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The role and function of the otolith organs might well hold continuing interest for those studying cochlear mechanics. The otoliths, utricle, saccule (and lagena in birds) are intriguing, not just because of their role in the evolutionary origins of inner ear function, but because, in mammals, their membranous structures are contained within the bony vestibule, directly in line with the action of the stapes[1]. Intriguingly they display highly-organised morphology[2]; [3]) and offer an apparently redundant low-frequency channel[4]. This duplication is puzzling considering cochlear low-frequency reception is generally less vulnerable than high. Unexplained is how pressures within the labyrinth are regulated[5]. A hypothesis is developed that the saccule’s low-frequency pressure sensitivity may represent another function entirely, connected with the mechanics of cochlear homeostasis. A mathematical model is presented to illustrate how the otoliths may have two orthogonal modes, sensing otolith shear in differential mode, but sensing ambient pressure in common mode.

The MHC class Ib molecule HLA-G has previously been reported to be the ligand for the NK cell receptor killer Ig-like receptor (KIR)2DL4, but this remains controversial. In this study, we investigated IFN-γ production by freshly isolated NK cells in response to both soluble and solid-phase ligands, including anti-KIR2DL4 mAbs and rHLA-G. Although freshly isolated CD56bright NK cells produced IFN-γ in response to soluble HLA-G preparations, the response was found to be absolutely dependent on the presence of small numbers of contaminating CD56−, CD14−, CD11c+ myeloid dendritic cells (mDCs). HLA-G tetramers bound only to the contaminating mDCs in the NK preparations, and Abs to KIR2DL4 and HLA-G did not block NK cell IFN-γ production. NK cells did not respond to plate-bound HLA-G. Freshly isolated NK cells also produced IFN-γ in response to unpurified soluble anti-KIR2DL4 mAb but not to low endotoxin affinity–purified Ab. The data suggest that previous reports of functional interactions between KIR2DL4 and HLA-G may have resulted from the use of purified NK cells that were contaminated with mDCs and HLA-G preparations that were contaminated with material capable of stimulating mDCs to produce cytokines that stimulate NK cells to produce IFN-γ.

Resume Propos Depuis dix ans, plus de 1000 patients souffrant de maladies auto-immunes severes ont beneficie d’une autogreffe de cellules souches peripheriques. Cette therapeutique innovante a ete utilisee chez des patients souffrant de sclerodermie, de sclerose en plaque, de polyarthrite rhumatoide, d’arthrite chronique juvenile et de lupus erythemateux dissemine. Points forts L’autogreffe de cellules souches hematopoietique est devenue une alternative therapeutique dans le traitement de certaines maladies auto-immunes de mauvais pronostic. Cette revue, resume l’experience des essais de phase I et II conduits en Europe et aux Etats-Unis, en decrit les resultats et les limites. Perspectives et projets L’autogreffe de cellules souches hematopoietiques dans le traitement des maladies auto-immunes a evolue du stade de concept experimental, a la demonstration de sa faisabilite chez des patients selectionnes souffrant de formes severes de maladies auto-immunes.

Resume La maladie de Horton est la plus frequente des vascularites. Elle peut se compliquer par des accidents cardiovasculaires (infarctus du myocarde, accidents vasculaires cerebraux), mais leur incidence reelle et leur risque relatif par rapport a la population generale sont inconnus. Objectif. – Evaluer l'incidence des accidents cardiovasculaires dans une etude en double cohorte prospective de patients avec maladie de Horton par rapport a des temoins, apres ajustement sur les facteurs de risque cardiovasculaire. Patients et methodes. – Quatre cent trente-deux patients nouvellement diagnostiques ont ete inclus sur des criteres preetablis, et apparies par âge et par sexe a des temoins tires au sort dans la population generale. Les facteurs de risque cardiovasculaire majeurs etaient mesures a l'inclusion : tabagisme, maladie atheromateuse, diabete, hypertension arterielle, hypercholesterolemie. Les cas et les temoins ont ete suivis pendant 24 mois avec recueil de la survenue d'accidents cardiovasculaires : infarctus du myocarde, angor, accidents vasculaires cerebraux constitues ou transitoires, arteriopathie obliterante des membres inferieurs. La survenue d'accidents cardiovasculaires au cours du temps a ete etudiee en analyse univariee par un test du log-rank apres stratification sur les facteurs de risque cardiovasculaire et en analyse multivariee par un modele de survie parametrique. Resultats. – Les accidents cardiovasculaires sont globalement plus frequents chez les cas que chez les temoins (RR = 2,15 [1,21–3,81], p = 0,009) ; ils sont lies a l'âge (p = 0,0001), aux antecedents d'accidents cardiovasculaires (p = 0,023) et a la maladie de Horton (p = 0,009). Pris separement, les accidents neurologiques (RR = 2,42 [0,84–7]) et les accidents cardiaques (RR = 1,67 [0,72–3,89]) sont plus frequents sans que les ecarts soient cependant significatifs. Conclusion. – La mise en evidence d'un surrisque d'accidents cardiovasculaires en cas de maladie de Horton doit faire discuter l'adjonction d'un traitement antiagregant preventif au long cours.

Serum ferritin levels may be increased in many conditions: renal diseases, liver diseases, human immunodeficiency virus infection. The purpose of this study was to assess the aetiological spectrum of high serum ferritin levels in a 1200-bed university hospital, to compare our results with the data already published and to assess a potential association between aetiology and ferritin levels. Patients and methods. – Patients with a serum ferritin level higher than 600 μg/l were retrospectively included between 15 November 2003 and 15 January 2004, and their medical records were reviewed. Results. – Ninety-eight patients (38 women and 60 men; median age: 59,5 years [19–92]) were recruited in departments of hepatology and gastroenterology (22%), haematology (14%) and internal medicine (18%). Diagnosis performed were: non-HIV systemic infections (23,8%), haematological diseases (16,1%), alcoholism (11,2%) and malignancies (9,8%). Dialysed chronic renal failure, liver diseases, haemochromatosis and systemic inflammatory diseases counted for 4.2 to 5.2% of cases. Serum ferritin level lied between 600 and 1000 μg/l for 50 patients, between 1000 and 1500 μg/l for 24, and over 1500 μg/l for 24. There was no significant difference between the three groups as regards the etiological distribution. Discussion. – In our study, chronic renal failure was not a major cause of high ferritin level: this is probably due to the current use of erythropoietin, which has decreased the use of blood transfusions. The two major aetiology of hyperferritinemia were non-HIV infections and malignancies.

Dr. Long’s assertion that killer Ig-like receptor (KIR)2DL4 is not detectable at the cell surface is misleading. KIR2DL4 is not detectable on the membrane of resting CD56dim NK cells. However, we and others ([1][1]) have demonstrated surface expression of KIR2DL4 on freshly isolated CD56bright NK

Although insulin-like growth factor-binding protein (IGFBP)-3 and IGFBP-5 are known to modulate cell growth by reversibly sequestering extracellular insulin-like growth factors, several reports have suggested that IGFBP-3, and possibly also IGFBP-5, have important insulin-like growth factor-independent effects on cell growth. These effects may be related to the putative nuclear actions of IGFBP-3 and IGFBP-5, which we have recently shown are transported to the nuclei of T47D breast cancer cells. We now describe the mechanism for nuclear import of IGFBP-3 and IGFBP-5. In digitonin-permeabilized cells, where the nuclear envelope remained intact, nuclear translocation of wild-type IGFBP-3 appears to occur by a nuclear localization sequence (NLS)-dependent pathway mediated principally by the importin beta nuclear transport factor and requiring both ATP and GTP hydrolysis. Under identical conditions, an NLS mutant form of IGFBP-3, IGFBP-3[(228)KGRKR --MDGEA], was unable to translocate to the nucleus. In cells where both the plasma membrane and nuclear envelope were permeabilized, wild-type IGFBP-3, but not the mutant form, accumulated in the nucleus, implying that the NLS was also involved in mediating binding to nuclear components. By fusing wild-type and mutant forms of NLS sequences (IGFBP-3 [215-232] and IGFBP-5 [201-218]) to the green fluorescent protein, we identified the critical residues of the NLS necessary and sufficient for nuclear accumulation. Using a Western ligand binding assay, wild-type IGFBP-3 and IGFBP-5, but not an NLS mutant form of IGFBP-3, were shown to be recognized by importin beta and the alpha/beta heterodimer but only poorly by importin alpha. Together these results suggest that the NLSs within the C-terminal domain of IGFBP-3 and IGFBP-5 are required for importin-beta-dependent nuclear uptake and probably also accumulation through mediating binding to nuclear components.

Resume Propos. – L'article aborde la hierarchie des etudes analytiques, en partant des etudes d'observation pour arriver aux etudes experimentales. Actualites et points forts. – Les etudes cas-temoins, les plus frequentes parmi les etudes analytiques, peuvent servir a generer ou a confirmer des hypotheses. Elles conviennent particulierement pour les maladies rares. Les etudes de cohorte servent a confirmer des hypotheses prealablement testees et a mesurer l'amplitude d'un effet. La randomisation a pour but en principe d'eliminer les facteurs confondants, et la meta-analyse, de diminuer les biais de selection et d'augmenter la puissance. Ces buts peuvent ne pas etre atteints. Perspectives et projets. – La puissance d'une etude, ou l'erreur beta, sont des notions majeures a determiner lors de la construction de l'etude avant tout debut de realisation.

Resume Propos. – Cet article decrit rapidement la hierarchie entre les principales etudes cliniques descriptives, avec leurs forces et faiblesses respectives. Actualites et points forts. – Sont abordes successivement les cas rapportes et les series de cas, qui ont ete tres utiles pour la reconnaissance des pathologies et l'etablissement de la nosologie, mais ne possedent pas de groupes temoins, les etudes ecologiques, generatrices d'hypotheses sur des groupes ou populations, n'approchant pas l'individu, et les etudes de prevalence a simple ou double question, qui approchent l'individu dans un groupe mais peuvent amener a des conclusions trompeuses des lors que la notion de facteur de risque est abordee. Perspectives et projets. – La description de ces etudes permet d'aborder la notion de facteur confondant, a laquelle les etudes analytiques permettent de mieux repondre.

Human leukocyte antigen (HLA)-G is upregulated on the bronchial epithelium of asthma patients and genetic polymorphism affecting expression of HLA-G has been reported to influence susceptibility to asthma. As the NK cell receptor KIR2DL4 has been reported to induce interferon gamma (IFNγ) secretion when ligated with HLA-G, we postulated that the 9A/10A genetic polymorphism of KIR2DL4 which influences receptor structure may influence susceptibility to asthma. KIR2DL4 genotypes were determined in two cohorts of children (n = 219 and n = 1356) in whom total serum IgE, allergen-specific IgE, atopy, bronchial reactivity and asthma symptoms had been studied between birth and 14 years. No reproducible associations with KIR2DL4 genotype were identified, leading us to conclude that the KIR2DL4 9A/10A polymorphism has no influence on susceptibility to asthma.

Human leukocyte antigen (HLA)-G is upregulated on the bronchial epithelium of asthma patients and genetic polymorphism affecting expression of HLA-G has been reported to influence susceptibility to asthma. As the NK cell receptor KIR2DL4 has been reported to induce interferon gamma (IFNγ) secretion when ligated with HLA-G, we postulated that the 9A/10A genetic polymorphism of KIR2DL4 which influences receptor structure may influence susceptibility to asthma. KIR2DL4 genotypes were determined in two cohorts of children (n = 219 and n = 1356) in whom total serum IgE, allergen-specific IgE, atopy, bronchial reactivity and asthma symptoms had been studied between birth and 14 years. No reproducible associations with KIR2DL4 genotype were identified, leading us to conclude that the KIR2DL4 9A/10A polymorphism has no influence on susceptibility to asthma.

We describe a case of indolent vascular prosthesis infection due to Propionibacterium acnes. The microorganism was identified only by amplification and sequencing of 16S rDNA, while standard cultures remained negative. This observation underscores the usefulness of molecular techniques for the diagnosis of infection caused by fastidious microorganisms.

Summary Background Systematic screening for liver fibrosis in heavy-drinking patients is a challenge. Aims To assess Fibroscan for non-invasive diagnosis of asymptomatic liver fibrosis in alcohol abuse patients, to determine diagnostic liver stiffness cut-off values and to compare performance of Fibroscan with seven non-invasive laboratory tests. Methods One hundred and three alcoholic patients were studied. Liver fibrosis was staged by METAVIR system. Fibroscan, Fibrotest, Fibrometer, Hepascore, APRI, PGA, PGAA and hyaluronic acid tests were performed. Liver stiffness cut-offs were determined using receiver-operating characteristic (ROC) curves. Results Liver stiffness was correlated with fibrosis (r = 0.72, P

During the past ten years, more than 1000 patients suffering from severe autoimmune disease have received an autologous haematopoietic stem cell transplant. These new therapeutic have been used in systemic sclerosis (scleroderma), multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis and systemic lupus erythematosus.Autologous haematopoietic stem cell transplantation has become a curative option for condition with very poor prognosis as severe systemic sclerosis, lupus erythematosus or other systemic diseases. This review summarizes the current experience in the phase I and II clinical trials in Europe and North America. We describe the main results and the limits of stem cell transplantation in systemic diseases.Autologous haematopoietic stem cell transplant in the treatment of autoimmune disease has evolved from a experimental concept to a clinically feasible and powerful therapy for selected patients with severe disease.

Giant cell arteritis is the most frequent vasculitis. Cardiovascular events such as cerebrovascular accident or ischemic heart disease may occur in patients with giant cell arteritis. However, their real incidence, as well as their relative risk compared to the general population, remains unknown.To assess in a prospective, double cohort study, the incidence of cardiovascular events in giant cell arteritis patients compared to controls, after controlling for cardiovascular risk factors.We included on predefined criteria 432 newly diagnosed patients with giant cell arteritis, each assigned to sex- and age-matched controls randomly selected from the general population. Cardiovascular risk factors (high-blood pressure, diabetes, smoking, hypercholesterolemia and preexisting peripheral vascular disease) were collected at inclusion. During the 24-month follow-up, all cardiovascular events were collected. After stratification for cardiovascular risk factors, a log-rank test was performed to compare cases and controls. A parametric survival model was used for multivariate analysis.Cardiovascular events all combined were significantly increased in patients with giant cell arteritis (RR = 2.15 [1.21-3.81], P = 0.009), and were mainly associated with age (P = 0.0001), past history of cardiovascular disease (P = 0.023) but also with giant cell arteritis (P = 0.009). However, each subset of cerebrovascular accident (RR = 2.42 [0.84-7]) or ischemic heart disease (RR = 1.67 [0.72-3.89]) increased but did not significantly.Cardiovascular events incidence is increased in patients with giant cell arteritis, and prescription of preventive antiagregant treatment may be discussed.

This paper describes the hierarchy of analytical studies, from the observational studies to the experimental ones.Case-control studies, the most frequently performed among analytical studies, may generate or confirm hypotheses. They are of particular use for rare diseases. Cohort studies aim mainly at confirming hypotheses already tested, and at precisely quantifying the magnitude of effect. Randomisation aims at the elimination of confounding factors, and meta-analysis, at decreasing potential selection biases and increasing power. Those goals may not always be achieved. PERSPECTIVES AND PROJETS: The study power, or the beta error, are major factors to be determined when designing a study, before any attempt of realization.

This paper provides an overview of the hierarchy between the main descriptives clinical studies, with their respective weaknesses and strength.Case-reports and case-series are first described, which do not provide control groups but have been very useful in disease recognition and nosology building. Ecological studies, which are hypothesis generating at the group or population level, but which do not study individuals, and prevalence studies with one simple or a double question, which study individuals within groups but may lead to erroneous conclusions so far are risk factors are involved, are then reviewed.The overview of the descriptive studies leads to the notion of confounding factor, which may be better addressed by analytical studies.

Supramaximal stimulation of isolated pancreatic acini with specific agonists such as CCK induces the formation of large basolateral blebs, redistributes filamentous actin, and inhibits secretion. Rho family small G proteins are well documented for their function in actin reorganization that determines cell shape and have been suggested to play a role in secretion. Here, we determined whether Rho and Rac are involved in the morphological changes, actin redistribution, and inhibition of amylase secretion induced by high concentrations of CCK. Introduction of constitutively active RhoV14 and RacV12 but not Cdc42V12 in mouse pancreatic acini by adenoviral vectors stimulated acinar morphological changes including basolateral protrusions, increased the total amount of F-actin, and reorganized the actin cytoskeleton. Dominant-negative RhoN19, Clostridium botulinum C3 exotoxin, which inhibits Rho, and dominant-negative RacN17 all partially blocked CCK-induced acinar morphological changes and actin redistribution. To study the correlation between actin polymerization and acinar shape changes, two marine toxins were employed. Jasplakinolide, a reagent that facilitates actin polymerization and stabilizes F-actin, stimulated acinar basolateral protrusions, whereas latrunculin, which sequesters actin monomers, blocked CCK-induced acinar blebbing. Unexpectedly, RhoV14, RacV12, and jasplakinolide all increased amylase secretion by CCK from 30 pM to 10 nM. The data suggest that Rho and Rac are involved in CCK-evoked changes in acinar morphology, actin redistribution, and secretion and that inhibition of secretion by high concentrations of CCK is not directly coupled to the changes in acinar morphology.

Serum ferritin levels may be increased in many conditions: renal diseases, liver diseases, human immunodeficiency virus infection. The purpose of this study was to assess the aetiological spectrum of high serum ferritin levels in a 1200-bed university hospital, to compare our results with the data already published and to assess a potential association between aetiology and ferritin levels.Patients with a serum ferritin level higher than 600 microg/l were retrospectively included between 15 November 2003 and 15 January 2004, and their medical records were reviewed.Ninety-eight patients (38 women and 60 men; median age: 59,5 years [19-92]) were recruited in departments of hepatology and gastroenterology (22%), haematology (14%) and internal medicine (18%). Diagnosis performed were: non-HIV systemic infections (23,8%), haematological diseases (16,1%), alcoholism (11,2%) and malignancies (9,8%). Dialysed chronic renal failure, liver diseases, haemochromatosis and systemic inflammatory diseases counted for 4.2 to 5.2% of cases. Serum ferritin level lied between 600 and 1000 microg/l for 50 patients, between 1000 and 1500 microg/l for 24, and over 1500 microg/l for 24. There was no significant difference between the three groups as regards the etiological distribution.In our study, chronic renal failure was not a major cause of high ferritin level: this is probably due to the current use of erythropoietin, which has decreased the use of blood transfusions. The two major aetiology of hyperferritinemia were non-HIV infections and malignancies.

The overprevalence of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) in women remains unexplained. Microchimerism pathogenicity has been discussed in some systemic diseases. We tested history of pregnancy as a risk factor for GCA.Prospective, multicenter case-control study with multiple, age-matched, control groups. Patients have been included in 40 different centers. The first control group has been randomly selected in the general population, consecutive hospitalized patients in two geographically distant departments of internal medicine made up the second and third ones.Three hundred and fifteen patients (249 GCA and 66 PMR), 242 general population controls, 333 in the first hospitalized control group, and 355 in the second, have been included in the 1991-1998 period. Pregnancy has been constantly protective against GCA/PMR (Wilcoxon rank sum test: P = 0.0001, 0.0005, and 0.054, respectively, for the three control groups), more particularly for parity equal or greater than 4 (OR = 0.32, 95% CI: 0.18-0.57, P = 0.00003; OR = 0.44, 95% CI: 0.26-0.74; P = 0.0009, and OR = 0.42; 95% CI: 0.25-0.71, P = 0.0006, respectively). In multivariate analysis, risk for GCA on pre-existing degenerative, vascular disease is decreased by half for each pregnancy (OR = 0.49, 95% CI = 0.27-0.90, P = 0.022).Contrary to the initial hypothesis, multiparity is a protective factor against GCA. Mechanism is unknown.