful resolution of the symptoms is usually achieved unless the hip joint becomes involved. Our patients showed good results at a mean follow up of 5 1/2 years.

An exceptional case of vertebral hydatidosis with involvement of the cervical, dorsal, lumbar and sacral segments of the spine is presented. Vertebral hydatidosis is a rare form of hydatid disease. It is found in less than 2% of all cases in echinococcosis. The initial parasite localization is usually univertebral. Extensive primary lesions were related to massive infestation by tapeworm ova at multivertebral levels. At this stage, the disease presents as a malignant tumor resistant to all surgical procedures. The prognosis is poor because of severe neurological complications and inexorable spinal destruction. The hope remains that in the future an effective medical parasiticidal treatment will be available.

Phaeochromocytoma is an endocrine neuroectodermal tumour usually located in the adrenal gland, but occasionally arising in other organs. The authors report a case of a vesical phaeochromocytoma presenting with haematuria. Radiological and endoscopic investigations revealed a right laterovesical submucosal tumour. Partial cystectomy was performed. The normality of the postoperative endocrine survey suggested disappearance of the tumour and absence of any other sites.

One hundred and three strains of Actinomyces pyogenes isolated from ruminants were examined for morphological, cultural and biochemical properties by standard tests and by the Api 50 CH and Api Coryne methods. No biotype could be demonstrated, but a few atypical non- or practically non-proteolytic strains were detected which should be differentiated from Arcanobacterium haemolyticum. Criteria for laboratory identification of A pyogenes were established: Gram stain; culture on blood agar; deep agar and Loeffler's medium; catalase, nitrate reduction, acid formation from xylose; Hugh and Leifson test. The Api Coryne system correctly identified only 58 of 103 A pyogenes cultures, which implies that it should be re-evaluated before use in veterinary diagnosis laboratories.

Interleukin-4 (IL-4) counteracts a number of the direct effects of interleukin-2 (IL-2) on B-cells. We here summarize and extend our results, obtained in two different experimental systems, on the antagonism between these two major interleukins. IL-4 inhibits the effect of IL-2 on the proliferation as well as the differentiation of B-type chronic lymphocytic leukemia (B-CLL) cells. When B-CLL cells are activated by anti-mu Ab in the presence of IL-4, this latter enhances the expression of the p55 as well as the p70/75 chain of the IL-2 receptor. In contrast IL-4 profoundly suppresses the number of high affinity binding sites for IL-2 on in vitro activated B-CLL cells. Such a discrepancy between the suppression of IL-2 binding sites and the enhancement of each component of the heterodimeric IL-2 receptor, is as far as we know, yet undescribed. The interaction of IL-4 with its own receptors might influence the state of p55-p70/75 complex association or act on a third subunit of the IL-2 receptor. When used alone, IL-4 enhances the expression of other activation molecules by B-CLL cells: CD23, DR antigen. Similarly IL-4 can concomitantly enhance the specific response of normal B-cells while suppressing the action of IL-2. When normal human B-cells are specifically stimulated by an insolubilized antigen, IL-4 alone induces an expansion of the number of specific antigen-binding cells. In contrast IL-4 profoundly suppresses the generation of antigen-induced IL-2-dependent specific IgM antibody forming cells.(ABSTRACT TRUNCATED AT 250 WORDS)

In this work, we studied the expression of B8.7 antigen on B lymphocytes from patients suffering from B type chronic lymphocytic leukemia (B-CLL) as well as on non Hodgkin lymphoma cells (NHL). B8.7 is an activation marker, which has been reported to be associated with the capacity of activated B cells to respond to LMW-BCGF. B lymphocytes of 11 out of 22 patients tested were B8.7 positive. With the exception of one case, LMW-BCGF is able to induce DNA synthesis by these cells in the absence of costimulation by anti-mu antibodies (anti-mu Ab). The LMW-BCGF dependent proliferation of these malignant cells is inhibited by the anti-B8.7 monoclonal antibody (anti-B8.7 MoAb), in the same line as that of normal B cells. These results obtained with monoclonal B cells confirm that the B8.7 molecule is involved in the signalling pathway of the LMW-BCGF.