Depression in the early phase of MS: influence of functional disability, cognitive impairment and brain abnormalities

This study investigated the relationship between depression, physical disability, cognitive deficit and brain abnormalities on magnetic resonance imaging (MRI) in patients with early MS. Eighteen relapsing-remitting MS patients were evaluated: depression was diagnosed according to DSM-III R and measured by the MMPI depression subscale, physical disability was assessed by using the Kurtzke Expanded Disability Status Scale (EDSS) and cognitive functions by means of an extensive neuropsychological test battery. A neuroradiologist blinded to clinical findings quantified cerebral lesion on MRI. Weighted brain area lesion score were developed according to number and size of cerebral lesions. On the basis of DSM-III criteria, six patients were classified as having major depression, seven patients had minor depression and five patients were without depressive symptoms. No significant differences were found among the three groups on both neuropsychological performances and weighted MRI lesion scores. However patients with major depression exhibit greater physical disability than the other MS subgroups. A significant correlation was found between MMPI depression subscale and physical disability. This study suggests that at least in the early phase of MS, depression appears more related to the physical disability than to the severity of pathological brain involvement.     

Circulating platelet aggregates: a chronic platelet activation in patients with transient ischaemic attacks

Platelet hyperaggregability was tested in 62 TIA patients by means of the formalin fixing principle of Wu and Hoak. Compared to age-matched controls, the platelet aggregates ratio (PAR) was reduced from 0.99±0.04 SD to 0.807±0.14 SD. This means a highly significant increase of circulating platelet aggregates (CPA) in untreated TIA patients, regardless of the interval sinche the last attack (from 2 days to 1 year). PAR was especially reduced in patients with abnormal angiography (expressing pronounced cerebral or diffuse ATS) and it was possibly affected by previous antiplatelet treatment with ASA.     

Long-term noninvasive single photon emission computed tomography monitoring of perfusional changes after EC-IC bypass surgery.

The rCBF was evaluated using I-123 HIPDM and single photon emission computed tomography (SPECT) on 14 patients undergoing extracranial-intracranial (EC-IC) bypass surgery because of internal carotid artery (ICA) occlusion. Before surgery, all patients showed cortical areas of hypoperfusion over the affected cerebral hemisphere. Shortly after EC-IC bypass a rCBF increase was observed in six patients. However, at the 6 and 12 month follow-ups, with angiographic control of bypass patency, rCBF studies did not show any significant rCBF change. Long-term noninvasive tomographic monitoring of perfusion changes occurring after EC-IC bypass surgery failed to show a long-lasting improvement in perfusion.     

The human spleen is a major reservoir for long-lived vaccinia virus-specific memory B cells

The fact that you can vaccinate a child at 5 years of age and find lymphoid B cells and antibodies specific for this vaccination 70 years later remains an immunologic enigma. It has never been determined how these long-lived memory B cells are maintained and whether they are protected by storage in a special niche. We report that, whereas blood and spleen compartments present similar frequencies of IgG⁺ cells, antismallpox memory B cells are specifically enriched in the spleen where they account for 0.24% of all IgG⁺ cells (ie, 10-20 million cells) more than 30 years after vaccination. They represent, in contrast, only 0.07% of circulating IgG⁺ B cells in blood (ie, 50-100 000 cells). An analysis of patients either splenectomized or rituximab-treated confirmed that the spleen is a major reservoir for long-lived memory B cells. No significant correlation was observed between the abundance of these cells in blood and serum titers of antivaccinia virus antibodies in this study, including in the contrasted cases of B cell– depleting treatments. Altogether, these data provide evidence that in humans, the two arms of B-cell memory—long-lived memory B cells and plasma cells—have specific anatomic distributions—spleen and bone marrow—and homeostatic regulation.     

Common variable immunodeficiency disorders: division into distinct clinical phenotypes

The European Common Variable Immunodeficiency Disorders registry was started in 1996 to define distinct clinical phenotypes and determine overlap within individual patients. A total of 7 centers contributed patient data, resulting in the largest cohort yet reported. Patients (334), validated for the diagnosis, were followed for an average of 25.6 years (9461 patient-years). Data were used to define 5 distinct clinical phenotypes: no complications, autoimmunity, polyclonal lymphocytic infiltration, enteropathy, and lymphoid malignancy. A total of 83% of patients had only one of these phenotypes. Analysis of mortality showed a considerable reduction in the last 15 years and that different phenotypes were associated with different survival times. Types of complications and clinical phenotypes varied significantly between countries, indicating the need for large, international registries. Ages at onset of symptoms and diagnosis were shown to have a Gaussian distribution, but were not useful predictors of phenotype. The only clinical predictor was polyclonal lymphocytic infiltration, which was associated with a 5-fold increased risk of lymphoid malignancy. There was widespread variation in the levels of serum immunoglobulin isotypes as well as in the percentages and absolute numbers of B cells, confirming the heterogeneity of these conditions. Higher serum IgM and lower circulating CD8 proportions were found to be predictive markers for polyclonal lymphocytic infiltration and autoimmunity, respectively.     

Leu505 of Nox2 is crucial for optimal p67phox-dependent activation of the flavocytochrome b558 during phagocytic NADPH oxidase assembly

The role of Leu505 of Nox2 on the NADPH oxidase activation process was investigated. An X-CGD PLB-985 cell line expressing the Leu505Arg Nox2 mutant was obtained, exactly mimicking the phenotype of a previously published X91+-CGD case. In a reconstituted cell-free system (CFS), NADPH oxidase and iodonitrotetrazolium (INT) reductase activities were partially maintained concomitantly with a partial cytosolic factors translocation to the plasma membrane. This suggests that assembly and electron transfer from NADPH occurred partially in the Leu505Arg Nox2 mutant. Moreover, in a simplified CFS using purified mutant cytochrome b558 and recombinant p67phox, p47phox, and Rac1proteins, we found that the Km for NADPH and for NADH was about three times higher than those of purified WT cytochrome b558, indicating that the Leu505Arg mutation induces a slight decrease of the affinity for NADPH and NADH. In addition, oxidase activity can be extended by increasing the amount of p67phox in the simplified CFS assay. However, the maximal reconstituted oxidase activity using WT purified cytochrome b558 could not be reached using mutant cytochrome b558. In a three-dimensional model of the C-terminal tail of Nox2, Leu505 appears to have a strategic position just at the entry of the NADPH binding site and at the end of the alpha-helical loop (residues 484-504), a potential cytosolic factor binding region. The Leu505Arg mutation seems to affect the oxidase complex activation process through alteration of cytosolic factors binding and more particularly the p67phox interaction with cytochrome b558, thus affecting NADPH access to its binding site.     

Genetic screening of male patients with primary hypogammaglobulinemia can guide diagnosis and clinical management

The precise diagnosis of an immunodeficiency is sometimes difficult to assess, especially due to the large spectrum of phenotypic variation reported among patients. Common variable immunodeficiency disorders (CVID) do not have, for a large part, an identified genetic cause. The identification of a causal genetic mutation is important to confirm, or in some cases correct, the diagnosis. We screened >150 male patients with hypogammaglobulinemia for mutations in three genes involved in pediatric X-linked primary immunoglobulin deficiency: CD40LG, SH2D1A and BTK. The SH2D1A screening allowed to reclassify two individuals with an initial CVID presentation as XLP after mutations identification. All these mutations were associated with a lack of protein expression. In addition, 4 patients with a primary diagnosis of CVID and one with a primary IgG subclass deficiency were requalified as XLA after identifying BTK mutations. Interestingly, two out of these 5 patients carried a damaging coding BTK mutation associated with a lower, but detectable, BTK expression in monocytes, suggesting that a dysfunctional protein explains the disease phenotype in these patients. In conclusion, our results advocate to include SH2D1A and BTK in newly developed targeted NGS genetic testing, to contribute to providing the most appropriate medical treatment and genetic counselling.     

Collaborative and workflow-oriented digital portfolio: Creating a web-based tool to support a nationwide program of practices evaluation in the blood transfusion area

PURPOSE: The French National Blood Transfusion Institute received approval from the French National Health Authority to organize a nationwide program for the evaluation of professional practices in the area of blood transfusion. Major issues of the project were: (1) managing numerous physicians spread nationwide; (2) tracking and storing the physician's entire process (from his/her enrollment to his/her lifelong follow-up); (3) creating a collaborative technique for processing an evaluation program; (4) enhancing exchanges between participants; (5) proposing effective implementation of the assessment. METHODS: As faculty members with experience in distance learning, we considered the digital/electronic portfolio to be one of the most suitable techniques to support such a project. Due to the lack of methods and tools to meet users' expectations, the decision was made to prototype a new and innovative assessment environment. A team was formed to complete the design phase within 6 months (information content, roles and functions). Implementation of the prototype, which includes tests, was also planned over a 6-month period. The methodology involves two approaches: one concerns business process modelling; the other is related to object-oriented methods for design and implementation. RESULTS: This primary work was aimed at describing a specific object, the evaluation program, which can be shared between players within a web-based collaborative platform. Four types of players were identified: (1) physicians enrolled into the assessment program; (2) tutors assigned to follow physicians' assessment process; (3) program directors who manage the content of the assessment program and the application of follow-up rules; (4) supervisors who administrate the global system. The evaluation program is composed of a set of actions, which has to be performed by the physicians. These actions are directly related to the activities of the business processes to which the candidate belongs. For each action, elements of proof have to be uploaded by the physician, according to a predefined schedule. The status of this object and its changes are followed and managed by a workflow engine. Implementation of the system required an object-oriented content management system (Zope/Plone). CONCLUSION: The object-oriented approach helped us to focus on the topic of interest, the assessment program, without being concerned by the whole environment. The assessment model we designed attempts to make a link with the business process performed in daily routine. This article explores the way business process modelling can contribute to the modelling of a professional practices assessment system. Apart from the modelling and technical aspects, this nationwide project contains major challenges: to enroll all physicians on an individualized basis and to create appropriate conditions for the extension of the evaluation program and device to other specialties.     

Bortezomib and dexamethasone,an original approach for treating multi-refractory warm autoimmune haemolytic anaemia

We report the off-label use of bortezomib combined with dexamethasone in eight adults with severe and multi-refractory warm auto-immune haemolytic anaemia (wAIHA). After six cycles of induction therapy, 6 of the 8 patients achieved response (3 complete response, 3 response). Response was obtained after a median of 2 (1–4) cycles. After a median follow-up of 14 (6–36) months, six patients maintained a response (bortezomib/dexamethasone maintenance, n = 4); five patients experienced at least one moderate adverse event, including peripheral neuropathy (n = 2). These results suggest that bortezomib/dexamethasone combination is a promising approach with acceptable toxicity for treating severe refractory wAIHA in adults.