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C Fieschi

Publications and source records attributed to C Fieschi.

At least 19 recordsLinked to original sources
PubMed2007

Detection and follow-up of fibroblast growth factor receptor 3 expression on bone marrow and circulating plasma cells by flow cytometry in patients with t(4;14) multiple myeloma.

The t(4;14)(p16;q32) translocation, found in 15% of multiple myeloma (MM) cases, indicates a poor prognosis. Plasma cells (PC) with t(4;14) ectopically express the fibroblast growth factor receptor 3 (FGFR3) tyrosine kinase receptor, which has potential transforming activity and may represent a therapeutic target. To detect FGFR3 protein expression, bone marrow (BM) aspirate from 200 consecutive newly diagnosed (n = 116) or relapsing (n = 74) MM patients was studied by flow cytometry (FC) using anti-CD138 and anti-FGFR3 antibodies. FC data was compared to real time quantitative-polymerase chain reaction (RQ-PCR) of the IGH-MMSET and FGFR3 transcripts. An IGH-MMSET transcript was found in 24/200 patients (12%). In 20 of these, FC detected CD138(+)/FGFR3(+) cells. No expression of FGFR3 was detected in the 4 FGFR3(-) cases by RQ-PCR. FGFR3 was never expressed on PC without t(4;14). Circulating PC (CPC) were detected in patients with (11/11) and patients without (13/41) t(4;14). In 2/8 t(4;14) cases studied longitudinally, coexisting FGFR3(+) and FGFR3(-) CPC were observed. Fluorescent in situ hybridisation (FISH) analysis of the FGFR3(-) subclones showed deletion of the der(14) in one patient. In conclusion, as a supplemental method to RQ-PCR or FISH, FC analysis of FGFR3 expression is a reliable and routinely available method for the detection and management of new therapeutic approaches of t(4;14) MM.

Biomarkers, Tumor↗
PubMed2005

[Genetic susceptibility to mycobacterial disease: Mendelian disorders of the interleukin-12 -interferon-gamma axis].

INTRODUCTION: Environmental non tuberculous mycobacteria and Bacillus Calmette-Guerin vaccines are weakly virulent mycobacteria. Nevertheless they may cause severe diseases in otherwise healthy children with no overt immunodeficiency. Parental consanguinity and familial forms are frequently observed among these patients, therefore this syndrome was named "Mendelian Susceptibility to Mycobacterial Disease". STATE OF THE ART: In the last nine years, fife genes have been found to be mutated in patients with this syndrome: IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1. Allelic heterogeneity accounts for ten distinct genetic disorders. Clinical phenotype differs between patients. The spectrum of disease extends from early-onset overwhelming mycobacterial infection to adult-onset localized disease and tuberculosis. Impaired IFN-gamma-mediated immunity is the common mechanism of the disease, outlining its major role in mycobacterial immunity. PERSPECTIVES AND CONCLUSIONS: Better understanding of these disorders reveals an expanding clinical phenotype which justifies studying adult patients with pulmonary non tuberculous mycobacterial infection without known risk factors, severe BCGitis and recurrent tuberculosis. Molecular diagnosis makes it possible to introduce a specific regimen based on physiopathology.

Anti-Bacterial Agents↗
PubMed2005

Medical education and MS: getting the training right.

Medical education needs continuous improvements to meet the changing demands of medical practice in the 21st century. We need to review the teaching methods used and the curriculum taught during various stages of a doctors training. General practitioners need to recognize the symptoms indicative of MS and refer the patient to a specialist; neurologists should confirm the diagnosis, and effectively treat, manage and support the patient. Training should be adapted to reflect these different tasks and equip the physician accordingly. We suggest a training programme for undergraduate students comprising three lectures and two interactive sessions. These would provide the student with a basic knowledge of MS and its management. For those wishing to specialize in neurology, we recommend a series of eight lectures, interactive sessions discussing case reports with typical and atypical presentations, two magnetic resonance imaging reading sessions with a specialist neuroradiologist and active practice in an MS clinic.

Brain↗
PubMed2004

Chlamydia pneumoniae infection in young stroke patients: a case--control study.

Retrospective and cross-sectional studies have suggested that both bacterial and viral infections may be risk factors for atherosclerosis, ischemic stroke and acute coronary events. The correlation between Chlamydia pneumoniae and atherosclerosis remains a source of controversy. Our case-control study is aimed at evaluating the frequency of C. pneumoniae infection in a cohort of young adults with recent cerebrovascular disease and in particular etiologic stroke subtypes. Chlamydia pneumoniae IgG, IgM and IgA antibodies were evaluated by microimmunofluorescence method and antibody titers to both recombinant antigens chlamydial outer protein 2 and 60-kDa chlamydial heat shock protein (HSP60) by ELISA. The two groups differed with regard to the prevalence of C. pneumoniae IgA (P < 0.001) and IgG (P < 0.0001), as well as the titer of anti-R-HSP60 IgG (P < 0.001). We found an increase in IgA titers, suggestive of persistent, chronic active infection, in 16 patients in whom the etiology of the cerebral ischemic event was large-vessel atherothrombosis. Persistent, active C. pneumoniae infection may be an additional risk factor for ischemic stroke mainly of atherotrombotic origin in young subjects. However, a large-scale prospective confirmation of our findings is required.

Adolescent↗
PubMed2004

Teaching of neuroepidemiology in Europe: time for action.

Many epidemiological and clinical studies in Europe, especially in Eastern Europe and countries in transition, are of poor methodological quality because of lack of background knowledge in clinical epidemiology methods and study designs. The only way to improve the quality of epidemiological studies is to provide adequate undergraduate and/or postgraduate education for the health professionals and allied health professions. To facilitate this process, the European Federation of Neurological Societies (EFNS) Task Force on teaching of clinical epidemiology in Europe was set up in October 2000. Based on analyses of the current teaching and research activities in neuroepidemiology in Europe, this paper describes the Task Force recommendations aimed to improve these activities.

Education, Medical↗
PubMed2003

Interferon beta treatment of MS in the daily clinical setting: a 3-year post-marketing study.

We performed a post-marketing study of patients with multiple sclerosis (MS) attending the outpatient service to evaluate the impact of interferon beta-1b (IFNbeta-1b) in the daily clinical setting. The absolute changes in relapse frequency and in the mean EDSS score over a three-year period were compared between 83 patients with relapsing remitting MS treated with IFNbeta-1b and 83 RRMS patients who did not take the drug. Annualized relapse frequency significantly decreased in patients undergoing therapy while no statistically significant changes in EDSS score were observed. These findings point out the role of post-marketing studies in evaluating the impact of approved drugs in the daily clinical setting in terms of safety and tolerability. Furthermore, our results confirm the positive effect of immunomodulatory treatment in decreasing the occurrence of inflammatory events.

Adult↗
PubMed2002

Inherited disorders of IL-12- and IFNgamma-mediated immunity: a molecular genetics update.

In the last 6 years, considerable advances have been made in the molecular analysis of a rare clinical syndrome: Mendelian susceptibility to mycobacterial disease (MSMD). Infection with poorly virulent environmental non-tuberculous mycobacteria (NTM) or vaccination with bacillus Calmette-Guerin (BCG) may cause disseminating and even fatal disease in individuals suffering from this syndrome. Mutations in five genes (IFNGR1, IFNGR2, STAT1, IL12B and IL12RB1) have been shown to be responsible for MSMD and further allelic heterogeneity accounts for the existence of nine distinct inherited disorders. All of these disorders are caused by impaired IFNgamma-mediated immunity. These results have important medical and biological implications. In this report, we update the disease-causing mutations reported in the literature.

Adult↗
PubMed2001

Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation.

Interferons (IFN) alpha/beta and gamma induce the formation of two transcriptional activators: gamma-activating factor (GAF) and interferon-stimulated gamma factor 3 (ISGF3). We report a natural heterozygous germline STAT1 mutation associated with susceptibility to mycobacterial but not viral disease. This mutation causes a loss of GAF and ISGF3 activation but is dominant for one cellular phenotype and recessive for the other. It impairs the nuclear accumulation of GAF but not of ISGF3 in heterozygous cells stimulated by IFNs. Thus, the antimycobacterial, but not the antiviral, effects of human IFNs are principally mediated by GAF.

Adult↗
PubMed2001

Migraine and arterial dissection in a young woman.

Ischemic stroke in young adults is rare (5%-10% of all ischemic strokes) and, in absence of other risk factors, may be associated with migraine. We describe the case of a 34-year-old woman, with a history of migraine without aura, who presented a sudden onset of headache with Horner's syndrome, and in whom neuroimaging showed evidence compatible with fibromuscular dysplasia (FMD) and arterial dissection of the extracranial internal carotid artery (ICA) and the carotid siphon. In our opinion, in young women with a long history of migraine, a careful study of the extracranial and intracranial arteries would be useful, although the cost/benefit ratio does not at present justify such a procedure. Our aim in the future is, therefore, to study a larger sample of migraine patients in order to find those patients who are most at risk of arterial dissection and who should, consequently, be carefully studied.

Adult↗
PubMed2001

Treatment of cerebrovascular diseases: state of the art and perspectives.

Ischaemic penumbra is defined as the area of brain tissue that maintains some blood flow following ischaemic accident. This zone may be rescued by both neuroprotection and arterial revascularization. Early thrombolysis has been used with encouraging results since 1995 in several trials testing both streptokinase and recombinant tissue plasminogen activator (r-TPA): the r-TPA results are definitely more positive than those of streptokinase, despite an increased incidence of symptomatic haemorrhagic transformation, r-TPA significantly reducing death or dependency at the end of follow-up. Despite the fact that some experimental periods of application of these therapeutic strategies demonstrated real cost-effective benefits, only 1% of patients reaching hospital in time for thrombolysis are currently treated. This is because the profile of patients at risk of haemorrhagic transformation, which is definitely the most feared side-effect of thrombolysis in stroke, is yet to be clearly defined. Extended computerized tomography (CT) signs of the index stroke have been repeatedly indicated as reliable predictors of haemorrhagic transformation even if currently there are significant discrepancies in the criteria adopted by different researchers to define early CT signs. Based on experimental ischaemia, strategies for protecting the basal lamina during thrombolysis are suggested: neuroprotection is the second approach to stroke therapy; pharmacological reperfusion and brain protection are probably mutually dependent.

Cerebrovascular Disorders↗
PubMed2001

Keynote address.

"Acute strokes are here to stay": this could be the sad conclusion after decades of stroke research. Generalized prevention of ischemic stroke is not fully successful. After the decline in stroke incidence observed by 1970, partly related to better management of vascular risk factors, there has again been an increase in stroke frequency all around the world. This phenomenon may be explained by the lack of educational modalities for modification of lifestyle behavior, the small impact of high-risk individual prevention strategy, and the lack of rationale and guidelines for multiple approaches. In the meantime, the benefits of acute intensive management of stroke have been demonstrated. There is now considerable evidence that careful monitoring and management of general and cerebral functions in a dedicated stroke unit or by a specialized stroke team are superior to management in a neurologic or general ward. Currently, one way of optimizing limited personnel resources is to connect the stroke unit of a main hospital with peripheral hospitals via a computer network. Experts in the central stroke unit can then make on-line evaluations of CT and ultrasound examinations performed in the local hospital and recommend the best course of patient management. This new approach of treating stroke as an emergency will also require educational programs directed at the general public, general practitioners, and primary and emergency department physicians, to teach the recognition of stroke symptoms and the importance of treating stroke with the same urgency as for myocardial infarction (MI).

Brain Ischemia↗
PubMed2001

High levels of interferon gamma in the plasma of children with complete interferon gamma receptor deficiency.

We have found that children with complete interferon gamma (IFNgamma) receptor deficiency, unlike patients with other genetic defects predisposing them to mycobacterial diseases, have very high levels of IFNgamma in their plasma. This unexpected observation provides a simple and accurate diagnostic method for complete IFNgamma receptor deficiency in children with clinical disease caused by bacille Calmette-Guérin vaccines or environmental nontuberculous mycobacteria.

BCG Vaccine↗
PubMed2000

Impairment of STAT activation by IL-12 in a patient with atypical mycobacterial and staphylococcal infections.

IL-12 plays a pivotal role in the stimulation of immune responses against intracellular infections. This role is manifested in the increased susceptibility to atypical mycobacterial and salmonella infections among individuals whose lymphocytes lack expression of IL-12Rbeta1. Here, we report on a patient with Mycobacterium avium infection, recurrent Staphylococcus aureus sinusitis, and multiple adverse drug reactions whose T cells were unable to produce IFN-gamma or proliferate in response to IL-12 despite the expression of wild-type IL-12Rbeta1 and IL-12Rbeta2. The defect in these functional responses to IL-12 was selective, as cytolytic activity induced by IL-12 was intact, and lymphocytes were responsive to stimulation by IL-2. An examination of cytokine signaling revealed that STAT4 and extracellular regulated kinase 1 (ERK1) activation by IL-12 was intact, whereas the activation of STAT1, -3, and -5 by IL-12 was lost. This impairment of STAT activation was specific for IL-12, as STAT activation by IL-2, IL-15, and IFN-gamma was unaffected. These findings demonstrate that the activation of STAT4 alone is not sufficient for IL-12-induced IFN-gamma production and proliferation and suggest that other STATs play a role in these responses to IL-12. While the etiology of the impaired IL-12 signaling in this patient has not yet been elucidated, the absence of mutations in IL-12Rbeta1 or IL-12Rbeta2 and the preservation of STAT4 activation raise the possibility that there may be a mutation in an as yet undiscovered component of the IL-12 signaling complex that is normally required for the recruitment and activation of STAT1, -3, and -5.

Child, Preschool↗
PubMed2000

A novel missense mutation (C30S) in the gene encoding tumor necrosis factor receptor 1 linked to autosomal-dominant recurrent fever with localized myositis in a French family.

OBJECTIVE: To characterize both phenotypic (clinical features and magnetic resonance imaging [MRI] findings) and genotypic aspects of autosomal-dominant recurrent fever, also known as tumor necrosis factor receptor (TNFR)-associated periodic syndrome (TRAPS), in a French family and to investigate the role of the mutated 55-kd tumor necrosis factor alpha (TNFalpha) receptor (TNFR1) in the pathogenesis of the disease. METHODS: The coding region of TNFR1 was sequenced in 2 individuals with TRAPS (the propositus and her grandfather) and in 3 clinically unaffected relatives. Expression of soluble TNFR1 (sTNFR1) was investigated in 3 of the family members carrying a C30S mutation in TNFR1, and was compared with the levels of soluble TNFR2 (sTNFR2) by enzyme-linked immunosorbent assay. The membrane TNFR1 expression was then compared with membrane TNFR2 levels at the surface of peripheral blood mononuclear cells by flow cytometric analysis. The clinical heterogeneity in this French family was investigated by searching polymorphic variants in the TNFalpha promoter by DNA sequencing. RESULTS: Both the disease course and the clinical presentation in the propositus were highly indicative of TRAPS. MRI study of the segmental inflammatory process in the limbs showed abnormal signals in the muscle and subcutaneous tissue without involvement of adjacent joints or fascia. A novel missense mutation, C30S, in the first extracellular N-terminal cysteine-rich domain (CRD1) of TNFR1 was characterized in the propositus, her affected grandfather, and her clinically unaffected father. Expression of membrane TNFR1 at the surface of monocytes and polymorphonuclear leukocytes, as well as the levels of sTNFR1 in serum when the disease was not active were not modified in the 3 individuals carrying the TNFR1 C30S mutation. In contrast, during attacks, sTNFR1 levels remained abnormally low, as compared with the levels in unrelated patients with active adult-onset systemic Still's disease. The clinical heterogeneity could not be explained by a polymorphic variant in the TNFalpha promoter. CONCLUSION: TRAPS is a distinct clinical and radiologic disease entity that is responsible for recurrent fever and migratory cellulitis-like processes with localized myositis. We have identified a novel TNFR1 mutation, C30S, that is located in the CRD1 domain in a French family affected by the disease. This mutation seems to affect the level of sTNFR1, which did not increase in the propositus during inflammatory attacks.

Adolescent↗
PubMed2000

Human interferon-gamma-mediated immunity is a genetically controlled continuous trait that determines the outcome of mycobacterial invasion.

Individuals with inherited disorders of interferon gamma (IFN-gamma)-mediated immunity appear to be specifically vulnerable to mycobacterial infections. The severity of clinical features of affected individuals differs between cases. Some patients die of mycobacterial infection in early childhood, whereas others have long asymptomatic periods in childhood and as adults. This rare syndrome also shows high allelic and non-allelic genetic heterogeneity. Mutations in IL12B, encoding the interleukin (IL)-12 p40 subunit, and in IL12RB1, encoding the beta1 chain of the IL-12 receptor, result in impaired IFN-gamma production. Mutations in IFNGR1 and IFNGR2, encoding the two IFN-gamma receptor chains, and mutations in STAT1, encoding an essential signaling component, result in impaired cellular responses to IFN gamma. Different types of mutation define two types of complete and two types of partial IFNgammaR1 deficiency. Complete and partial IFNgammaR2 deficiency have also been described. We herein compare the genotypes, cellular phenotypes, and clinical phenotypes of healthy individuals and patients with the seven known genetic disorders impairing cellular responses to IFN-gamma. Patients with defective IFN-gamma production were not considered in this study. The mutations and clinical features of patients with IFNgammaR1, IFNgammaR2, and STAT-1 deficiency are reviewed. Selected cell lines from each of the eight groups were tested for their response to IFN-gamma. We find that individuals may be classified into four broad groups based on genotype, cellular phenotype, and clinical phenotype (normal individuals and patients with mild, intermediate, or severe disease). This correlation suggests that IFN-gamma-mediated cell activation is a genetically controlled quantitative trait and that it determines the outcome of mycobacterial invasion in man.

Adult↗
PubMed2000

Morphological and functional characteristics of patent foramen ovale and their embolic implications.

BACKGROUND AND PURPOSE: Transesophageal echocardiography (TEE) has detected a high prevalence of patent foramen ovale (PFO) in stroke patients, but the clinical implications of the distinctive characteristics of this patency are still a matter of debate. METHODS: We studied 350 patients with acute ischemic stroke or transient ischemic attack (TIA) within 1 week of admission. Of these, 101 (29%) were identified by contrast TEE to have a PFO; 86 patients (25%) were cryptogenic stroke patients, and 163 were excluded because of the presence of a definite or possible arterial or clinical evidence of a source of emboli or small-vessel disease. Thirteen PFO subjects without a history of embolism were designated as the control group. All PFO and cryptogenic stroke patients were followed up by neurological visits. RESULTS: Compared with controls, PFO patients with acute stroke or TIA more frequently presented with a right-to-left shunt at rest and a higher membrane mobility (P:<0. 05). Patients with these characteristics were considered to be at high risk. During a median follow-up period of 31 months (range, 4 to 58 months), 8 PFO and 18 cryptogenic stroke patients experienced recurrent cerebrovascular events. The cumulative estimate of risk of cerebrovascular event recurrence at 3 years was 4.3% (95% confidence interval [CI], 0% to 10.2%) for "low-risk" PFO patients, 12.5% (95% CI, 0% to 26.1%) for "high-risk" PFO patients, and 16.3% (95% CI, 7. 2% to 25.4%) for cryptogenic stroke patients (high-risk PFO versus low-risk PFO, P:=0.05). CONCLUSIONS: The association of right-to-left shunting at rest and high membrane mobility, as detected by contrast TEE, seems to identify PFO patients with cerebrovascular ischemic events who are at higher risk for recurrent brain embolism.

Aorta↗