Patient-specific and real-time model of numerical simulation of the hemodynamics of type B aortic dissections.

INTRODUCTION: Regular monitoring of uncomplicated type B aortic dissection is essential because 25-30% will progress to aneurysmal form. The predictive factors of this evolution are not clearly defined, but they seem to be correlated with hemodynamic data. HYPOTHESIS: Our goal is to create a patient-specific and real-time model of numerical simulation of the hemodynamics of uncomplicated type B aortic dissections in order to predict the evolution of these pathologies for earlier treatment. METHOD: This model consists in a coupling 0D (hydraulic-electric analogy) - 3D (CT angiography segmentation) of the aortic arch with optimization by comparison to the 2D Phase Contrast MRI data and using Reduced Order Models to drastically reduce computing times. We tested our model on a healthy and a dissected patient. Then we realized different systolic blood pressure scenarios for each case, which we compared. RESULTS: In the dissected patient, the blood pressure at the false lumen wall was less important than the true lumen. Furthermore, the aortic wall shear stress and the velocity fields in aorta increase at the entry and re-entry tears between the two lumens. The simulation of different blood pressures scenarios shows a decrease in all these three parameters related to the decrease of the systolic blood pressure. CONCLUSION: Our model provides reliable patient-specific and real-time 3D rendering. It has also allowed us to realize different flow variation scenarios to simulate different clinical conditions and to compare them. However, the model still needs improvement in view of a daily clinical application.

Surgical management of an epithelioid hemangioendothelioma of the superior vena cava protruding into the right atrium.

Epithelioid hemangioendothelioma (EH) is a rare malignant tumor of vascular origin that often involves soft tissues and visceral organs, and less commonly, large veins. We report a case of EH of the superior vena cava protruding into the right atrium and its surgical management.

Belgian recommendations on ANA, anti-dsDNA and anti-ENA antibody testing.

Autoantibodies to nuclear antigens, i.e. antinuclear antibodies (ANA), antibodies to double-stranded DNA (dsDNA) and extractable nuclear antigens (ENA), are useful as diagnostic markers for a variety of autoimmune diseases. In March 2010, the Belgian national External Quality Assessment Scheme sent a questionnaire on ANA, anti-dsDNA and anti-ENA antibody testing designed by the Dutch EASI (European Autoimmunity Standardization Initiative) team, to all clinical laboratories performing ANA testing. Virtually all laboratories completed the questionnaire (97·7%, 127/130). This paper discusses the results of this questionnaire and provides valuable information on the state-of-the-art of ANA, anti-dsDNA and anti-ENA antibody testing as practiced in the Belgian laboratories. In addition, this work presents practical recommendations developed by the members of the advisory board of the scheme as a result of the outcome of this study.

Calculation and analysis of the harmonic vibrational frequencies in molecules at extreme pressure: methodology and diborane as a test case.

We present a new quantum chemical method for the calculation of the equilibrium geometry and the harmonic vibrational frequencies of molecular systems in dense medium at high pressures (of the order of GPa). The new computational method, named PCM-XP, is based on the polarizable continuum model (PCM), amply used for the study of the solvent effects at standard condition of pressure, and it is accompanied by a new method of analysis for the interpretation of the mechanisms underpinning the effects of pressure on the molecular geometries and the harmonic vibrational frequencies. The PCM-XP has been applied at the density functional theory level to diborane as a molecular system under high pressure. The computed harmonic vibrational frequencies as a function of the pressure have shown a satisfactory agreement with the corresponding experimental results, and the parallel application of the method of analysis has reveled that the effects of the pressure on the equilibrium geometry can be interpreted in terms of direct effects on the electronic charge distribution of the molecular solutes, and that the effects on the harmonic vibrational frequencies can be described in terms of two physically distinct effects of the pressure (curvature and relaxation) on the potential energy for the motion of the nuclei.

[Pathophysiology of cholesteatoma]. / La physiopathogénie des cholestéatomes.

OBJECTIVE: To describe the development of cholesteatoma using current knowledge. METHOD: Review of the literature. RESULTS: Cholesteatoma describes a mass of keratin (skin) in the middle ear which consists of a perimatrix and matrix. There are at least three kinds of cholesteatoma in the middle ear one resulting from invagination (retraction's pocket), another from migration and the last one from congenital inclusion. Cholesteatoma needs three successive inflammatory phases, the first leading to a retraction pocket, the second leading to pathology of the epidermis and of the floor of the external auditory canal and the third is the actual phase of cholesteatoma with invasion and middle ear auto-destruction with bone resorption. In this last phase, many factors play a role, collagenasis, osteoclats, cytokines, NO, bacteria and their biofilm and rupture of the retraction pocket. CONCLUSION: Cholesteatoma is an inflammatory disease of the ear caracterised by bone resorption. Current research is starting to appreciate the important role the immune system plays in the pathophysiology of cholesteatoma.

Effects of human pituitary FSH isoforms on mouse follicles in vitro.

The effects of human FSH glycoforms on mouse follicle development and function in vitro were analysed, and an attempt was made to relate markers of follicular maturation to the expression of immunolocalized connexin (Cx) 43 and Cx26-based gap junctions. Three FSH fractions comprising discrete pI ranges [7.10-5.99 (pool I), pI 5.62-4.95 (pool II) and <3.75 (pool III)] were studied. Pool I produced the strongest effect on preantral granulosa cell proliferation and oestradiol production, and was highly effective for stimulating antral formation; this isoform also evoked a peripheral distribution of Cx43-containing gap junctions. Pool II was effective in promoting preantral granulosa cell proliferation but required higher FSH doses. This particular isoform provoked a more central distribution of Cx43-containing gap junctions, which was associated with a lower oestradiol production and less effective antral formation. Pool III was the least active for all markers of follicle development, and this was associated with minimal induction of Cx43-based gap junctions. The effects of the three FSH isoform pools on Cx26 expression were similar. The pattern of differences strongly suggests that FSH isoforms have complementary and specific actions on developing follicles, and that a shifting stage specific balance of isoforms is required for optimal follicle development.

Electronic excitation energies of molecules in solution within continuum solvation models: investigating the discrepancy between state-specific and linear-response methods.

In a recent article [R. Cammi, S. Corni, B. Mennucci, and J. Tomasi, J. Chem. Phys. 122, 104513 (2005)], we demonstrated that the state-specific (SS) and the linear-response (LR) approaches, two different ways to calculate solute excitation energies in the framework of quantum-mechanical continuum models of solvation, give different excitation energy expressions. In particular, they differ in the terms related to the electronic response of the solvent. In the present work, we further investigate this difference by comparing the excitation energy expressions of SS and LR with those obtained through a simple model for solute-solvent systems that bypasses one of the basic assumptions of continuum solvation models, i.e., the use of a single Hartree product of a solute and a solvent wave function to describe the total solute-solvent wave function. In particular, we consider the total solute-solvent wave function as a linear combination of the four products of two solute states and two solvent electronic states. To maximize the comparability with quantum-mechanical continuum model the resulting excitation energy expression is recast in terms of response functions of the solvent and quantities proper for the solvated molecule. The comparison of the presented expressions with the LR and SS ones enlightens the physical meaning of the terms included or neglected by these approaches and shows that SS agrees with the results of the four-level model, while LR includes a term classified as dispersion in previous treatments and neglects another related to electrostatic. A discussion on the possible origin of the LR flaw is finally given.

Prospective screening for biopsy proven coeliac disease, autoimmunity and malabsorption markers in Belgian subjects with Type 1 diabetes.

AIMS: To determine prospectively the prevalence of biopsy proven coeliac disease (CD) in an adult Type 1 diabetic population from Belgium with regards to associated auto-immunity and malabsorption. METHODS AND RESULTS: Determination in 400 Type 1 diabetic patients of serum anti-endomysial and/or anti-transglutaminase auto-antibodies. All subjects with abnormal serology underwent an intestinal biopsy. Ten patients (2.5%) had positive antibodies. Diagnosis of CD was confirmed by an intestinal biopsy. Eight patients were symptom-free, although laboratory findings suggesting malabsorption were prominent in the presence of CD [microcytic anaemia, iron and folate deficiencies, low levels of 25(OH)vitamin D3, calcium and cholesterol]. Other auto-immune conditions, especially vitiligo, were found in patients with CD. CONCLUSIONS: Asymptomatic coeliac disease occurs frequently in adult Type 1 diabetic patients, and is often associated with subclinical malabsorption. Screening should be part of routine evaluation, to implement life-long dietary gluten avoidance.

Electronic excitation energies of molecules in solution: state specific and linear response methods for nonequilibrium continuum solvation models.

We present a formal comparison between the two different approaches to the calculation of electronic excitation energies of molecules in solution within the continuum solvation model framework, taking also into account nonequilibrium effects. These two approaches, one based on the explicit evaluation of the excited state wave function of the solute and the other based on the linear response theory, are here proven to give formally different expressions for the excitation energies even when exact eigenstates are considered. Calculations performed for some illustrative examples show that this formal difference has sensible effects on absolute solvatochromic shifts (i.e., with respect to gas phase) while it has small effects on relative (i.e., nonpolar to polar solvent) solvatochromic shifts.

Assessment of the in vitro and in vivo biological activities of the human follicle-stimulating isohormones.

Gonadotropins are synthesized and released in different molecular forms. In this article, we present evidence that the glycosylation variants of human pituitary FSH exhibit differential and divergent effects at the target cell level and that less sialylated, short-lived variants may exert significant effects in in vivo conditions. Less acidic/sialylated glycoforms (elution pH value 6.60-4.60 as disclosed by high resolution chromatofocusing of anterior glycoprotein extracts), induced higher cAMP release, estrogen production and tissue-type plasminogen activator (tPA) enzyme activity as well as cytochrome P450 aromatase and tPA mRNA expression in cultured rat granulosa cells than the more acidic analogs (pH<4.76). By contrast, the more acidic/sialylated glycoforms induced higher alpha-inhibin subunit mRNA expression than their less acidic counterparts. In cumulus enclosed oocytes isolated from mice ovaries, addition of less acidic isoforms induced resumption of meiosis more efficiently than the more acidic analogs. Interestingly, the least acidic isoform (pH>7.10) behave as a strong antagonist of several FSH-mediated effects. Assessment of the in vivo effects of the isoforms on granulosa cell proliferation in follicles from immature rats, revealed that short-lived isoforms were equally or even more efficient than their more acidic counterparts in maintaining granulosa cell proliferation when administered immediately after hypophysectomy. These results show that the naturally occurring human FSH isoforms may exhibit differential or even unique effects at the target cell level and that factors other than the metabolic clearance rate of the molecule (including receptor-binding affinity and capability of the ligand to activate its receptor and trigger intracellular signaling) also play an important role in determining the net in vivo effects of a particular FSH variant.

COCH5B2 is a target antigen of anti-inner ear antibodies in autoimmune inner ear diseases.

OBJECTIVE: This study was designed to identify the 58-kDa inner ear protein against which the sera of some patients with idiopathic, progressive sensorineural hearing loss or Ménière's disease strongly react. BACKGROUND: We and other groups have previously demonstrated that a 58-kDa protein extracted from guinea pig or bovine inner ear tissue is a target of antibodies in serum samples from some patients with autoimmune inner ear diseases. METHODS: After separation of inner ear proteins by 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis, the bands corresponding to 58 kDa were localized and excised from the gel. The concentrated protein was then digested with trypsin, and the peptide fragments were separated by high-pressure liquid chromatography. Three fractions were subjected to amino acid sequencing by the classic Edman degradation. RESULTS: The sequence of a stretch of 14 amino acids of the first fragment was identical to that of amino acids 526 to 539 of the COCH5B2 protein. The sequences of 11 and 10 amino acids of the second and third fragments, respectively, also were identical to residues 417 to 427 and 396 to 405 of the COCH5B2 protein. These data, together with two-dimensional gel electrophoresis followed by Western blot experiments, confirmed that the 58-kDa inner ear protein is the COCH5B2 protein. DISCUSSION: These findings indicate that the 58-kDa target protein of antibodies in serum samples of patients with autoimmune inner ear diseases is the COCH5B2 protein, a molecule that is highly and specifically expressed in the cochlea and vestibule.

Antepartum bed rest: effect upon the family.

OBJECTIVE: To identify the effects of antepartum bed rest upon the family. DESIGN: Descriptive, retrospective survey. PARTICIPANTS: A national random selection of 89 women who had been prescribed antepartum bed rest in the hospital or at home and who contacted a high-risk pregnancy support group for information. MAIN OUTCOME MEASURE: An open-ended questionnaire. RESULTS: Families experienced difficulty assuming maternal responsibilities, anxiety about maternalfetal outcomes, and adverse emotional effects on the children. Child care was managed by various people across time. Child care problems included negative reactions from the children, concern about the quality of the provider, and maternal worry about care. Families also experienced financial difficulties, the majority of which were not compensated by insurance or work benefits. Almost all, 96.6%, families received some type of support during bed rest. Instrumental support was the most commonly received; however, emotional support was considered the most helpful. The least helpful type of support was that which was unreliable. The primary providers of support to the family were parents and family, followed by friends. The women reported that health care providers offered minimal support to the family. CONCLUSION: Despite support, antepartum bed rest creates difficulties that affect the entire family and its finances.

Expression level-dependent contribution of glucocorticoid receptor domains for functional interaction with STAT5.

The action of the glucocorticoid receptor (GR) on beta-casein gene transcription serves as a well-studied example of a case where the action of the GR is dependent on the activity of another transcription factor, STAT5. We have investigated the domain-requirement of the GR for this synergistic response in transfection experiments employing GR mutants and CV-1 or COS-7 cells. The results were influenced by the expression levels of the GR constructs. At low expression, STAT5-dependent transactivation by mutants of the GR DNA binding domain or N-terminal transactivation domain was impaired and the antiglucocorticoid RU486 exhibited a weak agonistic activity. When the N-terminal region of the GR was exchanged with the respective domain of the progesterone receptor, STAT5-dependent transactivation was reduced at low and high expression levels. Only at high expression levels did the GR exhibit the properties of a coactivator and enhanced STAT5 activity in the absence of a functional DNA binding domain and of GR binding sites in the proximal region of the beta-casein gene promoter. Furthermore, at high GR expression levels RU486 was nearly as efficient as dexamethasone in activating transcription via the STAT5 dependent beta-casein gene promoter. The results reconcile the controversial issue regarding the DNA binding-independent action of the GR together with STAT5 and provide evidence that the mode of action of the GR depends not only on the type of the particular promoter at which it acts but also on the concentration of the GR. GR DNA binding function appears to be mandatory for beta-casein gene expression in mammary epithelial cells, since the promoter function is completely dependent on the integrity of GR binding sites in the promoter.

Inner ear autoantibodies and their targets in patients with autoimmune inner ear diseases.

Immunological mechanisms are thought to play an important role in the pathogenesis of some cochleo-vestibular diseases. This study attempts to present further evidence of autoantibodies reactive against guinea pig inner ear proteins found in patients with autoimmune inner ear diseases (AIED) and specifically identifies the main target antigens of these antibodies. Sera from 110 patients with a clinical diagnosis of either rapidly progressive sensorineural hearing loss (n = 32). Ménière's disease (n = 41), sudden deafness (n = 6) or other aetiologies of hearing loss (n = 11) were screened by the Western blot technique. Forty-four percent of the patients' sera had antibodies to several inner ear proteins, of which the 30, 42 and 68 kDa proteins were found to be the most reactive. These highly reactive proteins were identified by gas-phase micro sequencing after digestion with trypsin and separation of peptide fragments by high-performance liquid chromatography. A partial sequence of each protein was determined. These data, together with those obtained from 2-dimensional gel electrophoresis followed by Western blotting, demonstrated that the 30 and 42 kDa inner ear proteins are the major peripheral myelin protein P0 and the beta-actin protein, respectively, while sequence analysis indicated that the 68 kDa protein is novel. These findings further support the hypothesis that several populations of antibodies may contribute to the enhanced immunological activity of AIED patients. They also add a new dimension to our knowledge of AIED and may open new avenues in the development of simple serological assays, which are easier to perform and more rapid than Western blotting.

Effect of different FSH isoforms on cyclic-AMP production by mouse cumulus-oocyte-complexes: a time course study.

The ability of different isoforms of follicle stimulating hormone (FSH) to induce accumulation of cAMP in cultured mouse cumulus-oocyte-complexes (COC) was evaluated in a time course study. Using isoform fractions representing less acidic (pI 6.43-5.69), mid-acidic (pI 5.62-4.96) and acidic (pI 4.69-3.75) isoforms, the accumulation of cAMP was monitored after an exposure time of 0, 5, 10, 15, 30, 60, 120 and 180 min. In addition, cAMP production was monitored for 0, 5, 10, 15 and 30 min following a 5 min exposure to FSH isoform fractions. Based on FSH measurements using radioimmunoassays, the less and mid-acidic isoforms caused almost twice as much cAMP to be accumulated than the acidic isoform fraction, thereby confirming an enhanced biological activity of FSH isoforms with a isoelectric point (pI) of >5.0. For all isoform fractions, maximal accumulation of cAMP was achieved after 30 min of exposure, after which the production declined to background levels. After a 5 min exposure to isoform fractions, levels of cAMP were significantly higher in the less acidic isoform fractions, but after isoform removal, the decline in cAMP production to background levels followed a similar time course. The results demonstrate that FSH isoforms with a pI of >5.0 induced significant biological responses within a period of 30 min and that prolonged exposure caused attenuated signal transduction. The present results, set in the context of the pulsatile characteristics of FSH release from the pituitary and the reported half-life of less acidic isoforms of approximately 35 min, make it conceivable that isoforms with a pI >5.0 actually possess important physiological functions during the periovulatory period.

No increased serum levels of antifood antibodies in patients with Ménière's disease.

The etiology of Ménière's disease (MD) is still unknown, but it is likely to be multifactorial, one of the factors being an immunological causation. Antifood allergens as well as anti-baker's yeast antibodies are humoral factors that may be linked with allergenic disorders and other autoimmune conditions. To determine their possible role in MD activity, we investigated 29 MD sera for the presence of antibodies against gliadin, beta-lactoglobulin, albumin, ovalbumin, soya, and Dermatophagoides pteronyssinus and Saccharomyces cerevisiae strains using an ELISA technique. The patients were compared with 29 healthy individuals matched for sex and age. A serum was regarded as positive if the absorbance was two standard deviations higher than values obtained with sera from healthy subjects. Historical data, including factors which the patients believed to provoke their Ménière's symptoms, were obtained from patients' questionnaires. MD patients showed no significant symptoms of allergenic disorders suggesting allergies when compared to controls (p > 0.05). IgG and IgA antibody levels were not significantly raised in MD patients as compared with healthy controls (p > 0.05) for gliadin, beta-lactoglobulin, soya, albumin, ovalbumin, and D. pteronyssinus and S. cerevisiae strains. These data do not convincingly support a hypothesis of increased serum levels of antifood antibodies in patients with MD, as very few patients were antibody positive.

No evidence of auditory dysfunction in guinea pigs immunized with myelin P0 protein.

Recent data have focused on the peripheral nerve myelin glycoprotein P0 as a putative autoantigen involved in the autoimmune etiology of some cases of Meniere's disease, idiopathic sensorineural hearing loss and sudden deafness. To determine whether antibodies to myelin P0 can alter cochlear function, 13 healthy guinea pigs were immunized with purified porcine myelin P0 while 10 controls were injected with saline water. The animals were then evaluated for evidence of evolving inner ear disease using immunological, electrophysiological and morphological methods. Twenty-six experimental ears were tested weekly with a brainstem auditory evoked potential technique for a period of 4 months and were compared to 20 control ears. Uniformly, all P0-sensitized guinea pigs showed antibodies to myelin protein P0 as evidenced by ELISA. Clinical signs of inflammatory demyelination were not discernible in P0-sensitized guinea pigs and all the animals were qualitatively normal. No significant increase of evoked potential thresholds was found in the P0-sensitized animals when compared to controls (P>0.05). Peak latencies of waves I, II, III, IV and V and inter-peak latencies in P0-sensitized guinea pigs did not significantly differ from those of controls (P>0.05). Histological sections of inner ear and peripheral nerves were free of disease in both groups. These findings indicate that the sole presence of antibodies to myelin P0 in the sera of guinea pigs or patients suspected of having autoimmune inner ear diseases is unlikely to elicit auditory abnormalities and that additional factors are necessary for the pathogenic development of these disorders.

Autoimmune sensorineural hearing loss in young patients: an exploratory study.

OBJECTIVES: P0 protein is expressed exclusively in myelinating Schwann cells of the peripheral nervous system. In a previous study from our laboratory, 27% of patients with sensorineural hearing loss (SNHL) had antibodies to P0 protein in their serum. The purpose of the present exploratory study was to examine the relationship between the clinical presentation of SNHL among children and young adults (age range, 5-30 y) and the presence of serum anti-P0 antibodies. STUDY DESIGN: The data were collected by retrospective questionnaires from Belgian otolaryngologists. METHODS: Patients were divided for comparison into two groups according to the presence or absence of anti-P0 antibodies. RESULTS: Analyses of clinical data and audiometric results indicated that a progressive hearing loss was more frequently recorded in the patients in the anti-P0 antibody-positive group (82% [14 of 17]) than in those in the anti-P0 antibody-negative group (35% [6 of 17]) (P <.005). CONCLUSIONS: Thus, in the age group in the present study, autoimmune SNHL (as measured in the present study by the presence of anti-P0 antibodies) is more frequently associated with progressive than with sudden hearing loss. The implications of this finding for preventive screening of hearing loss in children and young adults are discussed.