Dental and extra-oral clinical features in 41 patients with WNT10A gene mutations: A multicentric genotype-phenotype study.

WNT10A gene encodes a canonical wingless pathway signaling molecule involved in cell fate specification as well as morphogenetic patterning of the developing ectoderm, nervous system, skeleton, and tooth. In patients, WNT10A mutations are responsible for ectodermal-derived pathologies including isolated hypo-oligodontia, tricho-odonto-onycho-dermal dysplasia and Schöpf-Schulz-Passarge syndrome (SSPS). Here we describe the dental, ectodermal, and extra-ectodermal phenotypic features of a cohort of 41 patients from 32 unrelated families. Correlations with WNT10A molecular status (heterozygous carrier, compound heterozygous, homozygous) and patient's phenotypes were performed. Mild to severe oligodontia was observed in all patients bearing biallelic WNT10A mutations. However, patients with compound heterozygous mutations presented no significant difference in phenotypes compared with homozygous individuals. Anomalies in tooth morphology were frequently observed with heterozygous patients displaying hypodontia. No signs of SSPS, especially eyelids cysts, were detected in our cohort. Interestingly, extra-ectodermal signs consisted of skeletal, neurological and vascular anomalies, the latter suggesting a wider phenotypic spectrum associated with WNT10A mutations. Indeed, the Wnt pathway plays a crucial role in skeletal development, lipid metabolism, and neurogenesis, potentially explaining patient's clinical manifestations.

[Effectiveness of flexible ureteroscopy versus extracorporeal shock wave lithotripsy for kidney stones treatment]. / Efficacité de l'urétéroscopie souple versus lithotritie extracorporelle dans le traitement des calculs du rein.

Primary endpoint was to objective a better effectiveness of flexible ureteroscopy (fURS) compared to extracorporeal shock wave lithotripsy (ESWL) 3 months after treatment of a unique kidney stone from 5 to 20mm. Secondary endpoints were to evaluate effectiveness in subgroup and tolerance. We conducted a prospective comparative randomised trial between May 2012 and February 2014. A computerised tomography was done before treatment and another 3 months after treatment. Of the 30 randomised patients, 8 dropped out from the study and 4 were lost to follow-up. Median time of follow-up was 3.82 months. In per-protocol analysis, success rate was 60% for fURS group versus 28.6% for ESWL group (P=0.29). In intention to treat analysis, success rate was 77.8% in fURS group versus 53.8% in ESWL group (P=0.38). In ESWL group, 5 patients (41.7%) needed a second treatment versus none in fURS group but it was not significant. During follow-up, 1 patient in each group presented a complication. Results of this feasibility study did not allowed to conclude on superiority of a technic. A multicenter study with more important enrollment is necessary considering economic side and tolerance of these treatments.

Alignment and scaling of large-scale fluctuations in the solar wind.

We investigate the dependence of solar wind fluctuations measured by the Wind spacecraft on scale and on the degree of alignment between oppositely directed Elsasser fields. This alignment controls the strength of the nonlinear interactions and, therefore, the turbulence. We find that at scales larger than the outer scale of the turbulence the Elsasser fluctuations become on average more antialigned as the outer scale is approached from above. Conditioning structure functions using the alignment angle reveals turbulent scaling of unaligned fluctuations at scales previously believed to lie outside the turbulent cascade in the "1/f range." We argue that the 1/f range contains a mixture of a noninteracting antialigned population of Alfvén waves and magnetic force-free structures plus a subdominant population of unaligned cascading turbulent fluctuations.

Identification of the first nonsense CDSN mutation with expression of a truncated protein causing peeling skin syndrome type B.

BACKGROUND: Peeling skin disease (PSD), a generalized inflammatory form of peeling skin syndrome, is caused by autosomal recessive nonsense mutations in the corneodesmosin gene (CDSN). OBJECTIVES: To investigate a novel mutation in CDSN. METHODS: A 50-year-old white woman showed widespread peeling with erythema and elevated serum IgE. DNA sequencing, immunohistochemistry, Western blot and real-time polymerase chain reaction analyses of skin biopsies were performed in order to study the genetics and to characterize the molecular profile of the disease. RESULTS: Histology showed hyperkeratosis and acanthosis of the epidermis, and inflammatory infiltrates in the dermis. DNA sequencing revealed a homozygous mutation leading to a premature termination codon in CDSN: p.Gly142*. Protein analyses showed reduced expression of a 16-kDa corneodesmosin mutant in the upper epidermal layers, whereas the full-length protein was absent. CONCLUSIONS: These results are interesting regarding the genotype-phenotype correlations in diseases caused by CDSN mutations. The PSD-causing CDSN mutations identified heretofore result in total corneodesmosin loss, suggesting that PSD is due to full corneodesmosin deficiency. Here, we show for the first time that a mutant corneodesmosin can be stably expressed in some patients with PSD, and that this truncated protein is very probably nonfunctional.

Bone marrow oedema predicts structural progression in a 1-year follow-up of 85 patients with RA in remission or with low disease activity with low-field MRI.

OBJECTIVES: To identify the predictive factors of MRI-determined structural progression in patients with rheumatoid arthritis (RA) in remission or with low disease activity (LDA). METHODS: In this 1-year longitudinal study, patients with RA in clinical remission (disease activity score (DAS) 44≤1.6) or with LDA (1.6

Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils.

Thrombin stimulation of human platelets results in the release of a preformed proteinaceous human eosinophil (Eo)-chemotactic activity. By the use of different high-performance liquid chromatography techniques, two Eo-chemotactic polypeptides (EoCPs), tentatively termed EoCP-1 and EoCP-2, were purified to homogeneity. Upon SDS-PAGE analysis, these chemotaxins showed molecular masses near 8 kD. NH2-terminal amino acid sequence analysis revealed identical sequences for both EoCP-1 and EoCP-2, which are also identical to that of RANTES, a cytokine that structurally belongs to the interleukin 8 superfamily of leukocyte selective attractants, and that is known to be a "memory-type" T lymphocyte-selective attractant. In the major Eo chemotaxin, EoCP-1, the residues 4 and 5, which in EoCP-2 were found to be serine residues, could not be identified. Electrospray mass spectrometry (ESP-MS) of EoCPs revealed for EoCP-2 a molecular mass of 7,862.8 +/- 1.1 daltons, which is 15.8 mass units higher than the calculated value of RANTES, indicating that EoCP-2 is identical to the full-length cytokine, and oxygenation, probably at methionine residue number 64, has taken place. Upon ESP-MS, EoCP-1 showed an average molecular mass of 8,355 +/- 10 daltons, suggesting O-glycosylation at these serine residues. Both natural forms of RANTES showed strong Eo-chemotactic activity (ED50 = 2 nM) with optimal chemotactic migration at concentrations near 10 nM, however, there were no significant migratory responses with human neutrophils. Chemotactic activity of RANTES for human Eos could be confirmed using recombinant material, which has been found to be as active as the natural forms. Since RANTES gene expression has been detected in activated T lymphocytes, and recombinant RANTES was shown to be a "memory" T lymphocyte-selective attractant, it is now tempting to speculate about an important role of RANTES in clinical situations such as allergene-induced late-phase skin reactions in atopic subjects or asthma, where in affected tissues both memory T cells and Eos are characteristic.

Transformation of binomial input by the postsynaptic membrane at a central synapse.

Although a binomial model gives an adequate description of the release properties of central afferent synapses, slight differences between experimental and predicted probability density functions are observed, with an excess number of responses recorded around the means. These discrepancies can be quantified by comparing experimental and theoretical entropies, which could relate to information transfer at these junctions. A model, based on the experimentally supported assumption that the postsynaptic membrane functions as a nonlinear processor, minimizes the differences between the distributions of the recorded and predicted potentials. According to this model, the nonlinearity is due to a localized interaction between the effects of simultaneously activated adjacent synapses.

Fluctuating responses at a central synapse: n of binomial fit predicts number of stained presynaptic boutons.

Binomial predictions provided a better description than the Poisson law of fluctuating unitary inhibitory postsynaptic potentials evoked in the goldfish Mauthner cell by impulses in presynaptic interneurons. The number of terminal boutons established on this target cell by each horseradish peroxidase-filled interneuron corresponded to the value of the binomial parameter n.

A medical simulator for subcutaneous contraceptive implant insertion.

New contraceptive methods like the subcutaneous implant offers a new kind of comfort for women with an efficiency similar to the contraceptive pill. Unfortunately the few numbers of unintended pregnancies that have been reported are generally due to a bad insertion of the implant. In order to give more security to patients, we have designed, in close collaboration with physicians, a new kind of medical simulator. This paper focuses on a device dedicated to a specific subcutaneous implant but it is worth noting that this simulator is relatively generic since it will be used for other subcutaneous techniques or other implant instruments. This simulator can be used for two purposes: one for training novice physicians in the correct manipulation and the other for physician certification which will help determine if they are capable of inserting the implant in vivo. This paper describes the approach which has led to the design of this simulator. It describes its functionalities, its several components but also methods used to analyze the manipulation of the implant insertion inside the patient. Finally first experimental results are reported and discussed. The system used in this paper makes possible to carry out training in a constraint-free context and provides the first mean of visualizing a maneuver that, until now, has been performed blindly.

A synthetic peptide adhesion epitope as a novel antimicrobial agent.

The earliest step in microbial infection is adherence by specific microbial adhesins to the mucosa of the oro-intestinal, nasorespiratory, or genitourinary tract. We inhibited binding of a cell surface adhesin of Streptococcus mutans to salivary receptors in vitro, as measured by surface plasmon resonance, using a synthetic peptide (p1025) corresponding to residues 1025-1044 of the adhesin. Two residues within p1025 that contribute to binding (Q1025, E1037) were identified by site-directed mutagenesis. In an in vivo human streptococcal adhesion model, direct application of p1025 to the teeth prevented recolonization of S. mutans but not Actinomyces, as compared with a control peptide or saline. This novel antimicrobial strategy, applying competitive peptide inhibitors of adhesion, may be used against other microorganisms in which adhesins mediate colonization of mucosal surfaces.

Anemia in the period immediately following renal transplantation.

INTRODUCTION: Anemia remains frequent in the first month following renal transplantation and is a risk factor for cardiovascular accidents. The purpose of this study was to analyze the prevalence of anemia during this period notably among different immunosuppressive treatment groups. METHODS: In this study, we entered the patients who had received a renal allograft in our transplant unit from 1993 to 2003, including patients who had received azathioprine (AZA) from 1993 to 1996 and mycophenolate mofetil (MMF) from 1996 to 2003. No patient received rHu-erythropoietin after transplantation during that period. A mathematical model normalized the hemoglobin (Hb) threshold level at which blood transfusion was decided and Hb on admission. RESULTS: One hundred and eighty-eight patients on AZA and 223 on MMF were included in the analysis. The mean age +/- SD was 41 +/- 12 years in the AZA group, and 45 +/- 12 years in the MMF group (P < .006). Before the transplantation, Hb was higher in the MMF group (11.4 +/- 1.9 vs 10.2 +/- 2 g/dL, P < .0001). After normalization at a threshold level of transfusion of 7 g/dL, transfusions were more frequent among the MMF group (72% vs 48%, P < .0001). Double therapy with MMF (1500 mg/d) + steroids or therapy with MMF (750 mg/d) + tacrolimus + steroids increased the risk of transfusion compared to the AZA group. MMF (750 mg/d) + cyclosporine conferred a similar risk of transfusion compared with the AZA group. CONCLUSION: MMF alone or in association with tacrolimus is associated with an increased risk of anemia and transfusion in the immediate posttransplantation period.

Kinematic and electromyographic analysis of rising from a chair during a "Sit-to-Walk" task in elderly subjects: role of strength.

BACKGROUND: With aging, the deterioration of the ability to rise from a chair constitutes a major source of disability and a factor contributing to the loss of autonomy. The aim of this study was to describe kinematic and electromyographic characteristics of rising from a chair during a Sit-to-Walk task and to investigate the relationships between lower limb muscle strength and Sit-to-Walk characteristics. METHODS: Twenty-four healthy elderly subjects (mean age: 73.8 (6.4) years) were included. The task analyzed consisted in standing up and taking a step. Kinematic data were obtained using a 3D motion analysis software. Surface electromyography of eight lower limb muscles was recorded. Isokinetic strength of ankle plantar flexor and knee flexors and extensors was evaluated. FINDINGS: The Sit-to-Walk was divided into four phases. For 19 subjects, this task can be considered as a continuum with an overlap of the phases. In comparison with the Sit-to-Stand description, the Sit-to-Walk transition phase, which combined trunk flexion and knee extension, appeared longer in order to increase the body forward transfer for gait initiation. In most cases, the tibialis anterior and peroneus longus muscles were first activated. The isokinetic strength of the knee extensors was negatively correlated with the amplitude of trunk flexion and the knee flexors/extensors torque ratio was correlated with the length of this phase. INTERPRETATION: Characterization of Sit-to-Walk movement provides information about the ability to rise from a chair. In the elderly, a better knowledge of its determinants could lead to improve strategies for rehabilitation of this critical task.

Prospective cohort study of phenotypic variation based on an anal sphincter function in adults with fecal incontinence.

BACKGROUND: One-third of patients with fecal incontinence (FI) do not have any anal dysfunction. The aim was to characterize patients with FI with normal anal function compared with patients with anal weakness. METHODS: The general characteristics and data of anal manometry, endosonography, and defecography of patients who were evaluated for FI at a single institution from 2005 to 2015 were prospectively assessed. Fecal incontinence was defined by the Cleveland Clinic Incontinence Score (CCIS) >4. Anal weakness was defined by one or more of the three following parameters: <25 mmHg at the upper part of the anal canal, <26 mmHg at the lower part of the anal canal, and <60 mmHg for the mean squeeze pressure. KEY RESULTS: A total of 439 patients with FI were included (152 with normal anal function/287 with anal weakness). Severe constipation (Kess score ≥21) was predominant in patients with normal anal function (44/151 vs 50/284, respectively; p = 0.0054). Fecal incontinence with normal anal function was significantly associated with lower age (>63 years; odds ratio [OR] = 0.29), higher weight (>65 kg; OR = 1.69), fecal urgency (OR = 1.58), less severe FI score (CCIS score >10; OR = 0.52), higher abdominal pressure (>36 mmHg; OR = 2.15), and paradoxical puborectal contraction (OR = 2.07) in a multivariate analysis model. CONCLUSION & INFERENCES: Fecal incontinence with normal anal function is a specific phenotype that involves distal constipation and may be an early stage of FI with anal weakness. Physicians should adapt their management to focus on the treatment of constipation.

Thin-layer chromatography and mass spectrometry of pentafluorobenzylidene derivatives of members of the phthiocerol family from Mycobacterium tuberculosis and Mycobacterium marinum.

The difference in relative stereochemistry of the 1.3-diol unit of mycobacterial phthiocerols can be determined by simple thin-layer chromatographic analysis of pentafluorobenzylidene acetal derivatives. The threo phthiocerol acetals from Mycobacterium tuberculosis are composed of equal amounts of two axial-equatorial stereoisomers but the erythro phthiocerols from Mycobacterium marinum form only one acetal with diequatorial substituents. The two acetals formed from a threo phthiocerol can be separated by thin-layer chromatography and mass spectra of the two stereoisomers allowed assignment of their structures.

Characterisation of phenolic glycolipids from Mycobacterium marinum.

The phenolic glycolipids from two strains of Mycobacterium marinum have been isolated and characterised. The glycolipids from M. marinum MNC 170 were principally glycosides of diacyl C37, C39 and C41 phenolphthiocerols A, but in M. marinum MNC 842, these lipids were accompanied by glycosides of diacyl phenolphthiodiolones A and novel phthiotriols A with the same overall chain-lengths. The main acyl components of the phenolic glycolipids from M. marinum MNC 170 were C26 dimethyl and C27 and C29 trimethyl-branched fatty acids, but in the lipids of M. marinum MNC 842, the C27 trimethyl acid was the only principal component. The sugar composition of all these glycolipids had been previously shown to correspond to 3-O-methylrhamnose.

Evidence for the glycosylation of porcine serum transferrin at a single site located within the C-terminal lobe.

In this study we report the number and location of the glycans on PST. Urea PAGE and SDS-PAGE have been used to follow the enzymatic removal of sialic acids and of glycans from PST and the masses of native and deglycosylated PST have been determined by electrospray mass spectrometry. The results are consistent with the presence of a single biantennary glycan chain. As amino acid sequence analysis demonstrated the absence of a glycosylated asparagine at position 25, the glycosylation site is restricted to Asp-497.

Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial.

BACKGROUND: beta-Blockade-induced benefit in heart failure (HF) could be related to baseline heart rate and treatment-induced heart rate reduction, but no such relationships have been demonstrated. METHODS AND RESULTS: In CIBIS II, we studied the relationships between baseline heart rate (BHR), heart rate changes at 2 months (HRC), nature of cardiac rhythm (sinus rhythm or atrial fibrillation), and outcomes (mortality and hospitalization for HF). Multivariate analysis of CIBIS II showed that in addition to beta-blocker treatment, BHR and HRC were both significantly related to survival and hospitalization for worsening HF, the lowest BHR and the greatest HRC being associated with best survival and reduction of hospital admissions. No interaction between the 3 variables was observed, meaning that on one hand, HRC-related improvement in survival was similar at all levels of BHR, and on the other hand, bisoprolol-induced benefit over placebo for survival was observed to a similar extent at any level of both BHR and HRC. Bisoprolol reduced mortality in patients with sinus rhythm (relative risk 0.58, P:<0.001) but not in patients with atrial fibrillation (relative risk 1.16, P:=NS). A similar result was observed for cardiovascular mortality and hospitalization for HF worsening. CONCLUSIONS: BHR and HRC are significantly related to prognosis in heart failure. beta-Blockade with bisoprolol further improves survival at any level of BHR and HRC and to a similar extent. The benefit of bisoprolol is questionable, however, in patients with atrial fibrillation.

COOH-terminal truncated cardiac myosin-binding protein C mutants resulting from familial hypertrophic cardiomyopathy mutations exhibit altered expression and/or incorporation in fetal rat cardiomyocytes.

Mutations in human cardiac myosin-binding protein C (cMyBP-C) gene are associated with familial hypertrophic cardiomyopathy (FHC), and most of them are predicted to produce COOH-truncated proteins. To understand the molecular mechanism(s) by which such mutations cause FHC, we analyzed (i) the accumulation of human cMyBP-C mutants in fetal rat cardiomyocytes, and (ii) the protein sequence of the human wild-type (wt) cMyBP-C by hydrophobic cluster analysis with the aim of identifying new putative myosin-binding site(s). Accumulation and sarcomeric localization of the wt protein and of four FHC-mutant cMyBP-Cs (E542Q and three COOH-truncated proteins) were studied in cardiomyocytes by immunostaining and confocal microscopy after transfection with myc-tagged constructs. We found that: (i) 10 % of the cells expressing COOH-truncated mutants exhibit an incorporation into the A-band of the sarcomere without any alteration of the myofibrillar architecture versus 76 % of those expressing the wt or E542Q mutant cMyBP-Cs (p<0.001); (ii) 90 % of the cells expressing the truncated mutants show a diffuse localization of these proteins in the cardiomyocytes, out of which 45 % exhibit a significant alteration of the sarcomeric structure (p<0.0001 versus wt); and (iii) the two shortest mutant cMyBP-Cs accumulate at very low levels in fetal rat cardiomyocytes as compared to the wt (p<0.008). Protein sequence analysis indicated that a 45-residue sequence in the NH2-terminal C0 domain of cMyBP-C exhibits a consistent homology (sequence similarity score of 42 %) with a segment of the NH2-terminal domain of myomesin, another myosin-binding protein. This result suggests that the C0 domain of human cMyBP-C contains a novel putative myosin-binding site that could account for the A-band incorporation of the truncated mutants. In addition, the faint accumulation and the diffuse localization of truncated mutants could probably be explained by a low affinity of the C0 domain for myosin. We conclude that COOH-truncated cMyBP-Cs may act as poison polypeptides that disrupt the myofibrillar architecture and result in the defects observed in FHC.

Beta-1,2-linked oligomannosides inhibit Candida albicans binding to murine macrophage.

Interaction of Candida albicans with cells of the macrophage lineage was examined by using heat-killed (HK) and live yeast cells. Laminarin, an analogue of the cell wall beta-glucans, strongly inhibited HK yeasts adherence to J774 cell line but had no effect on live yeast binding. Phosphopeptidomannan (PPM) from Saccharomyces cerevisiae had a limited effect on the binding of both HK and live yeasts but significant inhibition was achieved by the use of C. albicans PPM. The role of beta-1,2-oligomannosides was examined with regard to their exclusive presence within C. albicans PPM. PPM acid labile beta-1,2-oligomannosides or a synthetic beta-1,2-mannotetraose, inhibited yeasts binding in a manner comparable to the original PPM. These latter results were confirmed by using mouse peritoneal macrophages, thus suggesting a general role for beta-1,2-oligomannosides in the adherence of the yeast to the macrophage membrane.