Cerebral Phospho-Tau Acts Synergistically with Soluble Aß42 Leading to Mild Cognitive Impairment in AAV-AD Rats.

BACKGROUND: Alzheimer's disease (AD) is a continuum of events beginning with an increase in brain soluble Aß42 followed by the appearance of hyperphosphorylated tau (P-tau, asymptomatic stage). Mild Cognitive Impairment (MCI) then appears (prodromal stage). However, the individual contribution of these two soluble proteins in the onset of the first cognitive symptoms remains unclear. OBJECTIVES: We sought to understand the specific impact of p-tau on the development of MCI in the AAV-AD rat model, a model of late-onset Alzheimer's disease (LOAD) predementia. METHODS: We specifically reduced the phosphorylation level of tau while leaving Aß42 levels unchanged using a DYRK1A protein kinase inhibitor, Leucettine L41, in an adeno-associated virus-based Alzheimer's disease (AAV-AD) rat model. Leucettine L41 was administered by intraperitoneal injection at 20 mg/kg per day in AAV-AD rats from 9 (late asymptomatic phase) to 10 (prodromal phase) months of age. RESULTS: Decreased soluble forms of P-tau induced by chronic administration of Leucettine L41 did not change soluble Aß42 levels but prevented MCI onset in 10-month-old AAV-AD rats. CONCLUSIONS: The present study argues that P-tau is required to induce the development of MCI. Consistent with our previous findings that soluble Aß42 is also required for MCI onset, the data obtained in the AAV-AD rat model confirm that the transition from the asymptomatic to the prodromal stage may be caused by the combined presence of both soluble brain forms of Aß42 and p-tau, suggesting that the development of MCI may be the consequence of their synergistic action.

Evaluation of Memantine in AAV-AD Rat: A Model of Late-Onset Alzheimer's Disease Predementia.

BACKGROUND: Though our understanding of Alzheimer's disease (AD) remains elusive, it is well known that the disease starts long before the first signs of dementia. This is supported by the large number of symptomatic drug failures in clinical trials and the increased trend to enroll patients at predementia stages with either mild or no cognitive symptoms. However, the design of pre-clinical studies does not follow this attitude, in particular regarding the choice of animal models, often irrelevant to mimic predementia Late Onset Alzheimer's Disease (LOAD). OBJECTIVES: We aimed to pharmacologically validate the AAV-AD rat model to evaluate preventive treatment of AD. METHODS: We evaluated an N-methyl-D-aspartate receptor antagonist, named memantine, in AAV-AD rats, an age-dependent amyloid rat model which closely mimics Alzheimer's pathology including asymptomatic and prodromal stages. Memantine was used at a clinically relevant dose (20 mg daily oral administration) from 4 (asymptomatic phase) to 10 (mild cognitive impairment phase) months of age. RESULTS: A 6-month treatment with memantine promoted a non-amyloidogenic cleavage of APP followed by a decrease in soluble Aß42. Consequently, both long-term potentiation and cognitive impairments were prevented. By contrast, the levels of hyperphosphorylated endogenous tau remained unchanged, indicating that a long-term memantine treatment is ineffective to restrain the APP processing-induced tauopathy. CONCLUSIONS: Together, our data confirm that relevant models to LOAD, such as the AAV-AD rat, can provide a framework for a better understanding of the disease and accurate assessment of preventive treatments.

Review: Why screen for severe combined immunodeficiency disease?

Newborn screening for severe combined immunodeficiency (SCID) is now routinely performed in many countries across Europe and around the world. The number of T-cell receptor excision circles (TRECs) reflects T cell levels. TREC quantification is possible using dried blood spot (DBS) samples already collected from newborns to screen for other conditions. This method is very sensitive and highly specific. Data in the literature show that the survival rate for children with SCID is much higher when the disease is detected through early screening, as opposed to a later diagnosis. Newborns diagnosed with SCID may receive the appropriate care quickly, before the onset of serious infectious complications, which raises survival rates, improves quality of life, and limits side effects and treatment costs. At the request of the French Ministry of Health, France's National Authority for Health (Haute Autorité de Santé) is expected to issue recommendations on this topic soon. The nationwide DEPISTREC study, involving 48 maternity units across France, showed that routine SCID screening is feasible and effective. Such screening offers the additional benefit of also diagnosing non-SCID lymphopenia within the infant population.

[Neonatal screening of severe combined immunodeficiencies]. / Projet de mise en place du dépistage néonatal systématique des déficits immunitaires combinés sévères : présentation de l'étude DEPISTREC.

Severe combined immunodeficiencies (SCID) are a group of inherited diseases of the immune system characterized by profound abnormalities of T-cell development. Infants with SCID require prompt clinical intervention to prevent life-threatening infection and studies show significantly improved survival in babies diagnosed at birth based on previous family history. SCID follows the criteria for population-based newborn screening because it is asymptomatic at birth and fatal within the 1st year of life if there is no intervention, the confirmation of the disease is easy, there is a curative treatment, and it is known that early hematopoietic stem cell transplantation significantly improves survival, the quality of immune reconstitution, and quality of life. Quantification of T-cell receptor excision circles (TRECs) in DNA extracted from Guthrie samples is a sensitive and specific screening test for SCID. We conducted a nationwide prospective study of neonatal screening of SCID in a population of 200,000 French newborns over a period of 2 years. The objective was to study the clinical utility and the cost-effectiveness ratio, and to demonstrate that universal SCID screening could result in a substantial benefit to detect individuals, making screening relatively cost-effective in spite of the low incidence of the disease.

Evaluation of two antibodies against double-stranded DNA assays in discriminating between active and non-active systemic lupus erythematosus: correlation between the cut-off and the specificity.

This study aimed to evaluate, improve and compare the performances of two anti-double-stranded DNA (dsDNA) detection kits, differing by their affinity, in discriminating between active and non-active systemic lupus erythematosus (SLE). Eighty-two anti-nuclear antibody positive sera (45 patients) were tested by two anti-dsDNA commercial quantitative assays (Fidis™, Farrzyme™). All the patients fulfilled at least four of the revised American College of Rheumatology criteria. SLE disease activity was assessed using a modified SLEDAI to remove anti-dsDNA descriptors. When using the manufacturers' cut-offs, no difference in the frequency of positive results was found with respect to disease activity, with Fidis™. On the contrary, with Farrzyme™, a significantly higher frequency of positive sera was found in active SLE patients. Nonetheless, poor performances were observed for both tests. With thresholds defined by ROC methodology, 212IU/mL for Fidis™ (Se: 83.9%, Sp: 86.3%), and 68.8IU/mL for Farrzyme (Se: 71.0%, Sp: 96.1%), a great improvement of the accuracy of the two methods was observed. Moreover, the better specificity and pLR, obtained after optimization of the Farrzyme™ test, could also be obtained with the Fidis™ assay by using a higher threshold than that obtained after optimization of the test. We concluded that when using manufacturers' cut-offs, the two assays appeared to be of poor clinical usefulness in the determination of disease activity. A great improvement was observed using higher thresholds. Moreover, a good concordance could be observed between the two assays (κ=0.764).

[Autoimmune neutropenia]. / Neutropénies auto-immunes.

Autoimmune neutropenias (AIN) are classically divided into primary AIN and secondary AIN. The latter are associated with autoimmune disorders, hematologic malignancies, primary immune deficiencies, drug exposure or infections. In this review we will focus on the major aetiologies of AIN, their differential diagnosis, the various methods in biological diagnosis, and the treatment.

[An exceptional component C3 deficiency revealed by serum protein electrophoresis]. / Un exceptionnel déficit héréditaire en fraction C3 du complément dépisté par électrophorèse des protéines sériques.

We report the case of a 5-years old child referred to the pediatric clinic due to a prolonged history of recurrent otitis. Initial immunologic investigation was normal but a severe C3 complement deficiency was detected by the absence of beta 2-globulin protein fraction using serum protein capillary electrophoresis. C3 was not detected in serum and total complement haemolytic activity was decreased. His mother and father had half of the C3 normal plasma level and a heterozygous mutation of the C3 gene. The diagnosis of hereditary deficiency of the third complement component (C3) with compound heterozygous mutation of the gene was made. This defect in complement protein C3, described to date in only 20 families in the world, is associated with repeated infections. The child is treated with oracillin with relatively good control of symptoms.

[Autoimmunity induced by low doses of interferon in melanoma stage I]. / Auto-immunité induite par l'interféron à faible dose dans le mélanome stade I.

INTRODUCTION: The principal aim of this work was to determine the prevalence of antinuclear antibodies and antinucleosomes antibodies during a treatment by interferon alpha with low dose for 18 months among patients with a melanoma stage I. The secondary objective consisted to seek the existence or not of a correlation with the clinical relapse, to determine the prevalence of appearance of clinical signs of autoimmune diseases and dysthyroidie. PATIENT AND METHODS: It was an exploratory study. The patients included in the study had a melanoma stage I (French classification), whose excision was realized for 6 weeks maximum, with a Breslow index equal or higher than 1,5 mm. The statistical model of logistic regression was used. RESULTS: Eighty-forth patients were included (38 women and 46 men) old from 21 to 75 years. The prevalence of antinuclear antibodies was 39%. None of the following variables: age, sex, phototype, localisation of melanoma in exposed photo zone, index of Breslow or Clark, were significantly associated with the presence of antinuclear antibodies. As the percentage of patients with anti-nucleosomes was low (5%), no statistical study was carried out. The prevalence of clinical and/or biological dysthyroidie was 37%. 60% of the patients presented at a moment in the evolution antinuclear antibodies or a dysthyroidie. The prevalence of relapses and death different was not correlated significantly with antinuclear antibodies and/or a dysthyroidie. DISCUSSION: Many studies report the appearance of antinuclear antibodies, generally without clinical lesions during the treatment by interferon alpha for cancers (tumours carcinoids, hemopathies) and viral chronic hepatitis. Our study is, to our knowledge, the first evaluating the induction of an autoimmunity during the adjuvant treatment by interferon alpha of melanoma stage I. The induction of autoantibody during the treatment by interferon alpha could constitute a marker of effectiveness of the treatment with improvement of the survival of these patients. In our study, however auto immunity markers do not appear as factors of severity of evolution of the melanoma or predictive factors.

Difference in antigenic determinant profiles between human and rat myeloperoxidase.

We tested whether rat and human MPO have similar antigenic determinants using 36 human MPO-ANCA positive sera, one mouse anti-rat MPO and four mouse anti-human MPO monoclonal reagents. Purified rat and human MPO were used in ELISA, with or without crossinhibition by preincubation with human MPO or irrelevant antigen in the liquid phase. Only one human MPO ANCA positive serum exhibited significant binding in rat MPO ELISA. This binding was poorly inhibited by preincubation with human MPO in the liquid phase, but was conserved after adsorption of non specific anti-rat activity in a chromatography column. Three mouse anti-human MPO IgG monoclonal antibodies did not recognize rat MPO. Only one mouse anti-human MPO IgA monoclonal antibody bound to rat MPO. This binding was poorly inhibited by preincubation with human MPO (35% at 2 micro g/ml). Conversely, the mouse anti-rat MPO monoclonal did not bind human MPO. We have concluded that: (1) Most human MPO-ANCA recognize antigenic determinants on human MPO which are absent on rat MPO. Therefore, human auto-antibodies bind to epitopes which recently appeared after species evolution; (2) Inversely, the mouse anti-rat MPO monoclonal do not bind human MPO. Therefore, rat MPO epitopes have been altered during species evolution; (3) Mice injected with human MPO preferentially develop antibodies against xeno-epitopes which are not present in rodents. Therefore, human MPO may not be the best antigen to raise ANCA in animal models and (4) A comparison of the amino acid sequences of rat and human MPO may help elucidate the major antigenic epitopes.

[Compliance with hormone replacement therapy in menopause: effect of an original education program. The COMET study]. / Observance du traitement hormonal substitutif de la ménopause: effet d'un programme d'éducation original. L'étude COMET.

OBJECTIVE: To study the impact of an original education program on compliance to hormone replacement therapy (HRT) in post-menopausal women. METHODS: Data were obtained from 1,192 post-menopausal women (age: 53 +/- 5 years) included in the study with an onset less than six months: E2 gel (n = 791) or patch (n = 401) + progestins, and randomized in either educational program (Ep = 600) or regular verbal counselling (VC = 592). A patient is considered bad compliant with HRT when she prematurely stopped the study, whatever the reason of the cessation. The groups EP and VC are homogeneous for the age distribution, the HRT regimen, the date of onset and the climateric symptoms scores. RESULTS: There is a significant difference between EP and VC groups in compliance, respectively 86 and 81% (p < 0.027). This difference is partially explained by the significant improvement in the patch subgroups (EP: 86% versus VC: 77%, p = 0.028). The trend observed in the gel group is not significant (EP: 85% and VC: 82%) due to the high level of compliance usually noticed in women treated with the gel and the verbal counselling. The significative difference in the compliance observed during the verbal counselling between the continuous (76%) and the sequential (86%, p = 0.001) HRT regimen disappears with the educational program (continuous: 84% and sequential: 87%, NS). CONCLUSION: This first large study on the HRT compliance in France, using a patient educational material, validates its efficacy to reach a better compliance than with regular verbal counselling. Even though in the daily practice, about 40% of the patients discontinue the treatment during the first year, 81% of the women followed in this study continue to receive the HRT after nine months of use. The original educational program of the COMET study improves significatively this high compliance (+ 5% from the verbal counselling). Thus, the combination of the doctor verbal counselling and an educational material is desirable to obtain a good compliance with HRT.

Value of autoantibodies to beta(2)-glycoprotein 1 in the diagnosis of antiphospholipid syndrome.

OBJECTIVES: To define the specificity and positive predictive value of anti-beta(2)-glycoprotein 1 (anti-beta(2)GP1) antibodies for the diagnosis of antiphospholipid syndrome (APS). METHODS: We determined the presence of anticardiolipin (aCL) antibodies and anti-beta(2)-glycoprotein 1 (anti-beta(2)GP1) immunoglobulin (Ig) G and IgM in 191 consecutive sera from 191 patients and reviewed clinical data separately. aCL IgG and IgM were detected separately using commercial ELISA kits. Anti-beta(2)GP1 antibodies were detected with an in-house ELISA using beta(2)GP1. RESULTS: Seven patients were diagnosed as having APS and 184 as having other diseases. Thirty-six patients were aCL-positive and 12 were anti-beta(2)GP1-positive, seven of these 12 were APS patients. The specificity for anti-beta(2)GP1 in our population was 97%, with a positive predictive value (PPV) of 58%. Among the aCL-positive patients, specificity was 90% and PPV 70-87%. CONCLUSIONS: This study shows that anti-beta(2)GP1 antibodies have a higher specificity and PPV than aCL for APS. The PPV of anti-beta(2)GP1 was greater in aCL-positive than in all patients. We conclude that screening for anti-beta(2)GP1 antibodies in aCL-positive patients increases the specificity and the PPV of aCL testing. In addition, we show that there is no need to screen for anti-beta(2)GP1 antibodies in the absence of aCL antibodies and in the absence of strong clinical suspicion of APS.

[Immunologic response to antiretroviral treatment with combined stavudine, didanosine and nevirapine]. / Réponse immunologique sous traitement antirétroviral associant stavudine, didanosine et névirapine.

OBJECTIVE: The purpose of this study was to investigate the restoration of immune function in patients given two nucleoside-analogs and one non-nucleoside-analog (nevirapine). PATIENTS AND METHODS: The study was carried out in 27 HIV-1-infected patients, starting a treatment with d4T, ddl and nevirapine, included in the VIRGO trial and followed up to 52 weeks. RESULTS: Total CD4 T cells increased as early as the fourth week of treatment (+154/microliter, p < 0.001) with a gain maintained until week 52 (+201/microliter at week 52). A similar pattern was seen for memory CD4 T cells (+80/microliter at week 4, +110/microliter at week 52). The rise in naive CD4 T cells was slower, strongly significant for week 16 (p < 0.001) and maximum at week 24 (+105/microliter). DISCUSSION: In our study, rise in T cells was not correlated with virological response, however increase in total and naive CD4 T cells was correlated with the CD4 count at onset of therapy (p < 0.05). Our data indicate that patients on d4T-ddl-nevirapine therapy have the same immune restoration as patients given protease inhibitor-based regimens.

Analysis of anti-neutrophil cytoplasmic antibodies (ANCA): frequency and specificity in a sample of 191 homozygous (PiZZ) alpha1-antitrypsin-deficient subjects.

BACKGROUND: ANCA are autoantibodies directed against polymorphonuclear cell antigens, mainly proteinase 3 (PR3) and myeloperoxidase (MPO), which are implicated in the pathogenesis of small-vessel necrotizing vasculitis. Alpha1-antitrypsin is the main inhibitor of neutral serine proteinase [i.e. human leukocyte elastase (HLE) and PR3] present in PMN alpha-granules (alphaGr). An association first reported by us between PR3 ANCA and the deficient PiZZ phenotype in ANCA-positive systemic vasculitis, now widely confirmed by others, led us to study the incidence and specificity of ANCA among PiZZ subjects. METHODS: We tested a population of 191 PiZZ (273 sera) for ANCA activity versus 272 PiMM matched control subjects using alphaGr or antigen-specific ELISA [PR3, HLE, MPO, lactoferin (LF) and bactericidal/ permeability increasing protein (BPI)]. RESULTS: The incidence of antibodies directed against alphaGr and HLE but not PR3, MPO, LF or BPI was increased in the PiZZ as compared to the PiMM group (Fisher probability respectively P < 0.0001 and P < 0.05). CONCLUSIONS: ANCA not directed against classical antigens (MPO and PR3) may be found in PiZZ patients. However, these patients do not develop systemic vasculitis features. Therefore, alpha1-antitrypsin deficiency is not sufficient to induce ANCA positive vasculitides, and may only act as a second hit amplifying factor.

Systemic antineutrophil cytoplasmic antibody vasculitis associated with lymphoid neoplasia.

Two cases of systemic antineutrophil cytoplasmic antibody (ANCA) vasculitis in the setting of chronic lymphocytic leukaemia and angioimmunoblastic lymphadenopathy type T cell lymphoma are reported. The two patients had fever of unknown origin associated with cutaneous vasculitis and "pulmonary-renal syndrome" with alveolar haemorrhage. Despite anti-infectious treatments, steroids, and chemotherapy, the vasculitis had a fatal paraneoplastic course in several weeks. When infection is excluded in patients with malignancy, atypical features should be promptly investigated for systemic vasculitis, and an ANCA test performed.

Prevalence of rheumatic manifestations and antineutrophil cytoplasmic antibodies in haematological malignancies. A prospective study.

OBJECTIVE: To evaluate the prevalence of antineutrophil cytoplasmic antibodies (ANCA) and rheumatic manifestations associated with chronic haematological malignancies. METHODS: Two groups of patients were prospectively studied (group I: 60 patients with myelodysplastic syndromes and group II: 140 patients with lymphoid malignancies) for clinical 'immune' manifestations and ANCA. RESULTS: In the myelodysplastic group, six patients had ANCA-negative systemic medium-size vasculitis, one had systemic vasculitis with cytoplasmic ANCA, one relapsing polychondritis, one giant cell arteritis, one polymyalgia rheumatica, one polyarthritis and two fasciitis. In group II, two patients had ANCA-negative systemic vasculitis, two had leucocytoclastic vasculitis associated with tuberculosis, two had polyarthritis, one polymyalgia rheumatica and one giant cell arteritis. Six sera were ANCA-positive with perinuclear pattern in four cases, atypical pattern in one and cytoplasmic pattern in one. Two sera had anti-myeloperoxidase (MPO) specificity, and others had no known specificity; none had anti-proteinase 3 (PR3) specificity. Global prevalence of ANCA in our cohort was 3%, similar to the French general population. CONCLUSION: Polyarteritis nodosa-type systemic vasculitis and polymyalgia rheumatica were the most frequent findings (18%) in myelodysplastic syndromes and particularly in chronic myelomonocytic leukaemia. ANCA were not helpful for the diagnosis of vasculitis. Vasculitis associated with infection, in particular tuberculosis, must be ruled out.