38 resultados para Coherence function, X
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The histidine triad nucleotide-binding (Hint2) protein is a mitochondrial adenosine phosphoramidase expressed in liver and pancreas. Its physiological function is unknown. To elucidate the role of Hint2 in liver physiology, the Hint2 gene was deleted. Hint2(-/-) and Hint2(+/+) mice were generated in a mixed C57Bl6/J x 129Sv background. At 20 weeks, the phenotypic changes in Hint2(-/-) relative to Hint2(+/+) mice were an accumulation of hepatic triglycerides, decreased tolerance to glucose, a defective counter-regulatory response to insulin-provoked hypoglycaemia, an increase in plasma interprandial insulin but a decrease in glucose stimulated insulin secretion and defective thermoregulation upon fasting. Leptin mRNA in adipose tissue and plasma leptin were elevated. In mitochondria from Hint2(-/-) hepatocytes, state 3 respiration was decreased, a finding confirmed in HepG2 cells where HINT2 mRNA was silenced. The linked complex II to III electron transfer was decreased in Hint2(-/-) mitochondria, which was accompanied by a lower content of coenzyme Q. HIF-2α expression and the generation of reactive oxygen species were increased. Electron microscopy of mitochondria in Hint2(-/-) mice aged 12 months revealed clustered, fused organelles. The hepatic activities of 3-hydroxyacyl-CoA dehydrogenase short chain and glutamate dehydrogenase (GDH) were decreased by 68% and 60%, respectively, without a change in protein expression. GDH activity was similarly decreased in HINT2-silenced HepG2 cells. When measured in the presence of purified sirtuin 3, latent GDH activity was recovered (126% in Hint2(-/-) vs. 83% in Hint2(+/+) ). This suggests a greater extent of acetylation in Hint2(-/-) than in Hint2(+/+) . Conlusions: Hint2 positively regulates mitochondrial lipid metabolism and respiration, and glucose homeostasis. The absence of Hint2 provokes mitochondrial deformities and a change in the pattern of acetylation of selected proteins. (HEPATOLOGY 2012.).
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Ectodomain shedding at the cell surface is a major mechanism to regulate the extracellular and circulatory concentration or the activities of signaling proteins at the plasma membrane. Human meprin β is a 145-kDa disulfide-linked homodimeric multidomain type-I membrane metallopeptidase that sheds membrane-bound cytokines and growth factors, thereby contributing to inflammatory diseases, angiogenesis, and tumor progression. In addition, it cleaves amyloid precursor protein (APP) at the β-secretase site, giving rise to amyloidogenic peptides. We have solved the X-ray crystal structure of a major fragment of the meprin β ectoprotein, the first of a multidomain oligomeric transmembrane sheddase, and of its zymogen. The meprin β dimer displays a compact shape, whose catalytic domain undergoes major rearrangement upon activation, and reveals an exosite and a sugar-rich channel, both of which possibly engage in substrate binding. A plausible structure-derived working mechanism suggests that substrates such as APP are shed close to the plasma membrane surface following an "N-like" chain trace.
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In protein folding and secretion disorders, activation of endoplasmic reticulum (ER) stress signaling (ERSS) protects cells, alleviating stress that would otherwise trigger apoptosis. Whether the stress-surviving cells resume normal function is not known. We studied the in vivo impact of ER stress in terminally differentiating hypertrophic chondrocytes (HCs) during endochondral bone formation. In transgenic mice expressing mutant collagen X as a consequence of a 13-base pair deletion in Col10a1 (13del), misfolded alpha1(X) chains accumulate in HCs and elicit ERSS. Histological and gene expression analyses showed that these chondrocytes survived ER stress, but terminal differentiation is interrupted, and endochondral bone formation is delayed, producing a chondrodysplasia phenotype. This altered differentiation involves cell-cycle re-entry, the re-expression of genes characteristic of a prehypertrophic-like state, and is cell-autonomous. Concomitantly, expression of Col10a1 and 13del mRNAs are reduced, and ER stress is alleviated. ERSS, abnormal chondrocyte differentiation, and altered growth plate architecture also occur in mice expressing mutant collagen II and aggrecan. Alteration of the differentiation program in chondrocytes expressing unfolded or misfolded proteins may be part of an adaptive response that facilitates survival and recovery from the ensuing ER stress. However, the altered differentiation disrupts the highly coordinated events of endochondral ossification culminating in chondrodysplasia.
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Tissue engineering represents an attractive approach for the treatment of congestive heart failure. The influence of the differentiation of myogenic graft for functional recovery is not defined. We engineered a biodegradable skeletal muscle graft (ESMG) tissue and investigated its functional effect after implantation on the epicardium of an infarcted heart segment. ESMGs were synthesized by mixing collagen (2 mg/mL), Matrigel (2 mg/mL), and rat skeletal muscle cells (10(6)). Qualitative and quantitative aspects of ESMGs were optimized. Two weeks following coronary ligation, the animals were randomized in three groups: ESMG glued to the epicardial surface with fibrin (ESMG, n = 7), fibrin alone (fibrin, n = 5), or sham operation (sham, n = 4). Echocardiography, histology, and immunostaining were performed 4 weeks later. A cohesive three-dimensional tissular structure formed in vitro within 1 week. Myoblasts differentiated into randomly oriented myotubes. Four weeks postimplantation, ESMGs were vascularized and invaded by granulation tissue. Mean fractional shortening (FS) was, however, significantly increased in the ESMG group as compared with preimplantation values (42 +/- 6 vs. 33 +/- 5%, P < 0.05) and reached the values of controlled noninfarcted animals (control, n = 5; 45 +/- 3%; not significant). Pre- and postimplantation FS did not change over these 4 weeks in the sham group and the fibrin-treated animals. This study showed that it is possible to improve systolic heart function following myocardial infarction through implantation of differentiated muscle fibers seeded on a gel-type scaffold despite a low rate of survival.
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Post-natal exposure to air pollution is associated with diminished lung growth during school age. The current authors aimed to determine whether pre-natal exposure to air pollution is associated with lung function changes in the newborn. In a prospective birth cohort of 241 healthy term-born neonates, tidal breathing, lung volume, ventilation inhomogeneity and exhaled nitric oxide (eNO) were measured during unsedated sleep at age 5 weeks. Maternal exposure to particles with a 50% cut-off aerodynamic diameter of 10 microm (PM(10)), nitrogen dioxide (NO(2)) and ozone (O(3)), and distance to major roads were estimated during pregnancy. The association between these exposures and lung function was assessed using linear regression. Minute ventilation was higher in infants with higher pre-natal PM(10) exposure (24.9 mL x min(-1) per microg x m(-3) PM(10)). The eNO was increased in infants with higher pre-natal NO(2) exposure (0.98 ppb per microg x m(-3) NO(2)). Post-natal exposure to air pollution did not modify these findings. No association was found for pre-natal exposure to O(3) and lung function parameters. The present results suggest that pre-natal exposure to air pollution might be associated with higher respiratory need and airway inflammation in newborns. Such alterations during early lung development may be important regarding long-term respiratory morbidity.
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The alveolated structure of the pulmonary acinus plays a vital role in gas exchange function. Three-dimensional (3D) analysis of the parenchymal region is fundamental to understanding this structure-function relationship, but only a limited number of attempts have been conducted in the past because of technical limitations. In this study, we developed a new image processing methodology based on finite element (FE) analysis for accurate 3D structural reconstruction of the gas exchange regions of the lung. Stereologically well characterized rat lung samples (Pediatr Res 53: 72-80, 2003) were imaged using high-resolution synchrotron radiation-based X-ray tomographic microscopy. A stack of 1,024 images (each slice: 1024 x 1024 pixels) with resolution of 1.4 mum(3) per voxel were generated. For the development of FE algorithm, regions of interest (ROI), containing approximately 7.5 million voxels, were further extracted as a working subunit. 3D FEs were created overlaying the voxel map using a grid-based hexahedral algorithm. A proper threshold value for appropriate segmentation was iteratively determined to match the calculated volume density of tissue to the stereologically determined value (Pediatr Res 53: 72-80, 2003). The resulting 3D FEs are ready to be used for 3D structural analysis as well as for subsequent FE computational analyses like fluid dynamics and skeletonization.
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INTRODUCTION: Impact on sexual function has received little attention in the medical literature for a long time. Because of the site of insertion of permanent tension free vaginal tape (TVT) the G spot might be affected or the tape might interfere with arousal and sensory stimulation. Recent studies have reported varying degrees of sexual impairment after TVT insertion ranging from 0% to 15% including dyspareunia. AIM: The aim of this study was to evaluate sexual function before and after suburethral sling removal due to postoperative female de novo dyspareunia. As a secondary outcome, general patients' satisfaction with their overall continence situation was assessed. PATIENTS AND METHODS: Between December 2005 and December 2007, we included 18 female patients who complained of de novo dyspareunia after suburethral sling insertion for urinary stress incontinence. All patients filled in an FSFI questionnaire prior to sling removal and at 3 months postoperatively. Additionally, all women were asked to estimate their general satisfaction regarding their continence situation using a Visual Analogue Scale (VAS) from 0 to 10, with 0 being the least satisfying situation and 10 being the most satisfying situation. All patients underwent gynaecological examination including ICS-pelvic organ prolapse staging (ICS-POP score). RESULTS: Of the 18 slings, ten were transobturator tapes (6 x TVT-O, 2 x Monarch, 2 x unknown) and eight were retropubic tapes (7 x TVT, 1 x SPARC). Desire, arousal, lubrication, satisfaction, and pain improved statistically significant. Orgasm scores were low with median scoring of 1.5 scores before and 1.0 scores after sling removal, and they did not change significantly after sling removal. The satisfaction rate deteriorated from a median of 7 (95% confidence interval [CI] 6.3-7.7) to a median of 4 (95% CI 3.7-5.1; p=0.99) but not statistically significant. CONCLUSIONS: Sexual function in patients with de novo dyspareunia is likely to improve after sling removal but not in all domains. Bladder function may deteriorate.
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PURPOSE: To correlate the dimension of the visual field (VF) tested by Goldman kinetic perimetry with the extent of visibility of the highly reflective layer between inner and outer segments of photoreceptors (IOS) seen in optical coherence tomography (OCT) images in patients with retinitis pigmentosa (RP). METHODS: In a retrospectively designed cross-sectional study, 18 eyes of 18 patients with RP were examined with OCT and Goldmann perimetry using test target I4e and compared with 18 eyes of 18 control subjects. A-scans of raw scan data of Stratus OCT images (Carl Zeiss Meditec, AG, Oberkochen, Germany) were quantitatively analyzed for the presence of the signal generated by the highly reflective layer between the IOS in OCT images. Starting in the fovea, the distance to which this signal was detectable was measured. Visual fields were analyzed by measuring the distance from the center point to isopter I4e. OCT and visual field data were analyzed in a clockwise fashion every 30 degrees , and corresponding measures were correlated. RESULTS: In corresponding alignments, the distance from the center point to isopter I4e and the distance to which the highly reflective signal from the IOS can be detected correlate significantly (r = 0.75, P < 0.0001). The greater the distance in VF, the greater the distance measured in OCT. CONCLUSIONS: The authors hypothesize that the retinal structure from which the highly reflective layer between the IOS emanates is of critical importance for visual and photoreceptor function. Further research is warranted to determine whether this may be useful as an objective marker of progression of retinal degeneration in patients with RP.
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Siglec-8, the eighth member of the sialic acid-binding, immunoglobulin [Ig]-like lectin family, was initially discovered as a cell surface protein selectively expressed on human eosinophils. It is now know to also be expressed by mast cells and basophils. Siglec-8 engagement with specific antibodies causes apoptosis via caspase and mitochondrial-dependent pathways. For mast cells, inhibition of mediator release, but no apoptosis, is observed. Siglec-F is the closest mouse paralog to Siglec-8, and both selectively bind the sulfated glycan 6’-sulfo-sialyl Lewis X. Antibodies to Siglec-F reduce blood and tissue eosinophil numbers in vivo. This suggests that Siglec-8 may be a useful future therapeutic target for allergic and other eosinophilic disorders.
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End stage renal disease is a major complication after orthotopic liver transplantation (OLT). Vasoconstriction of renal arterial vessels because of calcineurin inhibitor (CNI) treatment plays a pivotal role in the development of renal insufficiency following OLT. Renal resistance can be measured non-invasively by determining the resistance index (RI) of segmental arteries by color-coded duplex ultrasonography, a measure with predictive value for future renal failure. Sixteen OLT patients on long-term CNI therapy were recruited prospectively and randomly assigned either to receive the m-TOR inhibitor sirolimus (SRL) or to continue on CNI treatment, and were followed for one yr. Serum creatinine (crea) declined after conversion to SRL, whereas it tended to increase in patients remaining on CNI (meanDelta crea SRL: -27, -18, -18, -15 micromol/L; meanDelta crea CNI: 4, 5, 8, 11 micromol/L at 1, 3, 6, 12 months, p = 0.02). RI improved after switching to SRL and was lower on SRL than on CNI (meanDeltaRI SRL: -0.04, -0.04, -0.03, -0.03; meanDeltaRI CNI: -0.006, 0.004, -0.007, -0.01 after 1, 3, 6, 12 months, p = 0.016). Individual changes of RI correlated significantly with individual changes of crea (r = 0.54, p < 0.001). Conversion from CNI to SRL can ameliorate renal function accompanied by a reduction of intrarenal RI after OLT.
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INTRODUCTION: Few data are available referring to male and female sexual function after prolapse repair of symptomatic pelvic organ. AIM: Primary aim of this study is to determine the male and female sexual function before and after surgery for pelvic organ prolapse. MAIN OUTCOME MEASURES: We used the Female Sexual Function Index (FSFI) questionnaire for female patients and for their male partners the Brief Male Sexual Inventory (BMSI) as measurement of sexual function. METHODS: We included sexually active heterosexual couples that were referred to the Department of Urogynaecology because of symptomatic cystocele, rectocele or vault descent. For cystoceles, anterior repair was performed, for rectoceles posterior repair, and for vault descent sacrospinous ligament fixation. FSFI and BMSI questionnaires were distributed before and after pelvic organ surgery and 4 months after. Female clinical examination assessing the degree of prolapse was performed before and 6 weeks after surgery. RESULTS: A full data set of 70 female questionnaires and 64 male questionnaires could be evaluated. Two cases of female de novo dyspareunia occurred. In women, FSFI scores improved significantly in the domains desire, arousal, lubrication, overall satisfaction, and particularly pain. Orgasm remained unchanged. In men, interest, sexual drive, and overall satisfaction improved significantly. Erection, ejaculatory function, and orgasm remained unchanged. Despite remaining unchanged, erection, strength of erection, ejaculation, and orgasm were not considered problems anymore compared to preoperative BMSI scores. CONCLUSION: Surgery for pelvic organ prolapse improves male and female sexual function in some domains but not in all.
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OBJECTIVE: Recent studies have shown that mechanically unloading a failing heart may induce reverse remodeling and functional improvement. However, these benefits may be balanced by an unloading-related remodeling including myocardial atrophy that might lead to decrease in function. Using a model of heterotopic heart transplantation, we aimed to characterize the myocardial changes induced by long-term unloading. MATERIAL AND METHODS: Macroscopic as well as cellular and functional changes were followed in normal hearts unloaded for a 3-month period. Microscopic parameters were evaluated with stereologic methodology. Myocardial contractile function was quantified with a Langendorff isolated, perfused heart technique. RESULTS: Atrophy was macroscopically obvious and accompanied by a 67% reduction of the myocyte volume and a 43% reduction of the interstitial tissue volume, thus accounting for a shift of the myocyte/connective tissue ratio in favor of noncontractile tissue. The absolute number of cardiomyocyte nuclei decreased from 64.7 +/- 5.1 x 10(7) in controls to 22.6 +/- 3.7 x 10(7) (30 days) and 21.6 +/- 3.1 x 10(7) (90 days) after unloading (P < .05). The numeric nucleic density in the unloaded myocardium, as well as the mean cardiomyocyte volume per cardiomyocyte nucleus, remained constant throughout the 90 days of observation. Functional data indicated an increase in ventricular stiffness, although contractile function was preserved, as confirmed by unaltered maximal developed pressure and increased contractility (maximum rate of left ventricular pressure development) and relaxation (minimum rate of left ventricular pressure development). CONCLUSION: Atrophic remodeling involves both the myocyte and interstitial tissue compartment. These data suggest that although there is decreased myocardial volume and increased stiffness, contractile capacity is preserved in the long-term unloaded heart.
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PURPOSE: To test the reproducibility of retinal thickness measurements in healthy volunteers of a new Frequency-domain optical coherence tomography (OCT) device (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany). DESIGN: Prospective, observational study. METHODS: Forty-one eyes of 41 healthy subjects were included into the study. Intraobserver reproducibility was tested with 20 x 15 degree raster scans consisting of 37 high-resolution line scans that were repeated three times by one examiner (M.N.M.). Mean retinal thickness was calculated for nine areas corresponding to the Early Treatment Diabetic Retinopathy Study (ETDRS) areas. Coefficients of variation (COV) were calculated. RESULTS: Retinal thickness measurements were highly reproducible for all ETDRS areas. Mean total retinal thickness was 342 +/- 15 microm. Mean foveal thickness was 286 +/- 17 microm. COVs ranged from 0.38% to 0.86%. Lowest COV was found for the temporal outer ETDRS area (area 7; COV, 0.38%). Highest COV was found for the temporal inner ETDRS area (area 3; COV, 0.86%). Mean difference between measurement 1 and 2, measurement 1 and 3, and measurement 2 and 3 for all ETDRS areas was 1.01 microm, 0.98 microm, and 0.99 microm, respectively. CONCLUSION: Spectralis OCT retinal thickness measurements in healthy volunteers showed excellent intraobserver reproducibility with virtually identical results between retinal thickness measurements performed by one operator.