A2 gene of Old World cutaneous <Emphasis Type="Italic">Leishmania</Emphasis> is a single highly conserved functional gene

Background  

Leishmaniases are among the most proteiform parasitic infections in humans ranging from unapparent to cutaneous, mucocutaneous or visceral diseases. The various clinical issues depend on complex and still poorly understood mechanisms where both host and parasite factors are interacting. Among the candidate factors of parasite virulence are the A2 genes, a family of multiple genes that are developmentally expressed in species of the Leishmania donovani group responsible for visceral diseases (VL). By contrast, in L. major determining cutaneous infections (CL) we showed that A2 genes are present in a truncated form only. Furthermore, the A2 genomic sequences of L. major were considered subsequently to represent non-expressed pseudogenes [1]. Consequently, it was suggested that the structural and functional properties of A2 genes could play a role in the differential tropism of CL and VL leishmanias. On this basis, it was of importance to determine whether the observed structural/functional particularities of the L. major A2 genes were shared by other CL Leishmania, therefore representing a proper characteristic of CL A2 genes as opposed to those of VL isolates.     

Modern management of non-chemotherapy drug-induced agranulocytosis: a monocentric cohort study of 90 cases and review of the literature

BACKGROUND: The present study reports a monocentric experience of 90 drug-induced agranulocytosis cases and discusses their management, in particular the role of hematopoietic growth factors. METHODS: Data from 90 patients with drug-induced agranulocytosis who met the criteria of the IAAAS group and of Bénichou and Solal-Celigny [Nouv Rev Fr Hematol 1993; 33: 257.] were retrospectively reviewed. All cases were extracted from a cohort study of the Hopitaux Universitaires de Strasbourg, France. Data were specifically analyzed with regard to the use of hematopoietic growth factors (in 42 patients). RESULTS: Mean patient age was 63 (range 17-95) years and the sex ratio (M/F) was 0.39. An underlying disease was present in 37% of the patients. Antibiotics (25%), antithyroid drugs (23%), and antiaggregative platelet agents (16%) were the most frequent causative drugs. Main clinical features included isolated fever (41%), septicemia or septic shock (31%), and pneumonia (10%). Mean neutrophil count was 0.13 (range 0-0.46)x10(9)/l. Outcome was favorable in 98% of patients. The mean durations of hematological recovery (neutrophil count over 1.5x10(9)/l), antibiotic therapy, and hospitalization was 8.5 (range 2-21) days, 9.2 (range 2-21) days, and 10.5 (range 3-23) days, respectively. All patients were treated with broad-spectrum antibiotics and 42 patients with hematopoietic growth factors. In these 42 patients, the mean durations for hematological recovery, antibiotic therapy, and hospitalization were significantly reduced at: 6.3 (range 2-16) days, 7.1 (range 2-16) days, and 9.1 (range 3-23) days, respectively (all P<0.05). CONCLUSIONS: The present study shows that new causative drugs are emerging (antibiotics, antithyroid, and antiaggregative platelet agents), that drug-induced agranulocytosis remains typically a serious accident with severe sepsis, and that modern management with broad spectrum antibiotics and hematopoietic growth factors may reduce the mortality.     

Platelet-melanoma cell interaction is mediated by the glycoprotein IIb- IIIa complex

A human malignant melanoma cell line (M3Dau) was observed by electron microscopy to interact directly with human platelets and induced platelet aggregation. Fab fragments of a monoclonal antibody MoAb (LYP18), directed against the platelet glycoprotein (GP) IIb-IIIa complex, inhibited platelet-melanoma interactions and platelet-platelet aggregation. M3Dau melanoma cells bind LYP 18 and synthesize IIb-IIIa- like GPs. When the melanoma cells were preincubated with LYP 18, tumor- platelet interaction did not occur, suggesting that the interaction may be mediated by the IIb-IIIa-like GPs present on the melanoma cell surface. Glanzmann's thrombasthenic platelets, lacking GPIIb and IIIa, did not interact with melanoma cells, indicating that the platelet GPIIb-IIIa complex is also necessary for the platelet-melanoma cell interaction. This work demonstrates the importance of the IIb-IIIa-like GPs, present on M3Dau melanoma cells, in mediating tumor-platelet interactions.     

Action of retinoids on embryonic and early postnatal testis development

The current study investigates the hypothesis that retinoids have a role in embryonic testis development. The action of retinoids on testis development and the expression of retinoic acid receptors (RAR alpha, RAR beta, RAR gamma) were examined. In embryonic day 13 (E13; plug date = E0) testis organ cultures an RAR-selective agonist and all-trans retinoic acid completely inhibited seminiferous cord formation. In contrast, an RAR alpha-selective antagonist had no effect. RT-PCR demonstrated that RAR alpha messenger RNA (mRNA) was expressed at all developmental time points evaluated, which included embryonic day 14 (E14) through postnatal day 30 (P30). Expression of RAR beta mRNA was present at E15 through P2, whereas RAR gamma mRNA was expressed at E18 through P2. Cellular localization of receptors by immunohistochemistry indicated that RAR alpha was localized to the interstitium at E18 and to the seminiferous cords by P0. RAR beta and RAR gamma were detected in both interstitium and cords at E16 and by E18 were mainly expressed in the cords. At P0 RAR beta and RAR gamma were localized to the germ cell populations. To examine retinoid actions, the growth of P0 testis cultures were investigated. Interestingly, retinol and retinoic acid did not inhibit growth of P0 testis cultures but did inhibit the action of growth stimulators. Retinoic acid inhibited FSH, EGF, and 10% calf serum stimulated growth in P0 testis cultures. The hypothesis tested was that the inhibitory effects of retinoids on P0 testis growth may be mediated through the growth inhibitor, transforming growth factor-beta (TGF beta). The action of retinoids on TGF beta mRNA expression was examined in P0 testis cultures. Retinoic acid stimulated TGFbeta3 mRNA expression within 24 h and increased expression of TGFbeta1 and TGFbeta2 after 72 h. Retinol increased expression of TGFbeta1 and TGFbeta2 but not TGFbeta3 after 72 h of treatment. These observations indicate that retinoic acid can influence seminiferous cord formation and testis growth. The inhibitory actions of retinoids may in part be mediated through increased expression of TGFbeta isoforms.     

Metabolic activity of phagocytosing granulocytes in chronic granulocytic leukemia: ultrastructural observation of a degranulation defect

The functional capacities of granulocytes in patients with chronic granulocytic leukemia are still a subject of controversy, probably due to the heterogeneity of the abnormalities observed from patient to patient. For a better definition of these abnormalities, 14 patients with untreated chronic granulocytic leukemia were studied. The patients were divided into three groups on the basis of the functional activities of their phagocytosing granulocytes. In four patients (group I), the granulocytes were normal in respect to particle ingestion, nitroblue tetrazolium (NBT)-stimulated reduction, cyanide-insensitive oxygen (O2) consumption, superoxide anion (O2-)-stimulated production, hydrogen peroxide (H2O2) production, and iodination. They also had a normal myeloperoxidase (MPO) content. In four patients (group III), the granulocytes were significantly defective in all of these activities. In the six remaining patients (group II), all the initial metabolic steps of the phagocytosing granulocytes (ingestion, NBT reduction, O2 consumption, O2-production, H2O2 production) were normal, as were the MPO content of the granulocytes, while iodination was strikingly decreased. These metabolic features suggested a degranulation defect which was observed ultrastructurally in the only patient studied among these six. The phagocytosing granulocytes of this patient did not degranulate and no deposits of MPO activity were seen in the phagosomes.     

TCR gamma delta bearing lymphocyte clones with lymphokine-activated killer activity against autologous leukemic cells

Activated T lymphocytes with the T-cell receptor (TCR) gamma delta (CD3+ and TCR delta 1+) exhibit strong cytotoxic activity against the standard natural killer (NK) and lymphokine-activated killer (LAK) sensitive target cells. In order to test the cytotoxic activity of gamma delta T lymphocytes against autologous leukemic cells, 84 clones of gamma delta T lymphocytes were obtained from the peripheral blood of three acute lymphoblastic leukemia (ALL) patients. Forty-four of these T-cell clones were active against an LAK-sensitive cell line and the other 40 were active against K562, an NK target cell line. In each of the three patients, cytotoxic clones against autologous leukemic cells were obtained. Among the 84 clones, ten were able to kill autologous tumor cells, including eight that lyse the LAK-sensitive target and two with NK activity. The clones were highly cytotoxic, stable, and easily expanded in large quantity.     

Isolation of 10 differentially expressed cDNAs in p53-induced apoptosis: activation of the vertebrate homologue of the drosophila seven in absentia gene.

We report the isolation of 10 differentially expressed cDNAs in the process of apoptosis induced by the p53 tamor suppressor. As a global analytical method, we performed a differential display of mRNA between mouse M1 myeloid leukemia cells and derived clone LTR6 cells, which contain a stably transfected temperature-sensitive mutant of p53. At 32 degrees C wild-type p53 function is activated in LTR6 cells, resulting in programmed cell death. Eight genes are activated (TSAP; tumor suppressor activated pathway), and two are inhibited (TSIP, tumor suppressor inhibited pathway) in their expression. None of the 10 sequences has hitherto been recognized as part of the p53 signaling pathway. Three TSAPs are homologous to known genes. TSAP1 corresponds to phospholipase C beta 4. TSAP2 has a conserved domain homologous to a multiple endocrine neoplasia I (ZFM1) candidate gene. TSAP3 is the mouse homologue of the Drosophila seven in absentia gene. These data provide novel molecules involved in the pathway of wild-type p53 activation. They establish a functional link between a homologue of a conserved developmental Drosophila gene and signal transduction in tumor suppression leading to programmed cell death.     

Submandibular puncture of the facial vein: An original route for endovascular therapy of cavernous sinus dural fistulas

Introduction

Carotid cavernous sinus fistulas are a potentially severe pathology. Their basic standard treatment is an occlusion of the CCF performed by retrograde venous catheterization via the inferior petrous sinus. When the inferior petrous sinuses are occluded, other alternative venous routes are possible with various subsequent difficulties and risks. We report an original and safe method for endovascular treatment using submandibular puncture of the facial vein.

Clinical cases

We report 4 cases of patients with severe unilateral carotid cavernous sinus fistula associated with the occlusion of both inferior petrous sinuses. A submandibular surgical puncture of the ipsilateral inferior facial vein permitted the catheterization of the fistula. Complete occlusion of carotid cavernous sinus fistula was obtained by using a combination of microcoils and Onyx™.

Discussion

When inferior petrous sinuses are occluded, endovascular treatment of carotid cavernous sinus fistulas is more difficult. After reviewing the other treatment options reported in the literature and their respective advantages and adverse effects, we describe an original technique based on the surgical puncture of the ipsilateral facial vein. The occlusion of the fistula is then obtained by using a combination of microcoils and Onyx™.

Conclusion

When the inferior petrous sinuses are occluded, an endovascular treatment for a carotid cavernous sinus fistula can be performed using an original and secure method. This method relies on a simple surgical puncture of the facial vein in the submandibular region, which then permits a retrograde catheterization of the carotid cavernous sinus fistula with no significant risk.     

Outcome and management of pregnancies in severe chronic neutropenia patients by the European Branch of the Severe Chronic Neutropenia International Registry

Long-term granulocyte-colony stimulating factor treatment has been shown to be safe and effective in severe chronic neutropenia patients. However, data on its use during pregnancy are limited. To address this issue, we analyzed all pregnancies reported to the European branch of the Severe Chronic Neutropenia International Registry since 1994. A total of 38 pregnancies in 21 women with chronic neutropenia (16 pregnancies in 10 women with congenital, 10 in 6 women with cyclic, 12 in 5 women with idiopathic neutropenia) were reported. Granulocyte-colony stimulating factor was administered throughout pregnancy in 16 women and for at least one trimester in a further 5 women. No major differences were seen between treated and untreated women with respect to pregnancy outcome, newborn complications and infections. In addition, we evaluated the genetic transmission of known or suspected genetic defects in 16 mothers having 22 newborns as well as in 8 men fathering 15 children. As a proof of inheritance, neutropenia was passed on to the newborn in 58% from female and in 62% from male patients with ELANE mutations, but also to some newborns from parents with unknown gene mutation. Based on our results, granulocyte-colony stimulating factor therapy has been shown to be safe for mothers throughout pregnancies and for newborns without any signs of teratogenicity. With an increasing number of adult patients, genetic counseling prior to conception and supportive care of mothers during pregnancy are crucial. The acceptance of having affected children may reflect the high quality of life obtained due to this treatment.