Type III hereditary angio-oedema: clinical and biological features in a French cohort.

BACKGROUND: Hereditary angio-oedema (HAE) has been associated with C1inhibitor deficiency. The first cases of type III HAE were described in patients with normal C1Inh antigenic protein level and function and normal C4 levels in 2000. This finding has been reported mostly in women with a family history and may be influenced by exogenous oestrogen exposure. OBJECTIVES: The purpose of this article is to describe the clinical, biological and genetic characteristics of a French population suffering from type III HAE. PATIENTS AND METHODS: We conducted a retrospective analysis of angio-oedema (AE) cases seen in the National Reference Centre of AE between 2000 and 2009. RESULTS: We found 26 patients (from 15 unrelated families) with type III HAE. All but four were women and presented with typical AE attacks, exacerbated by pregnancy or oral contraceptives containing oestrogens (OC). We also found that 54.5% of women were worsened with oestrogen and 23% were oestrogen dependent. All patients improved on long-term prophylactic tranexamic acid treatment; some acute attacks improved with C1Inh concentrate infusion. All of the patients had normal C1Inh and C4 levels. C1Inh function was also normal, except in women receiving OC or during a pregnancy: transient, moderately low levels (32-74% of the normal range) were found in 18 patients tested (67%). No SERPING1 gene mutation was found. Six patients from three unrelated families were heterozygous for an F12 gene variant. CONCLUSION: Diagnosis of type III HAE should be based on clinical (typical attacks, often hormonally influenced), laboratory (normal C1Inh antigenic protein) and genetic (F12 gene mutation) evidence.

Estimation of epidemic size and incubation time based on age characteristics of vCJD in the United Kingdom.

The size of the variant Creutzfeldt-Jakob Disease (vCJD) epidemic in the United Kingdom is a major public health concern and a subject of speculation. The cases are young (mean age = 28). Assuming that the risk of developing the disease in susceptible exposed subjects decreases exponentially with age after age 15, that all infections occurred between 1980 and 1989, and that the distribution of the incubation period is lognormal, we estimate that the mean duration of the incubation period is 16.7 years [95% confidence interval (CI): 12.4 to 23.2] and that the total number of cases will be 205 (upper limit of the 95% CI: 403).

Pre-B-cell development in the absence of lambda 5 in transgenic mice expressing a heavy-chain disease protein.

BACKGROUND: Heavy-chain diseases (HCDs) are human lymphoproliferative neoplasias that are characterized by the secretion of truncated immunoglobulin heavy chains devoid of light chains. We have previously proposed--by analogy to the process by which mutated growth factor receptors can be oncogenic--that because the genetic defects in HCDs result in the production of abnormal membrane-associated heavy chains lacking an antigen-binding domain, these abnormal B-cell antigen receptors might engage in ligand-independent signalling. Normal pre-B-cell development requires the presence of the pre-B-cell receptor, formed by the association of mu heavy chains with two polypeptides--so-called surrogate light chains, Vpre-B and lambda 5--that are homologous to the variable and constant portions of immunoglobulin light chains, respectively. To assess whether amino-terminal truncation of membrane-associated heavy chains results in their constitutive activation, we have examined the ability of a HCD-associated mu protein to promote pre-B-cell development in transgenic mice. RESULTS: When the mu HCD transgene is introduced into SCID mice, CD43- pre-B cells develop normally. To determine whether this pre-B-cell development requires surrogate light chains, we backcrossed mice expressing full-length or truncated mu transgenes with lambda 5-deficient mice. Our results show that the truncated heavy chain, but not the normal chain, is able to promote pre-B-cell development in the absence of lambda 5. We also show that truncated mu chains spontaneously aggregate at the surface of bone marrow cells. CONCLUSIONS: Expression of the truncated mu heavy chain overrides a tightly controlled step of pre-B-cell development, which strongly suggests that a constitutive signal is delivered by the truncated mu chain disease protein. The self-aggregation of mu chain disease proteins might account for this constitutive activation. We conclude that amino-terminal truncation of heavy chains could play a role in the genesis of HCD neoplasia if it occurs at an appropriate stage of B-cell differentiation, namely in a mature B cell.

Can a second wave of new variant of the CJD be discarded in absence of observation of clinical non Met-Met cases?

BACKGROUND: Presently, all patients with clinical variant Creutzfeldt-Jakob disease in the United Kingdom have been Met-Met at codon 129 of the PrP gene. There is much worry about the possibility of a second wave of the epidemic in the 60% of the United Kingdom population which are not Met-Met. METHODS: A mathematical model of a putative United Kingdom variant Creutzfeldt-Jakob disease epidemic that could occur in non Met-Met is derived. The risk of infection is assumed to parallel the Met-Met risk which has been previously modelled. The reason for the present absence of clinical non Met-Met cases is assumed to be a longer incubation period in these subjects than in others. The incubation period is assumed to be lognormally distributed. The means and coefficients of variation compatible with the present absence of clinical cases are systematically searched. RESULTS: We show that the present absence of clinical cases of variant Creutzfeldt-Jakob disease in the Met-Val or Val-Val population can be compatible with a second wave only if the mean incubation period is more than 25 years. The best estimates of the size of the second wave are always below 250. A fraction of these cases however will never be observed, as they will die from other causes before the onset of the new variant. CONCLUSION: The mean incubation period values compatible with the absence of non Met-Met clinical cases that we found are not implausible, and the possibility of a second wave cannot yet be ruled out. However, should this second wave occur, it would be below 250 in the worst hypothesis.

Thymocyte and thymic microenvironment alterations during a systemic HIV infection in a severe combined immunodeficient mouse model.

OBJECTIVE: A new model for systemic and multifocal HIV-1 infection was developed in severe combined immunodeficient (SCID) mice to study the alterations of thymocytes and of the thymic microenvironment that occur during a disseminated HIV infection. DESIGN AND METHODS: We grafted SCID mice with the classical human fetal thymus/liver co-implants together with fragments of autologous lungs (SCID-huLLT). These organs achieved normal differentiation and were productively infected after an intraperitoneal inoculation of two HIV-1 primary isolates. At time of sacrifice, thymic biopsies and thymic cell suspensions were analysed by immunohistochemistry, flow cytometry and lymphocyte function assays. RESULTS: At weeks 2-4 post-inoculation we observed the following thymocyte abnormalities: a minor to severe depletion of the immature CD1+CD4+CD8+ T cells (range, 0-73% thymocytes), compared with the persistence of mature CD4+ cells (11-50%) and amplification of CD8+ T cells (6-92%). The immature subset depletion was inversely related to the thymic HIV-1 viral load, suggesting the preferential infection of this subset. The residual mature thymocytes were functional as assessed by their sustained proliferative responses to CD3-triggering which contrasted with the lack of HIV-specific cytotoxic activity. A quantitative analysis of immunostained thymic sections revealed a disorganization and a densification of the thymic epithelial cells (TEC) network which occurred in all HIV-infected SCID-hu mice independently of the thymic CD1+CD4+CD8+ T-cell depletion. CONCLUSION: These results suggest that a systemic HIV infection induces in human thymuses from SCID-huLLT mice a preferential depletion of the immature thymocytes in the absence of mature CD4+ T-cell depletion, HIV-specific cytotoxic T-lymphocyte activity or thymic epithelial cell death, but is associated with dysplasia of the thymic microenvironment, and is therefore opening new perspectives for studying immune cell reconstitution strategies in HIV infection.

Use of a monoclonal antibody in a double-sandwich ELISA for detection of IgM antibodies to Toxoplasma gondii major surface protein (P30).

A double-sandwich ELISA, developed for detection of IgM antibodies to the major surface protein of Toxoplasma gondii (P30), is proposed for the diagnosis of acute acquired toxoplasmosis. The method is based on the capture of serum IgM antibodies, which are revealed indirectly by the sequential addition of a Toxoplasma extract and a beta-galactosidase-conjugated anti-P30 monoclonal antibody. All 57 patients tested with serological characteristics of recently acquired toxoplasmosis showed high levels of IgM anti-P30 antibodies. In addition, 5 out of the 24 patients with chronic toxoplasmosis and all 7 patients with a clinical acute infection in which the classical IgM serology was negative, also presented significant anti-P30 IgM antibodies. Patients with either rheumatoid factor or antinuclear antibodies were all negative. In view of its simplicity, specificity and sensitivity, this method is recommended for the current diagnosis of T. gondii infection.

Human fascioliasis: cure by mebendazole? A case report.

We report a case of invasive human Fasciola hepatica infection in which, for the first time, a successful treatment with high doses of mebendazole (4 g/day for 3 weeks) was achieved. This therapy resulted in a prompt and prolonged normalization of eosinophil counts, liver enzymes abnormalities and specific serological tests together with the disappearance of liver necrosis indicating the eradication of liver flukes. The efficacy of mebendazole in the treatment of fascioliasis must be confirmed by further studies.

[Sensitivity and specificity of antineutrophil cytoplasmic antibodies in systemic vasculitis]. / Sensibilité et spécificité des anticorps anticytoplasme des neutrophiles (c-ANCA) au cours des vascularites systémiques.

The diagnostic value of c-ANCA as a specific marker of systemic vasculitis (particularly Wegener's granulomatosis) is well established. The prognostic value of c-ANCA for determining disease activity is controversial. We have prospectively studied in ten patients with systemic vasculitis over a mean period of 34 months (extreme 2-61 months). All patients had c-ANCA at the moment of the diagnosis: four patients had high titer of c-ANCA all over the period study; three clinical and biological exacerbations of the disease was observed without variation of the c-ANCA titer. In four patients c-ANCA disappeared within 6 months after the beginning of the treatment correlated with disease activity. Sometimes a rise of c-ANCA titer was observed with or without disease activity. In one case c-ANCA titer had a serrated evolution. The sensitivity and the specificity of the c-ANCA for disease activity in the ten studied patients were respectively 1 and 0.28. In patients with systemic vasculitis and c-ANCA at the time of the diagnosis, variation in c-ANCA titer alone is of limited prognostic value for predicting disease course.

[Homozygotic C5 deficiency disclosed by purulent Neisseria meningitidis meningitis]. / Déficit homozygote en C5 révélé par une méningite purulente à Neisseria meningitidis.

The complement system functions to protect the individual against infectious agents. Deficiencies of the late-acting complement proteins C5-C8 are associated with an increased susceptibility to Neisseria infection. This paper describes a deficiency in C5 in a Caucasoid family from the north of France that was revealed by the occurrence of a N. meningitidis meningitis in the homozygous C5-deficient propositus.

[A new ELISA method for the diagnosis of toxoplasmosis. Assay of serum IgM by immunocapture with an anti-Toxoplasma gondii monoclonal antibody]. / Une nouvelle méthode ELISA pour le diagnostic de la toxoplasmose. Dosage des IgM sériques par immunocapture avec un anticorps monoclonal anti-Toxoplasma gondii.

The diagnosis of acute toxoplasmosis is based exclusively on the detection of IgM anti-Toxoplasma antibodies. The principal of the immunoenzymatic test reported here is the capture of serum IgM antibodies which are detected indirectly by the sequential addition of antigen and a monoclonal antibody directed against the immunodominant epitope at the surface of the tachyzoite. This test combines the sensitivity of enzyme-based assays and the specificity of monoclonal reagents and represents an important contribution to the diagnosis of Toxoplasma gondii infection.

The effect of metal imbalances on scrapie neurodegeneration.

Environmental exposure to metal appears to enhance susceptibility to Transmissible Spongiform Encephalopathies (TSEs); however, published data are not conclusive. The current study focuses on assessing the effects of copper depletion and/or manganese enhancement in the diet on susceptibility to Scrapie and this disease progression. The degree of spongiosis was the highest in the animals that received a copper- depleted diet. These observations suggest that this diet contributes to the Scrapie lesions and to the worsening of the condition in animals that have been inoculated with Scrapie. The highest intensities of GFAP immunostaining were also associated with the copper- depleted diet. Dietary supplementation with manganese had a negative effect on neuronal counts. In conclusion, this study demonstrates that certain environmental factors may aggravate neuropathological Scrapie lesions. This is consistent with reports from other neurodegenerative diseases where some metalloenzymes play a pivotal protector role against the oxidative stress associated with pathogenesis.

Effect of the dimethoate administration on a Scrapie murine model.

Some authors have associated organophosphate compounds with susceptibility to transmissible spongiform encephalopathy (TSE) and even with the origin of this group of diseases. Nevertheless, the actual role played by these compounds still remains unclear. The aim of this study was to assess the effect of oral exposure to dimethoate (DMT) on the development of Scrapie using a genetically modified murine model. A total of 70 C57BL/6 mice over-expressing the PrP gene (Tg20) were included in the present study. A portion of the mice were intraperitoneally inoculated, while the rest were maintained as non-infected controls. Animals from the treated group were exposed to dimethoate dissolved in drinking water from the beginning of the experiment. Variables of incubation period, spongiosis, PrPsc deposits, glial over-expression, neuronal loss, and amyloid plaques were assessed in all animals. According to the results, a treatment consisting of a daily 15 mg/kg dose of DMT for 5 weeks did not show any effect on any of the variables assessed. Although more exhaustive studies for assessing different doses and organic compounds are required, this finding constitutes an empirical study that rules out the possibility that this compound may have a predisposing effect on TSEs.

The SCID mouse mutant: definition and potential use as a model for immune and hematological disorders.

Mice homozygous for a SCID mutation (SCID mice) are severely deficient in T and B lymphocytes. The absence of effector T and B cells has encouraged investigators to attempt engraftment of SCID mice with human fetal tissues, mature lymphocytes, hematopoietic progenitors and tumors. SCID mice can be reconstituted with human lymphocytes and are of interest for studying normal and abnormal lymphocyte development and function. SCID mice are also providing an in vivo model of infectious diseases. In addition, SCID mice readily support normal and pathologic human hematopoiesis differentiation and is useful for testing innovative hematological disease therapy. SCID mice with a fully functional human immune or hematopoietic system therefore seem to be extremely valuable for biomedical research.

Detection of circulating and urinary antigens in Mastomys natalensis experimentally infected with Brugia malayi, Brugia pahangi, or Litomosoides carinii.

The time-course of the detection of circulating and urinary filarial antigens was followed with a 2S-IRMA assay, using a mouse monoclonal antibody raised against Brugia malayi larvae, in Mastomys natalensis experimentally infected with Brugia malayi, Brugia pahangi, or Litomosoides carinii. In the prepatent phase of the infections, filarial antigen was detected 4-7 weeks before microfilariae appeared in the peripheral blood. Moreover, the sensitivity of the test was greater with urine than with serum. During the patent phase of infection, the level of circulating antigens detected varied considerably. However, there was a positive correlation (P less than 0.05) between antigenemia and microfilaremia. In L. carinii infection, filarial antigen could be easily detected in spite of the disappearance of microfilariae in peripheral blood, 49 weeks post infection. If these results are extrapolated to man, the 2S-IRMA should be useful for epidemiological surveys in endemic areas where transmission has been eliminated.