Expression of unmutated VH genes is a detrimental prognostic factor in chronic lymphocytic leukemia.
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Female↗
Biomedical subjects
F Vuillier
Publications and source records attributed to F Vuillier.
Status epilepticus in stroke: report on a hospital-based stroke cohort.
OBJECTIVE: To evaluate occurrence rate, clinical data, and prognostic factors of status epilepticus (SE) after stroke. METHODS: From 1984 to 1994, 3,205 patients were admitted to the Department of Neurology at our institution with first-time strokes. A total of 159 of these patients had first-time poststroke seizures. Among these 159 patients, cases of SE were identified and evaluated. RESULTS: SE was recognized in 31 patients (19%). In 17 patients, SE was the first epileptic symptom (initial SE), and in 4 patients, stroke began with SE (S-SE). In the 14 remaining patients, SE occurred after one or more seizure(s). After a mean follow-up period of 47 months, neurologic deterioration occurred after SE in 15 patients. This deterioration was permanent in two patients. Fifteen patients died; in five patients, death was directly related to SE. Eight of the 17 patients with initial SE and all 14 patients with SE after one or more seizure(s) developed other seizures or SE. S-SE, however, was not a predictive factor for additional seizure(s). CONCLUSIONS: Status epilepticus is common among patients with poststroke seizures. Although the immediate prognosis of patients with status epilepticus is poor, status epilepticus as the presenting sign did not necessarily predict subsequent epilepsy.
Adolescent↗
The human pineal gland: relationships with surrounding structures and blood supply.
After a short overview of the history of our knowledge of the pineal gland, its anatomy and its function, this work is primarily devoted to the relationships of the pineal gland to the nerve structures which delineate the pineal region. The complex surrounding blood vessels located in the quadrigeminal cistern are described with a special focus on the numerous venous trunks. Finally, the pineal blood supply is studied in three steps: (1) The arterial supply obtained through several groups of pineal arteries stemming mainly from the medial posterior choroidal arteries; (2) The venous drainage by the lateral pineal veins flowing, in most cases, into the cerebral vein of Galen; (3) The intrapineal vascular architecture with specific features concerning the central part of the gland highly vascularized by large sinusoid capillaries and its peripheral part poorly vascularized by small and fine blood vessels.
Cerebral Veins↗
Primary intracerebral hemorrhages in the Besançon stroke registry. Initial clinical and CT findings, early course and 30-day outcome in 350 patients.
The purpose of this study was to estimate the risk factors, early course, outcome and neuroimaging patterns in primary intracerebral hemorrhages (PIH). Using the Besançon Stroke Registry, 350 patients with first PIH documented by computed tomography (CT) between 1987 and 1993 were included in the present study. Patients with hemorrhage secondary to traumatism, brain tumor, thrombolytic treatment, vascular malformation or with hemorrhagic infarction were excluded. All CTs were evaluated to define the location, extension and volume of bleeding (55% of CT were performed within the first 12 h). Causes of death were classified and the 30-day outcome survival was evaluated with a modified Rankin scale (40 patients underwent a noncodified surgical procedure and were excluded from the outcome evaluation). Locations were lobar (36.5%), lenticular (32%), thalamic (15.7%), cerebellar (8.8%), midbrain and pons (2%), intraventricular (2%), caudate (1%) and multiple (2%). Risk factors included hypertension (54.8%), alcohol (18%) anticoagulant treatment (8.8%) and none (31.2%). The largest mean volume was in putaminal (41.7 ml) and lobar (39.8 ml) locations. Among 191 patients admitted before the 12th hour of evolution, 51 (26.7%) experienced an early clinical worsening. In this group, the percentage of patients with anticoagulant treatment (19.6%) was significantly higher (p<0.0001). PIH enlargement was documented in 3 patients. Overall, the 30-day mortality rate was 24.2% with 48% of all deaths occurring in the first 3 days. Death and 30-day survival status were closely associated with PIH volume (p<0.0001). Our study provides information on the natural history of PIH and especially on initial evolution. PIH volume seems to be an interesting indicator for death and functional status at 30 days.
Adolescent↗
[Emergency neurology consultations in the university hospital setting: contribution of the neurologist to inpatient management].
While outpatient management for chronic neurological diseases is well-established, the impact of inpatient neurological examination in emergency room and university hospital remain largely underestimated. We prospectively studied the role of the neurologist in patient management, in a primary care university hospital. Over a period of 12 months, we prospectively recorded the demographics of patients requiring examination in the emergency room, the initial suspected neurological diagnosis of the emergency room, the final diagnosis of the neurology team, and the patients' outcomes. For each patient, the time between admission, the call and the neurological examination were recorded. Neurological examinations were performed in 2220 patients in whom 75.6 p.100 were performed in the emergency room. These latter patients corresponded to 14 p.100 of all patients admitted in the emergency room. Of examined patients, 52 p.100 were male and mean age was 56.9 +/- 21 years. The time between admission and examination was 32 min. (+/- 36 min), irrespective of the day of the week, and depended on the suspected diagnosis: shorter in stroke and status epilepticus (p<0.05), and longer in loss of consciousness and vertigo (p<0.01). Forty-four percent of the examinations took place in the evening and night. The reasons for examinations were: stroke (28.3 p.100), epilepsy (17.7 p.100), headaches (8.4 p.100), loss of consciousness (7.9 p.100), cognitive dysfunctions (4.1 p.100), neuropathies (4 p.100) and miscellaneous (8.1 p.100). Neurological examinations modified neurological diagnosis and treatment in more than 86 p.100 of the patients. Following neurological examination, 17.2 p.100 of the patients were able to go home, while the rest were admitted to the stroke unit (27.2 p.100), the general neurological unit (27.3 p.100) or in other departments (28.3 p.100), of which intensive care unit (5.3 p.100) or neurosurgery (5.9 p.100). Emergency neurologic examination improves neurological diagnosis and has a positive impact both on treatment and, more globally, in patient management.
Consultants↗
Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death.
Peroxynitrite (ONOO-) is a potent oxidizing and nitrating agent produced by the reaction of nitric oxide with superoxide. It readily nitrates phenolic compounds such as tyrosine residues in proteins, and it has been demonstrated that nitration of tyrosine residues in proteins inhibits their phosphorylation. During immune responses, tyrosine phosphorylation of key substrates by protein tyrosine kinases is the earliest of the intracellular signaling pathways following activation through the TCR complex. This work was aimed to evaluate the effects of ONOO- on lymphocyte tyrosine phosphorylation, proliferation, and survival. Additionally, we studied the generation of nitrating species in vivo and in vitro during immune activation. Our results demonstrate that ONOO-, through nitration of tyrosine residues, is able to inhibit activation-induced protein tyrosine phosphorylation in purified lymphocytes and prime them to undergo apoptotic cell death after PHA- or CD3-mediated activation but not upon phorbol ester-mediated stimulation. We also provide evidence indicating that peroxynitrite is produced during in vitro immune activation, mainly by cells of the monocyte/macrophage lineage. Furthermore, immunohistochemical studies demonstrate the in vivo generation of nitrating species in human lymph nodes undergoing mild to strong immune activation. Our results point to a physiological role for ONOO- as a down-modulator of immune responses and also as key mediator in cellular and tissue injury associated with chronic activation of the immune system.
Apoptosis↗
[Brain CT scan for acute cerebral infarction: early signs of ischemia].
Computed tomography (CT) is widely used for early evaluation of acute strokes. Most importantly, CT excludes acute hemorrhage or other diseases mimicking ischemia. Therefore, CT is the main imaging examination in patients with brain ischemia and when antithrombotic agents are being considered. During the first hours after acute ischemic stroke, the CT does not usually show much in the first 24 hours. However, early abnormal findings on CT scan have been described such as the hyperdense middle cerebral artery sign (HMCAS), and reduced contrast attenuation of the cerebral parenchyma. HMCAS reflects arterial occlusion. Early parenchymal abnormalities, the attenuation of lentiform nucleus (ALN), loss of the insular ribbon (LIR) or hemispheric sulcus effacement (HSE) occur less frequently and they are positive criteria for cerebral in progress. Early parenchymal abnormalities might also predict subsequent infarct extension and hemorrhagic transformation. Therapeutic trials of ischemia in MCA territory involved decision making when the CT may not show obvious ischemic changes. Finally, initial CT findings may also help to predict response to therapy.
Acute Disease↗
In vitro antioxidant treatment recovers proliferative responses of anergic CD4+ lymphocytes from human immunodeficiency virus-infected individuals.
Oxidative stress has been proposed to be involved in the immunologic defeat observed in effector calls of the immune system as well as in lymphocyte cell death and viral replication in human immunodeficiency virus (HIV)-infected patients. Because thiol-containing antioxidants such as N-acetyl-L-cysteine have been shown to have beneficial effects on CD4+ lymphocyte survival and to inhibit programmed cell death and HIV-1 replication, they may play a role in therapeutic strategies of this disease. In this work we have studied the cellular thiol levels and the affect of in vitro antioxidant treatment of purified CD4+ lymphocytes from HIV-infected patients, and correlated these parameters to proliferative responses and programmed cell death. We show that CD4+ lymphocytes from HIV-infected patients display impaired proliferative responses and a significant decrease in cellular thiol levels, indicating a disturbed redox status. Interestingly, antioxidant treatment succeeded to restore defective proliferative responses to CD3-mediated activation in 8 of 11 patients (high antioxidant responders). In contrast to high responders, patients failing to respond to antioxidant treatment (low antioxidant responders), were characterized by an abnormal ratio of apoptotic cells, which was not affected by N-acetyl-L-cysteine and/or 2-beta-mercaptoethanol preincubation. These results demonstrate for the first time that antioxidant treatment is able to revert the impaired proliferative activity of CD4 cells from HIV-infected patients and could help designing therapeutic strategies with antioxidant drugs. However, this action is not observed in cells undergoing programmed cell death.
Acetylcysteine↗
CD4+ lymphocytes from HIV-infected patients display impaired CD45-associated tyrosine phosphatase activity which is enhanced by anti-oxidants.
It has been proposed that signal transduction defects may, at least partially, account for the functional impairment of CD4+ lymphocytes during HIV-1 infection. Recently, we have demonstrated that unresponsive CD4+ lymphocytes from these patients had reduced protein tyrosine phosphorylation after CD3 engagement, and that this defect was associated with constitutively altered levels of p56lck and p59fyn kinases. Since CD45 is essential for T cell receptor (TCR) and CD2-mediated activation of protein tyrosine kinases, we study here CD45-associated tyrosine phosphatase activity in resting and activated CD4 T cells from HIV-infected patients. We found a significant decrease in the basal and post-activation phosphatase activity of CD45 which correlated well with impairment of proliferative responses. In addition, decreased levels of cellular thiols observed in resting CD4+ lymphocytes from these patients suggested a disturbed redox status. Although expression levels of CD45 were decreased in most patients, a significant recovery of phosphatase activity and proliferative responses was observed in most patients by preincubating cells with N-acetyl-L-cysteine and beta2-mercaptoethanol. In some patients, anti-oxidant treatment failed to significantly enhance phosphatase activity and proliferative responses. The low responses of purified CD4+ lymphocytes from these patients were associated with a high ratio of apoptotic cell death which did not appear to be influenced by anti-oxidant treatment.
Apoptosis↗
Expression and production of cytokines by heterohybrids and their parental B cells in CLL.
Three hybrids derived from CD5+ B cell chronic lymphocytic leukemia (B-CLL) and their parental B cells were studied for phenotypic evolution, immunoglobulin (Ig), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) secretion. When phenotypic evolution was examined, hybrids showed the loss of classical B cell markers, indicating that they follow the same pattern of phenotypic differentiation as normal B cells. Hybrids displayed spontaneous high Ig secretion, which did not appear to be modified through stimulation by phorbol 12-myristate 13-acetate (PMA), recombinant interferon-gamma (rIFN-gamma) and Staphylococcus aureus Cowan I (SAC). Parental cells secreted minimal amounts of Ig spontaneously or through IFN-gamma and SAC stimulation, whereas PMA succeeded in increasing this secretion. An opposite pattern was observed when TNF-alpha and IL-6 secretion an expression at the mRNA level were assessed in hybrids and parental cells. TNF-alpha and IL-6 were spontaneously secreted by parental cells and this secretion was increased after PMA and SAC stimulation, both cytokine secretion and expression at the mRNA level were negative in hybrid cells. The absence of expression of these cytokines could be explained either by chromosomal loss or by down regulation. These results indicate that when parental CLL cells are induced to differentiate in the heterohybrid model, they acquire high spontaneous secretion of Ig, lose the classical B cell phenotypic markers and down regulate the expression of the cytokines studied.
B-Lymphocytes↗
Isolated cortical vein thrombosis and activated protein C resistance.
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Adult↗
Flow cytometric analysis of protein-tyrosine phosphorylation in peripheral T cell subsets. Application to healthy and HIV-seropositive subjects.
This paper describes an improved method for detecting tyrosine phosphorylation levels in T cell subsets by flow cytometry early after CD3 crosslinking stimulation. It consists in introducing gentle paraformaldehyde fixation between CD3 crosslinking in cold conditions and the shift to 37 degrees C, which activates downstream signalling machinery. We used the combined properties of monoclonal antibodies for stimulating cells and for detecting surface markers to analyze protein-tyrosine phosphorylation levels in T cells subsets following stimulations which mimic physiological activation. Overall data obtained in healthy subjects, using two- or three-color immunofluorescence, indicated that: (1) most CD3 positive cells phosphorylate tyrosine substrates following CD3 crosslinking stimulation and (2) helper cells phosphorylate tyrosine to a slightly better extent than cytotoxic cells after CD3 crosslinking. Nevertheless, the two subsets follow similar kinetic patterns and tend to retain a homogeneous profile. Processing of samples from HIV-seropositive patients showed heterogeneous phosphorylation levels in both subsets, when compared to normal donors. This assay should, in the future, lead to easy and rapid exploration of the signal transduction pathway in different subsets of T cells under normal and pathological conditions.
CD3 Complex↗
Viral superantigen-induced hyporesponsiveness of T cells and polyclonal B cell activation in HIV-1 infection.
The mechanisms of CD4 depletion and hyporesponsiveness during human immunodeficiency virus (HIV) infection are still unknown. Given the ability of superantigens to stimulate a higher number of lymphocytes than conventional antigens, they may play a major role in this process. Recently, a novel superantigen, the rabies virus nucleocapsid (NC), was described in humans. In the present work, we tested the responses of peripheral blood lymphocytes from asymptomatic HIV-infected patients to this superantigen. In contrast to its effect in normal controls, NC failed to expand T cells from HIV-infected individuals expressing the V beta 8 family, and induced a strong decrease in the response to CD3 activation. This absence of response was not the consequence of programmed cell death, and was explained by an anergic state induced by the superantigen. NC superantigen was also able to induce polyclonal activation of B cells, as measured by the secretion of anti-HIV antibodies and autoantibodies. Moreover, V beta 8 depletion experiments showed that induction of autoantibody secretion was V beta 8 dependent, whereas secretion of HIV-1 antibody was not. Interleukin secretion studies showed that NC was able to induce high levels of interleukin-4 and interleukin-10. Taken together, our results suggest a role for exogenous viral superantigens such as NC in the induction of T cell hyporesponsiveness and polyclonal B cell activation during HIV infection. The induction of a Th2 response and the role of these superantigens in the immunopathogenesis of acquired immunodeficiency syndrome are discussed.
Acquired Immunodeficiency Syndrome↗
Defective protein tyrosine phosphorylation and altered levels of p59fyn and p56lck in CD4 T cells from HIV-1 infected patients.
Early in HIV infection, CD4+ lymphocytes exhibit the properties of an anergic state characterized by unresponsiveness to mitogens or to TCR stimulation and by defective IL-2 production. As tyrosine phosphorylation is the earliest of the biochemical events initiated by stimulation of CD3-TCR, we studied protein tyrosine phosphorylation in purified CD4+ lymphocytes from 25 asymptomatic seropositive patients (CD4 T cells > 350/mm3) previously stimulated in vitro by immobilized anti-CD3 mAb or by co-immobilized anti-CD3 and anti-CD28 mAbs. Purified CD4+ lymphocytes from HIV-infected patients exhibited defective early protein tyrosine phosphorylation in response to CD3 activation when compared with normal subjects. This defect was observed mainly in patients in whom proliferative responses to immobilized anti-CD3 ranged from 2 to 50% of control values obtained in healthy donors, and was frequently associated with increased cellular levels of p59fyn and decreased cellular levels of p56lck. Interestingly, these defects appeared to correlate with the degree of impairment in thymidine incorporation. Since CD28 mAbs have been reported to enhance proliferative responses to the CD3-TCR pathway in cloned murine or human anergic models and to induce tyrosine phosphorylation in human T cells, we studied the role of CD28 mAb as a co-signal. Although anti-CD28 co-stimulation augmented the proliferative responses in both controls and HIV-infected patients, it failed to correct the tyrosine phosphorylation pattern in the latter. Our results suggest a relationship between defective early protein tyrosine phosphorylation and impairment of proliferative responses in CD4 T cells from HIV-infected patients, and evidence is provided that associated altered cellular levels of the fyn and lck tyrosine kinases might play an important role in the anergic response observed early during HIV infection.
CD4-Positive T-Lymphocytes↗
Two subpopulations of human triple-negative thymic cells are susceptible to infection by human immunodeficiency virus type 1 in vitro.
Some infants infected with human immunodeficiency virus type 1 (HIV-1) rapidly develop a fatal disease characterized by a severe lymphopenia. To explain the immune dysfunction, we proposed a mechanism by which a nongeneration of CD4+ T cells is caused by HIV-1 infection of thymic cells. To examine this hypothesis, we infected primary triple-negative (TN; phenotypically CD3- CD4- CD8-), CD1a- TN, or CD1a+ TN thymic cell subsets. Our data indicate that by flow cytometry, TN, CD1a- TN, and CD1a+ TN cells remain CD4 negative throughout the culture period. We demonstrated that TN and CD1a+ TN thymic cell subsets are susceptible to HIV-1 as is the entire thymic cell population, whereas CD1a- TN cells are not. A limited number of infected TN cells are expressing HIV-1 but the level of transcription is very high in permissive cells, as detected by in situ hybridization. We then performed blocking experiments on TN cells to examine the mechanism of HIV-1 entry into these cells. CD4 (OKT4a) monoclonal antibody blocks their infection. Finally, infection experiments on two subpopulations of TN cells (CD2+ CD7+ and CD2- CD7-) indicate that infected TN cells may correspond to both immature thymocytes and thymic dendritic cells. These data are of particular interest since infection of thymic stromal cells might result in an impairment of T-cell differentiation, which may explain a nongeneration of functional CD4+ T-cell population in the thymus. This phenomenon may play a role in AIDS pathogenesis, in particular in infants born from seropositive mothers.
Antibodies, Monoclonal↗
In vitro non-productive infection of purified natural killer cells by the BRU isolate of the human immunodeficiency virus type 1.
Highly purified natural killer (NK) cell lines and clones, displaying the typical phenotype, morphology and function and obtained from healthy blood donors, were infected in vitro with the BRU isolate of human immunodeficiency virus type 1 (HIV-1). There was no significant increase in reverse transcriptase activity and levels of p24 antigen in the supernatants, but positive staining was observed using an immunogold technique with polyclonal anti-HIV-1 antibodies. When infected NK cells were co-cultivated with autologous non-infected CD4+ mitogen-activated cells, significant levels of reverse transcriptase activity and p24 antigen in supernatants were detected. Giant syncytial cells and a high number of mature virion particles were also evident. When NK cell lines or clones from HIV-1-infected patients were studied, neither the presence of p24 antigen nor reverse transcriptase activity was detected in the supernatants after stimulation with mitogens, cytokines or co-culture with allogeneic CD4+ mitogen-activated cells. PCR studies did not detect HIV-1 genes in freshly purified NK cells, cell lines or clones from infected patients. Taken together these results suggest that (i) normal NK cells can be infected in vitro by the HIV-1 BRU isolate in a non-productive fashion, (ii) PCR with NK cell DNA of HIV-1-infected patients indicates that in vivo few of these cells, if any, are infected by HIV-1 and (iii) the mechanisms responsible for the impairment of NK cell function during HIV-1 infection remain to be determined and are probably not related to a direct cytopathic effect of the virus.
Cell Line↗
Differential requirements for HIV-1 replication in naive and memory CD4 T cells from asymptomatic HIV-1 seropositive carriers and AIDS patients.
One of the major routes for modulating HIV-1 expression by infected T cells is through the control of transcription initiation from the HIV-1 long terminal repeat (LTR), which is regulated either by its own viral gene products or by several cellular DNA-binding proteins induced during T cell activation. Previous work reported preferential HIV-1 infection and replication of memory CD4 T cells from infected individuals, which was explained either by a higher viral burden of this subset or by differences between naive and memory cells in the activation of the general transcription machinery involved in HIV-1 replication. In this work, we have studied HIV-1 replication by highly purified naive and memory CD4 T cells from asymptomatic seropositive carriers (ASC) and AIDS patients following different activation signals. Our results demonstrate that viral replication in memory cells from ASC was observed after mitogenic (phytohaemagglutinin (PHA) and/or phorbol myristate acetate (PMA)) recombinant tumour necrosis factor-alpha (rTNF-alpha) and CD3-mediated activation. In contrast, in naive subsets, early viral replication was almost exclusively observed upon CD3-mediated activation. AIDS patients are characterized by similar levels of viral replication in both subsets after PHA and soluble or immobilized anti-CD3 MoAb activation. However, naive subsets from AIDS patients still displayed differential requirements since they failed to replicate HIV-1 after treatment with PMA and rTNF-alpha. Taken together, these results provide evidence that HIV-1 replication in CD4+ T cells from infected individuals is a function of the differentiation stage of the cells, the disease stage of the patient and the activation signal employed.
Acquired Immunodeficiency Syndrome↗