Autosomal Recessive Posterior Microphthalmos/Nanophthalmos is Caused by Loss-of-function Mutations in LOC646960, a Novel Gene Encoding a Trypsin-like Serine Protease

Purpose: Posterior microphthalmos (MCOP)/nanophthalmos (NNO) is a developmental anomaly characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal recessive form (arMCOP). The gene mutated in arMCOP is not yet known.Methods: Genetic mapping by linkage analysis using microsatellite and single nucleotide polymorphisms, mutation analysis by PCR and sequencing, molecular modellingResults: Having refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in Faroese families, we detected 3 mutations in a novel gene, LOC646960: Patients of 10 different Faroese families were either homozygous (n=22) for c.926G>C (p.Trp309Ser) or compound heterozygous (n=6) for c.926G>C and c.526C>G (p.Arg176Gly), whereas a homozygous 1 bp duplication (c.1066dupC) was identified in patients with arNNO from a Tunisian family. In two unrelated patients with MCOP, no LOC646960 mutation was found. LOC646960 is expressed in the human adult retina and RPE. The expression of the mouse homologue in the eye can be first detected at E17 and is highest in adults. The predicted protein is a 603 amino acid long secreted trypsin-like serine peptidase. c.1066dupC should result in a functional null allele. Molecular modelling of the p.Trp309Ser mutant suggests that both affinity and reactivity of the enzyme towards in vivo substrates are substantially reduced.Conclusions: Postnatal growth of the eye is important for proper development of the refractive components (emmetropization), and is mainly due to elongation of the posterior segment from 10-11 mm at birth to 15-16 mm at the age of 13 years. Optical defocus leads to changes in axial length by moving the retina towards the image plane. arMCOP may theoretically be explained, in line with the expression pattern of LOC646960, by a postnatal growth retardation of the posterior segment.

Non-traumatic spinal cord ischaemia in childhood - clinical manifestation, neuroimaging and outcome.

BACKGROUND: Spinal cord ischaemia is rare in childhood and information on clinical presentation and outcome is scarce. METHODS: This is a retrospective analysis of eight patients and 75 additional cases from the literature. Data search included: patient's age, primary manifestation, risk factors, neuroimaging and outcome. RESULTS: Five female and three male patients gave consent to participate. Mean age was 12.5 years (10-15 years). Six patients presented with paraplegia; this was preceded by pain in four. Brown Sequard syndrome and quadriparesis were the two others' presenting condition. Sensation levels were thoracolumbar in seven cases. Bladder dysfunction only or bladder and bowel dysfunction were reported in eight and five patients respectively. Time to maximal symptom manifestation was <12 h in 7/8. Risk factors included surgery, minor trauma, recent infection, and thrombophilia. Mean follow-up was 3.3 years (0.25-6.3 years). Three patients remained wheelchair-dependent and three patients were ambulatory without aid. Bladder function recovered fully in five children. Most affected aspects of quality of life were physical and mental well-being and self-perception. T2-weighted-MR images showed pencil-like hyperintensity (8/8) in sagittal and H-shaped or snake-eyes-like lesion (6/8) in axial views. Analyses of all 83 patients were in congruence with the above results of the study group. CONCLUSION: Spinal cord ischaemia in childhood presenting with pain, paraplegia, and bladder dysfunction has high morbidity concerning motor problems and quality of life. Acute arterial ischaemic event in children seems similar to adult events with respect to clinical presentation and, surprisingly, also in outcome.

Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice.

Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site- and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc1(tm1a)) that reduces mRNA to ∼10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1(tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1(tm1a/tm1a) embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.

Rate and processes of river network rearrangement during incipient faulting: The case of the Cahabon river, Guatemala

Deeply incised river networks are generally regarded as robust features that are not easily modified by erosion or tectonics. Although the reorganization of deeply incised drainage systems has been documented, the corresponding importance with regard to the overall landscape evolution of mountain ranges and the factors that permit such reorganizations are poorly understood. To address this problem, we have explored the rapid drainage reorganization that affected the Cahabon River in Guatemala during the Quaternary. Sediment-provenance analysis, field mapping, and electrical resistivity tomography (ERT) imaging are used to reconstruct the geometry of the valley before the river was captured. Dating of the abandoned valley sediments by the Be-10-Al-26 burial method and geomagnetic polarity analysis allow us to determine the age of the capture events and then to quantify several processes, such as the rate of tectonic deformation of the paleovalley, the rate of propagation of post-capture drainage reversal, and the rate at which canyons that formed at the capture sites have propagated along the paleovalley. Transtensional faulting started 1 to 3 million years ago, produced ground tilting and ground faulting along the Cahabon River, and thus generated differential uplift rate of 0.3 +/- 0.1 up to 0.7 +/- 0.4 mm . y(-1) along the river's course. The river responded to faulting by incising the areas of relative uplift and depositing a few tens of meters of sediment above the areas of relative subsidence. Then, the river experienced two captures and one avulsion between 700 ky and 100 ky. The captures breached high-standing ridges that separate the Cahabon River from its captors. Captures occurred at specific points where ridges are made permeable by fault damage zones and/or soluble rocks. Groundwater flow from the Cahabon River down to its captors likely increased the erosive power of the captors thus promoting focused erosion of the ridges. Valley-fill formation and capture occurred in close temporal succession, suggesting a genetic link between the two. We suggest that the aquifers accumulated within the valley-fills, increased the head along the subterraneous system connecting the Cahabon River to its captors, and promoted their development. Upon capture, the breached valley experienced widespread drainage reversal toward the capture sites. We attribute the generalized reversal to combined effects of groundwater sapping in the valley-fill, axial drainage obstruction by lateral fans, and tectonic tilting. Drainage reversal increased the size of the captured areas by a factor of 4 to 6. At the capture sites, 500 m deep canyons have been incised into the bedrock and are propagating upstream at a rate of 3 to 11 mm . y(-1) deepening at a rate of 0.7 to 1 5 mm . y(-1). At this rate, 1 to 2 million years will be necessary for headward erosion to completely erase the topographic expression of the paleovalley. It is concluded that the rapid reorganization of this drainage system was made possible by the way the river adjusted to the new tectonic strain field, which involved transient sedimentation along the river's course. If the river had escaped its early reorganization and had been given the time necessary to reach a new dynamic equilibrium, then the transient conditions that promoted capture would have vanished and its vulnerability to capture would have been strongly reduced.

Brain Surface Segmentation of Magnetic Resonance Images of the Fetus

In this work we present a method for the image analysisof Magnetic Resonance Imaging (MRI) of fetuses. Our goalis to segment the brain surface from multiple volumes(axial, coronal and sagittal acquisitions) of a fetus. Tothis end we propose a two-step approach: first, a FiniteGaussian Mixture Model (FGMM) will segment the image into3 classes: brain, non-brain and mixture voxels. Second, aMarkov Random Field scheme will be applied tore-distribute mixture voxels into either brain ornon-brain tissue. Our main contributions are an adaptedenergy computation and an extended neighborhood frommultiple volumes in the MRF step. Preliminary results onfour fetuses of different gestational ages will be shown.

Management of fragility fractures in Switzerland: results of a nationwide survey.

A nationwide survey was conducted in Switzerland to assess the quality level of osteoporosis management in patients aged 50 years or older presenting with a fragility fracture to the emergency ward of the participating hospitals. Eight centres recruited 4966 consecutive patients who presented with one or more fractures between 2004 and 2006. Of these, 3667 (2797 women, 73.8 years old and 870 men, 73.0 years old in average) were considered as having a fragility fracture and included in the survey. Included patients presented with a fracture of the upper limbs (30.7%), lower limbs (26.4%), axial skeleton (19.5%) or another localisation, including malleolar fractures (23.4%). Thirty-two percent reported one or more previous fractures during adulthood. Of the 2941 (80.2%) hospitalised women and men, only half returned home after discharge. During diagnostic workup, dual x-ray absorptiometry (DXA) measurement was performed in 31.4% of the patients only. Of those 46.0% had a T-score < or =-2.5 SD and 81.1% < or =-1.0 SD. Osteoporosis treatment rate increased from 26.3% before fracture to 46.9% after fracture in women and from 13.0% to 30.3% in men. However, only 24.0% of the women and 13.8% of the men were finally adequately treated with a bone active substance, generally an oral bisphosphonate, with or without calcium / vitamin D supplements. A positive history of previous fracture vs none increased the likelihood of getting treatment with a bone active substance (36.6 vs 17.9%, ? 18.7%, 95% CI 15.1 to 22.3, and 22.6 vs 9.9%, ? 12.7%, CI 7.3 to 18.5, in women and men, respectively). In Switzerland, osteoporosis remains underdiagnosed and undertreated in patients aged 50 years and older presenting with a fragility fracture.

Seismic reflectivity of the sediment-covered seafloor: Effects of velocity gradients and fine-scale layering

Knowledge of the reflectivity of the sediment-covered seabed is of significant importance to marine seismic data acquisition and interpretation as it governs the generation of reverberations in the water layer. In this context pertinent, but largely unresolved, questions concern the importance of the typically very prominent vertical seismic velocity gradients as well as the potential presence and magnitude of anisotropy in soft surficial seabed sediments. To address these issues, we explore the seismic properties of granulometric end-member-type clastic sedimentary seabed models consisting of sand, silt, and clay as well as scale-invariant stochastic layer sequences of these components characterized by realistic vertical gradients of the P- and S-wave velocities. Using effective media theory, we then assess the nature and magnitude of seismic anisotropy associated with these models. Our results indicate that anisotropy is rather benign for P-waves, and that the S-wave velocities in the axial directions differ only slightly. Because of the very high P- to S-wave velocity ratios in the vicinity of the seabed our models nevertheless suggest that S-wave triplications may occur at very small incidence angles. To numerically evaluate the P-wave reflection coefficient of our seabed models, we apply a frequency-slowness technique to the corresponding synthetic seismic wavefields. Comparison with analytical plane-wave reflection coefficients calculated for corresponding isotropic elastic half-space models shows that the differences tend to be most pronounced in the vicinity of the elastic equivalent of the critical angle as well as in the post-critical range. We also find that the presence of intrinsic anisotropy in the clay component of our layered models tends to dramatically reduce the overall magnitude of the P-wave reflection coefficient as well as its variation with incidence angle.

Influence of the morphology of the dural sac on surgical decision making in lumbar spinal stenosis

Introduction: Surgical decision making in lumbar spinal stenosis (LSS) takes into account primarily clinical symptoms as well as concordant radiological findings. We hypothesized that a wide variation of operative threshold would be found in particular as far as judgment of severity of radiological stenosis is concerned. Patients and methods: The number of surgeons who would proceed to decompression was studied relative to the perceived severity of radiological stenosis based either on measurements of dural sac cross sectional area (DSCA) or on the recently described morphological grading as seen on axial T2 MRI images. A link to an electronic survey page with a set of ten axial T2 MRI images taken from ten patients with either low back pain or LSS were sent to members of three national or international spine societies. Those 10 images were randomly presented initially and re-shuffled on a second page including this time DSCA measurements in mm2, ranging from 14 to 226 mm2, giving a total of 20 images to appraise. Morphological grades were ranging from grade A to D. Surgeons were asked if they would consider decompression given the radiological appearance of stenosis and that symptoms of neurological claudication were severe in patients who were otherwise fit for surgery. Fisher's exact test was performed following dichotomization of data when appropriate. Results: A total of 142 spine surgeons (113 orthopedic spine surgeons, 29 neurosurgeons) responded from 25 countries. A substantial agreement was observed in operating patients with severe (grade C) or extreme (grade D) stenosis as defined by the morphological grade compared to lesser stenosis (A&B) grades (p<0.0001). Decision to operate was not dependent on number of years in practice, medical density in practicing country or specialty although more neurosurgeons would operate on grade C stenosis (p<0.005). Disclosing the DSCA measurement did not alter the decision to operate. Although 20 surgeons only had prior knowledge of the description of the morphological grading, their responses showed no statistically significant difference with those of the remaining 122 physicians. Conclusions: This study showed that surgeons across borders are less influenced by DSCA in their decision making than by the morphological appearance of the dural sac. Classifying LSS according to morphology rather than surface measurements appears to be consistent with current clinical practice.

Ankle joint pressure in pes cavovarus after lateralizing calcaneal osteotomies

BACKGROUND: Tendon transfers and calcaneal osteotomies are commonly used to treat symptoms related to medial ankle arthrosis in fixed pes cavovarus. However, the relative effect of these osteotomies in terms of lateralizing the ground contact point of the hindfoot and redistributing ankle joint contact stresses are unknown. MATERIALS AND METHODS: Pes cavovarus with fixed hindfoot varus was simulated in eight cadaver specimens. The effect of three types of calcaneal osteotomies on the migration of the center of force and tibiotalar peak pressure at 300 N axial static load (half-body weight) were recorded using pressure sensors. RESULTS: A significant lateral shift of the center of force was observed: 4.9 mm for the laterally closing Z-shaped osteotomy with additional lateralization of the tuberosity, 3.4 mm for the lateral sliding osteotomy of the calcaneal tuberosity, and 2.7 mm for the laterally closing Z-shaped osteotomy (all p < 0.001). A significant peak pressure reduction was recorded: -0.53 MPa for the Z-shaped osteotomy with lateralization, -0.58 MPa for the lateral sliding osteotomy of the calcaneal tuberosity, and -0.41 MPa for the Z-shaped osteotomy (all p < 0.01). CONCLUSION: This cadaver study supports the hypothesis that lateralizing calcaneal osteotomies substantially help to normalize ankle contact stresses in pes cavovarus.

The squeeze cell hypothesis for the activation of jasmonate synthesis in response to wounding

Jasmonates are lipid mediators that control defence gene expression in response to wounding and other environmental stresses. These small molecules can accumulate at distances up to several cm from sites of damage and this is likely to involve cell-to-cell jasmonate transport. Also, and independently of jasmonate synthesis, transport and perception, different long-distance wound signals that stimulate distal jasmonate synthesis are propagated at apparent speeds of several cmmin(-1) to tissues distal to wounds in a mechanism that involves clade 3 GLUTAMATE RECEPTOR-LIKE (GLR) genes. A search for jasmonate synthesis enzymes that might decode these signals revealed LOX6, a lipoxygenase that is necessary for much of the rapid accumulation of jasmonic acid at sites distal to wounds. Intriguingly, the LOX6 promoter is expressed in a distinct niche of cells that are adjacent to mature xylem vessels, a location that would make these contact cells sensitive to the release of xylem water column tension upon wounding. We propose a model in which rapid axial changes in xylem hydrostatic pressure caused by wounding travel through the vasculature and lead to slower, radially dispersed pressure changes that act in a clade 3 GLR-dependent mechanism to promote distal jasmonate synthesis.

Spatial analysis of erythrocyte membrane fluctuations by digital holographic microscopy.

Red blood cell (RBC) membrane fluctuations provide important insights into cell states. We present a spatial analysis of red blood cell membrane fluctuations by using digital holographic microscopy (DHM). This interferometric and dye-free technique, possessing nanometric axial and microsecond temporal sensitivities enables to measure cell membrane fluctuations (CMF) on the whole cell surface. DHM acquisition is combined with a model which allows extracting the membrane fluctuation amplitude, while taking into account cell membrane topology. Uneven distribution of CMF amplitudes over the RBC surface is observed, showing maximal values in a ring corresponding to the highest points on the RBC torus as well as in some scattered areas in the inner region of the RBC. CMF amplitudes of 35.9+/-8.9 nm and 4.7+/-0.5 nm (averaged over the cell surface) were determined for normal and ethanol-fixed RBCs, respectively.

De novo LMNA mutations cause a new form of congenital muscular dystrophy.

OBJECTIVE: To describe a new entity of congenital muscular dystrophies caused by de novo LMNA mutations. METHODS: Fifteen patients presenting with a myopathy of onset in the first year of life were subjected to neurological and genetic evaluation. Histopathological and immunohistochemical analyses were performed for all patients. RESULTS: The 15 patients presented with muscle weakness in the first year of life, and all had de novo heterozygous LMNA mutations. Three of them had severe early-onset disease, no motor development, and the rest experienced development of a "dropped head" syndrome phenotype. Despite variable severity, there was a consistent clinical pattern. Patients typically presented with selective axial weakness and wasting of the cervicoaxial muscles. Limb involvement was predominantly proximal in upper extremities and distal in lower extremities. Talipes feet and a rigid spine with thoracic lordosis developed early. Proximal contractures appeared later, most often in lower limbs, sparing the elbows. Ten children required ventilatory support, three continuously through tracheotomy. Cardiac arrhythmias were observed in four of the oldest patients but were symptomatic only in one. Creatine kinase levels were mild to moderately increased. Muscle biopsies showed dystrophic changes in nine children and nonspecific myopathic changes in the remaining. Markedly atrophic fibers were common, most often type 1, and a few patients showed positive inflammatory markers. INTERPRETATION: The LMNA mutations identified appear to correlate with a relatively severe phenotype. Our results further broaden the spectrum of laminopathies and define a new disease entity that we suggest is best classified as a congenital muscular dystrophy (LMNA-related congenital muscular dystrophy, or L-CMD).

High-density collagen gel tubes as a matrix for primary human bladder smooth muscle cells.

Tissue-engineered grafts for the urinary tract are being investigated for the potential treatment of several urologic diseases. These grafts, predominantly tubular-shaped, usually require in vitro culture prior to implantation to allow cell engraftment on initially cell-free scaffolds. We have developed a method to produce tubular-shaped collagen scaffolds based on plastic compression. Our approach produces a ready cell-seeded graft that does not need further in vitro culture prior to implantation. The tubular collagen scaffolds were in particular investigated for their structural, mechanical and biological properties. The resulting construct showed an especially high collagen density, and was characterized by favorable mechanical properties assessed by axial extension and radial dilation. Young modulus in particular was greater than non-compressed collagen tubes. Seeding densities affected proliferation rate of primary human bladder smooth muscle cells. An optimal seeding density of 10(6) cells per construct resulted in a 25-fold increase in Alamar blue-based fluorescence after 2 wk in culture. These high-density collagen gel tubes, ready seeded with smooth muscle cells could be further seeded with urothelial cells, drastically shortening the production time of graft for urinary tract regeneration.

Lack of Enantioselectivity in the SULT1A3-catalyzed Sulfoconjugation of Normetanephrine Enantiomers: An In Vitro and Computational Study.

(1R)-Normetanephrine is the natural stereoisomeric substrate for sulfotransferase 1A3 (SULT1A3)-catalyzed sulfonation. Nothing appears known on the enantioselectivity of the reaction despite its potential significance in the metabolism of adrenergic amines and in clinical biochemistry. We confronted the kinetic parameters of the sulfoconjugation of synthetic (1R)-normetanephrine and (1S)-normetanephrine by recombinant human SULT1A3 to a docking model of each normetanephrine enantiomer with SULT1A3 and the 3'-phosphoadenosine-5'-phosphosulfate cofactor on the basis of molecular modeling and molecular dynamics simulations of the stability of the complexes. The K(M) , V(max) , and k(cat) values for the sulfonation of (1R)-normetanephrine, (1S)-normetanephrine, and racemic normetanephrine were similar. In silico models were consistent with these findings as they showed that the binding modes of the two enantiomers were almost identical. In conclusion, SULT1A3 is not substrate-enantioselective toward normetanephrine, an unexpected finding explainable by a mutual adaptability between the ligands and SULT1A3 through an "induced-fit model" in the catalytic pocket. Chirality, 00:000-000, 2012.© 2012 Wiley Periodicals, Inc.

Antigène carcino-embryonnaire circulant, fortement élevé et persistant, sans cancer décelable

A markedly elevated circulating CEA level was observed in January 1978 in a 40-year-old male patient who complained of functional digestive disorders consisting of 2-3 bowel movements at the end of each night. During follow-up of more than 3 years the CEA level was always found to be higher than 300 ng/ml as determined on 12 different blood samples using 3 different assays: the Hansen assay, our own inhibition radioimmunoassay performed on perchloric acid extract of serum, and a newly developed solid phase non-competitive enzyme immunoassay involving monoclonal anti-CEA antibody. The clinical evolution showed no aggravation of the persistent but mild bowel troubles, i.e. no real diarrhea or blood in the stool. The patient enjoys excellent general health and shows no weight loss. Barium enema, colonoscopy and extensive investigation by computerized axial tomography showed no evidence of primary or metastatic tumor. Apart from CEA, the blood chemistry was within normal limits. Six members of the patient's family have normal CEA levels. A possible explanation for this unique case of marked and persistent elevation of circulating CEA without evidence of cancer is discussed.