A dynamical measure of the black hole mass in a quasar 11 billion years ago.

Tight relationships exist in the local Universe between the central stellar properties of galaxies and the mass of their supermassive black hole (SMBH)1-3. These suggest that galaxies and black holes co-evolve, with the main regulation mechanism being energetic feedback from accretion onto the black hole during its quasar phase4-6. A crucial question is how the relationship between black holes and galaxies evolves with time; a key epoch to examine this relationship is at the peaks of star formation and black hole growth 8-12 billion years ago (redshifts 1-3)7. Here we report a dynamical measurement of the mass of the black hole in a luminous quasar at a redshift of 2, with a look back in time of 11 billion years, by spatially resolving the broad-line region (BLR). We detect a 40-µas (0.31-pc) spatial offset between the red and blue photocentres of the Hα line that traces the velocity gradient of a rotating BLR. The flux and differential phase spectra are well reproduced by a thick, moderately inclined disk of gas clouds within the sphere of influence of a central black hole with a mass of 3.2 × 108 solar masses. Molecular gas data reveal a dynamical mass for the host galaxy of 6 × 1011 solar masses, which indicates an undermassive black hole accreting at a super-Eddington rate. This suggests a host galaxy that grew faster than the SMBH, indicating a delay between galaxy and black hole formation for some systems.

Systematic Evaluation of Benchmark G4 Probes and G4 Clinical Drugs using three Biophysical Methods: A Guideline to Evaluate Rapidly G4-Binding Affinity.

G-quadruplex DNA structures (G4) are proven to interfere with most genetic and epigenetic processes. Small molecules binding these structures (G4 ligands) are invaluable tools to probe G4-biology and address G4-druggability in various diseases (cancer, viral infections). However, the large number of reported G4 ligands (>1000) could lead to confusion while selecting one for a given application. Herein we conducted a systematic affinity ranking of 11 popular G4 ligands vs 5 classical G4 sequences using FRET-melting, G4-FID assays and SPR. Interestingly SPR data globally align with the rankings obtained from the two semi-quantitative assays despite discrepancies due to limits and characteristics of each assay. In the whole, PhenDC3 emerges as the most potent binder irrespective of the G4 sequence. Immediately below PDS, PDC-360A, BRACO19, TMPyP4 and RHPS4 feature strong to medium binding again with poor G4 topology discrimination. More strikingly, the G4 drugs Quarfloxin, CX5461 and c-PDS exhibit weak affinity with all G4s studied. Finally, NMM and Cu-ttpy showed heterogeneous behaviors due, in part, to their physicochemical particularities poorly compatible with screening conditions. The remarkable properties of PhenDC3 led us to propose its use for benchmarking FRET-melting and G4-FID assays for rapid G4-affinity evaluation of newly developed ligands.

Negative SPR Signals during Low Molecular Weight Analyte Recognition.

Surface plasmon resonance (SPR) is a powerful technique for studying biomolecular interactions mainly due to its sensitivity and real-time and label free advantages. While SPR signals are usually positive, only a few studies have reported sensorgrams with negative signals. The aim of the present work is to investigate and to explain the observation of negative SPR signals with the hypothesis that it reflects major changes in ligand conformation resulting from target binding. We demonstrated that these negative unconventional signals were due to the negative complex (ligand/analyte) refractive index increment (RII) deviation from the sum of the RII of the individual entities which counterbalanced the theoretical increase of the signal triggered by the target recognition and the ligand folding. We also found that the conformation change of biomolecules can induce a negative or a positive complex RII deviation depending on its sequence and immobilization mode.

Surface plasmon resonance study of the interaction of N-methyl mesoporphyrin IX with G-quadruplex DNA.

Surface plasmon resonance (SPR) was used to investigate the interaction between N-methyl mesoporphyrin IX (NMM) and different G-quadruplex (G4) topologies. The study was associated with circular dichroism analysis (CD) to assess the topology of the G4s when they interacted with NMM. We demonstrate the high selectivity of NMM for the parallel G4 structure with a dissociation constant at least ten times lower than those of other G4 topologies. We also confirm the ability of NMM to shift the G4 conformation from both the hybrid and antiparallel topologies toward the parallel structure.

Influence of the SPR Experimental Conditions on the G-Quadruplex DNA Recognition by Porphyrin Derivatives.

Surface plasmon resonance (SPR) is a powerful technique to study the interactions of ligands with analytes and therefore a number of biosensor surfaces and injection methods have been developed so far. However, many experimental parameters can affect the interactions and consequently the affinity measurements. In particular, the interactions of positively charged analytes (often used for anionic nucleic acids targets) can be influenced by the sensing surfaces (e.g., negatively charged), leading to significant nonspecific interactions as well as regeneration problems. The aim of the present work is to investigate the effect of different parameters, including ionic strength, SPR biosensor (i.e., nature of the surfaces), and the injection method on the recognition of porphyrin G-quadruplex ligands. We demonstrate that the injection method does not influence the affinity whereas the ionic strength and the nature of the surface impact the recognition properties of the porphyrin for the G-quadruplex DNA. We also found that self-assembled monolayer coating surface presents many advantages in comparison with carboxymethylated dextran surface for SPR studies of G-quadruplex DNA/ligand interactions: (i) the electrostatic interaction with charged analytes is less important, (ii) its structure/composition is less sensitive to the ionic concentration and less prone to unspecific adsorption, (iii) it is easily homemade, and (iv) the cost is approximately 10 times cheaper.

In vitro biocompatibility of a dentine substitute cement on human MG63 osteoblasts cells: Biodentine™ versus MTA(®).

AIM: To compare the in vitro biocompatibility of Biodentine™ and White ProRoot(®) mineral trioxide aggregate (MTA(®) ) with MG63 osteoblast-like cells and to characterize the cement surface. METHODOLOGY: A direct contact model for MG63 osteoblast-like cells with cements was used for 1, 3 and 5 days. Four end-points were investigated: (i) cement surface characterization by atomic force microscopy (AFM), (ii) cell viability by MTT assay, (iii) protein amount quantification by Bradford assay and (iv) cell morphology by SEM. Statistical analyses were performed by analysis of variance (anova) with a repetition test method. RESULTS: The roughness of the cements was comparable as revealed by AFM analysis. The MTT test for Biodentine™ was similar to that of MTA(®) . Biodentine™ and MTA(®) induced a similar but slight decrease in metabolic activity. The amount of total protein was significantly enhanced at day three (P < 0.05) but slightly decreased at day five for both tested samples. Biodentine™ was tolerated as well as MTA(®) in all cytotoxicity assays. SEM observations showed improvement of cell attachment and proliferation on both material surfaces following the three incubation periods. CONCLUSION: The biocompatibility of Biodentine™ to bone cells was comparable to MTA(®) .

[Granulomatous hepatitis revealing a Mycobacterium bovis widespread infection following intravesical BCG therapy]. / Hépatite granulomateuse révélant une infection disséminée à Mycobacterium bovis après BCG-thérapie intravésicale.

INTRODUCTION: Intravesical therapy with bacillus Calmette-Guérin (BCG) has proved to be effective in the treatment of superficial bladder tumors. Side-effects include local infections and rarely disseminated BCG infection with multiple end organ complications such as granulomatous hepatitis, pneumonitis, aortitis and bone marrow involvement. CASE REPORT: We report an 83-year-old man who presented with chronic granulomatous hepatitis. This was related to intravesical BCG therapy received two years earlier for superficial bladder cancer. Aortitis, splenic infarction and hematopoietic involvement were also diagnosed. Outcome was favorable following adapted antibiotic course. CONCLUSION: This case report highlights the possibility of widespread BCG infection following intravesical treatment, and the need for vigilance in patients with a history of such a therapy even several years later.

Fibroblast growth factor-2 (FGF-2) in the nucleus: translocation process and targets.

FGF-2 (basic fibroblast growth factor) was recently detected in the nucleus of a variety of cell types. The large isoforms contain a functional nuclear localization signal that allows their nuclear accumulation in producing cells, while a small amount of FGF-2 added exogenously to target cells is translocated to the nucleus in phase G1 of the cell cycle according to an unknown process. We report here using Chinese hamster ovary cell mutants bearing deficiency in heparan sulfate proteoglycans (HSPGs) synthesis that HSPGs are required for transport of exogenous FGF-2 to the nucleus. Furthermore a co-transport was suggested since an active complex containing FGF-2 and HSPGs was isolated from nuclei of treated cells. Several FGF-2 nuclear targets were described. In vivo as in vitro, it activates rDNA transcription and it binds to a specific DNA sequence that is present in the non-transcribed spacer of ribosomal genes. In vitro, FGF-2 has a strong affinity for histone H1 and it activates the protein kinase CKII. In the nucleus FGF-2 could regulate gene expression through modulation of chromatin structure.

Double-blind trial of amineptine and clomipramine in the treatment of depression.

A double-blind trial was carried out in 62 depressed patients to compare the clinical efficacy and acceptability of amineptine and clomipramine. Patients were allocated at random to one or other of two treatment groups and received daily doses of amineptine ranging from 100 to 300 mg (mean 180 mg) or of clomipramine ranging from 50 to 150 mg (mean 84 mg) over a period of 6 weeks. Global assessment of response to treatment and Hamilton Rating Scale scores, assessed before and after 1,3 and 6 weeks of treatment, indicated that the two drugs appeared to be equally effective and no differences between them could be demonstrated in the analysis of the individual items or grouped items of the scale used. Measurements of ocular tone showed that there was significantly less risk of amineptine producing an increase in tone, and blood pressure and electrocardiographic investigations also underlined the greater cardiovascular tolerance of amineptine. Five (16%) of the 32 patients in the clomipramine group were withdrawn from the study because of adverse effects.

The design of original antimalarial drugs. An example of phospholipid metabolism.

The aim of our program was to find an original chemotherapeutical treatment (and eventually a preventive treatment) of malaria, an illness largely predominant in developing countries, by interfering on an essential metabolism developed by Plasmodium during its erythrocytic phase. Apart from what has been learnt about metabolism and the pharmacological target, a crucial step has been taken during this contract by passing from micromolar in vitro active concentrations (during 1986-1990) to nanomolar ones (during 1990). These compounds should naturally short-circuit resistance phenomena already established against drugs in current use, as has already been verified on polypharmacoresistant strains or isolates of P. falciparum. The administration of a therapeutic dose of our molecules would now appear to be possible in all cases.

[So-called uremic heart diseases]. / Les cardiopathies dites urémiques.

The overall cardiovascular mortality in patients with chronic renal failure is about 30 per cent of which 10 per cent is attributed to myocardial infarction. This prevalence led some workers to propose a hypothesis of "accelerated atherosclerosis" due to the hyperlipidaemia observed in 30 to 70 per cent of patients. However, the concept of accelerated atherosclerosis, which was based essentially on clinical studies, has been questioned. Pericardial effusion is a common complication of chronic renal failure and has been reported in over 62 per cent of patients in echocardiographic studies. There are many causes and symptoms are often mild; systematic echocardiographic examination of patients with renal failure undergoing haemodialysis has shown 32 per cent of pericardial effusions to be asymptomatic. There are two potential complications: cardiac tamponade and, lesser frequently, constrictive pericarditis. Cardiac failure is a common cause of death in patients undergoing long-term dialysis. The myocardial histological appearances are those of fibrosis, the etiology of which is not fully understood although the dialysis membranes and hypotensive episodes occurring during haemodialysis have been thought to play a role. Left ventricular hypertrophy and fibrosis may give rise to ventricular arrhythmias which could explain some of the cases of sudden death observed in patients with renal failure and often wrongly attributed to ischemic heart disease. Another form of myocardial disease which is observed later is characterised by an alteration of systolic function with left ventricular dilatation and hypokinesia and increased end diastolic pressures without an increase in left ventricular wall thickness. Valvular heart disease may also result from renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

[Transient reduction of ventricular tachycardia with adenosine-5'-triphosphate. A possible action of ATP on purinergic receptors]. / Réduction transitoire d'une tachycardie ventriculaire par l'adénosine-5'-triphosphate. Action possible de l'ATP sur les récepteurs purinergiques.

The authors report the case of a 46 year old man in whom a regular, wide complex tachycardia was terminated temporarily by the injection of adenosine-5'-triphosphate (ATP:Striadyne); endocavitary electrophysiological studies showed the tachycardia to be of ventricular origin. After aminophylline, an inhibitor of certain purinergic receptors, the tachycardia could be reproduced at will and was sustained whereas only short runs of tachycardia could be induced under basal conditions. The mode of action of the ATP on this type of tachycardia could be a direct effect of the molecule on the purinergic receptors specifically inhibited by aminophylline.

[Late myocardial infarction after closure of coronary artery fistula]. / Infarctus myocardique tardif après fermeture d'une fistule coronaro-cardiaque.

Congenital coronary cardiac fistulae are rare conditions for which surgery is the usual indication. The authors report on the case of one female patient of 28 years with a coronary cardiac fistula responsible for exertional dyspnoea and relapsing pulmonary infections. The diagnosis was suggested by a continuous murmur and was confirmed by Doppler echocardiography and catheterization which showed a dilated, sinuous circumflex artery (2 cm) leading into the right atrium. Surgical closure of the fistula was complicated by an early myocardial infarction and a relapse in the same area with resulting mitral insufficiency. The surgical treatment of coronary cardiac fistulae is widely documented in the literature and recent series demonstrate that good results are usually obtained: however, a late infarction has not been described. The constitution of thrombi in the collateral vessels deriving from the distended vessel probably accounts for the particular evolution noted in this specific case.

[Thoracic electric bioimpedance. A non-invasive method for the measurement of cardiac output]. / Bioimpédance électrique thoracique. Une méthode non invasive de calcul du débit cardiaque.

Bioimpedance offers a simple non-invasive means of measuring systolic ejection volume and heart rate and thus cardiac output. Four pairs of electrodes are placed on precise locations on the chest and stroke volume is calculated according to the equation developed by Kubicek in 1966 and modified by Sramek in 1980. The aim of this work was to evaluate this method in patients with heart disease. In a series of 50 patients, the coefficient of correlation for cardiac index between impedance values (2.52 +/- 0.71 ml/min/m2) and thermodilution values (2.74 +/- 0.69 ml/min/m2) was 0.63 (p < 0.01). The mean difference was -0.2 l/min/m2 (confidence interval +1 l/min/m2 to -1.4 l/min/m2). There was no statistical correlation in patients with complete left bundle branch block, severe mitral or aortic regurgitation or dilatation of the aorta. In a group of 11 healthy volunteers, there was a good correlation between two measures taken at a 2 day interval (r = 0.95). The coefficient of variation ranged from 1.2 to 7% for ejection volume. Bioimpedance is reproducible and simple, authorizing its use for non-invasive monitoring of cardiac output in a given patient in various clinical situations.

[Peritoneal fistulization in pleural aspergillosis associated with skin lesions]. / Fistulisation péritonéale d'une aspergillose pleurale associée à des lésions cutanées.

This report describes the development of a pleuroperitoneal fistula complicating pleural aspergillosis in a 63-year old non-immunocompromised man treated with itraconazole. The patient presented a confluent granuloma of the abdomen while an abscess of the abdominal wall was disclosed. Skin involvement, usually described in disseminated aspergillosis, has not been reported in pleuropulmonary aspergillosis.

[Absence of interaction between thiomersal and aluminum occlusion chambers]. / Absence d'interaction entre le thiomersal et les chambres d'occlusion en aluminium.

BACKGROUND: Positive patch tests to thiomersal are frequent, but of little relevance. Interaction between aluminium occlusive chambers and the mercury of thiomersal may elicit skin irritation and cause false positive results. METHODS: Between January 1998 and May 1999, the patients were simultaneously patch tested with aluminium and plastic chambers. Positive skin tests were compared. RESULTS: Seventeen of 213 subjects showed positive tests: 15 with the 2 materials, 1 only for the aluminium chamber, 1 for the plastic chamber. DISCUSSION: The results did not differ for the two materials. We concluded that positive reactions observed were not caused by interaction between aluminium and thiomersal.

Factors associated with effective reassessment of antibiotic therapy on day 3.

UNLABELLED: Reassessment of antibiotic therapy (RA) after 3 days is constitutive of French antibiotic stewardship. This delay is required because of the need for clinical reappraisal and for obtaining microbiological data. Our aim was to determine the factors associated with an effective RA. PATIENTS AND METHOD: A prospective study was made in a 350-bed general hospital in which all prescriptions are computerized and validated daily by prescribers. All curative antibiotic therapies were reassessed during 4 weeks. RA was defined as effective if the initial antibiotic treatment was modified. All clinical, biological, and radiological data having contributed to the initial prescription and to RA were recorded during bedside visit with the prescribers, two hospital physicians and one infectious diseases specialist. RESULTS: In one month, 148 antibiotic treatments were reassessed. Pulmonary, digestive, and urinary infections accounted for two thirds of the cases. An effective RA was recorded in 28 cases (19%) and associated with hospitalization in the ICU (P=0.001), imaging supporting the diagnosis (P=0.016), and persistence or aggravation of clinical signs (P=0.007). Microbiological findings were not contributive to an effective RA. CONCLUSION: RA was associated to hospitalization in the ICU, to an inflammatory syndrome, and to the clinical outcome after 3 days. These results should help to improve the implementation of infectious diseases advice.