Notch signaling in the pigmented epithelium of the anterior eye segment promotes ciliary body development at the expense of iris formation.

The ciliary body and iris are pigmented epithelial structures in the anterior eye segment that function to maintain correct intra-ocular pressure and regulate exposure of the internal eye structures to light, respectively. The cellular and molecular factors that mediate the development of the ciliary body and iris from the ocular pigmented epithelium remain to be fully elucidated. Here, we have investigated the role of Notch signaling during the development of the anterior pigmented epithelium by using genetic loss- and gain-of-function approaches. Loss of canonical Notch signaling results in normal iris development but absence of the ciliary body. This causes progressive hypotony and over time leads to phthisis bulbi, a condition characterized by shrinkage of the eye and loss of structure/function. Conversely, Notch gain-of-function results in aniridia and profound ciliary body hyperplasia, which causes ocular hypertension and glaucoma-like disease. Collectively, these data indicate that Notch signaling promotes ciliary body development at the expense of iris formation and reveals novel animal models of human ocular pathologies.

Neuroanatomical and neuropsychological features of euthymic patients with bipolar disorder.

OBJECTIVE: Previous studies reported that the severity of cognitive deficits in euthymic patients with bipolar disorder (BD) increases with the duration of illness and postulated that progressive neuronal loss or shrinkage and white matter changes may be at the origin of this phenomenon. To explore this issue, the authors performed a case-control study including detailed neuropsychological and magnetic resonance imaging analyses in 17 euthymic elderly patients with BD and 17 healthy individuals. METHODS: Neuropsychological evaluation concerned working memory, episodic memory, processing speed, and executive functions. Volumetric estimates of the amygdala, hippocampus, entorhinal cortex, and anterior cingulate cortex were obtained using both voxel-based and region of interest morphometric methods. Periventricular and deep white matter were assessed semiquantitatively. Differences in cognitive performances and structural data between BD and comparison groups were analyzed using paired t-test or analysis of variance. Wilcoxon test was used in the absence of normal distribution. RESULTS: Compared with healthy individuals, patients with BD obtained significantly lower performances in processing speed, working memory, and episodic memory but not in executive functions. Morphometric analyses did not show significant volumetric or white matter differences between the two groups. CONCLUSIONS: Our results revealed impairment in verbal memory, working memory, and processing speed in euthymic older adults with BD. These cognitive deficits are comparable both in terms of affected functions and size effects to those previously reported in younger cohorts with BD. Both this observation and the absence of structural brain abnormalities in our cohort do not support a progressively evolving neurotoxic effect in BD.

Apoptotic markers in protozoan parasites.

ABSTRACT: The execution of the apoptotic death program in metazoans is characterized by a sequence of morphological and biochemical changes that include cell shrinkage, presentation of phosphatidylserine at the cell surface, mitochondrial alterations, chromatin condensation, nuclear fragmentation, membrane blebbing and the formation of apoptotic bodies. Methodologies for measuring apoptosis are based on these markers. Except for membrane blebbing and formation of apoptotic bodies, all other events have been observed in most protozoan parasites undergoing cell death. However, while techniques exist to detect these markers, they are often optimised for metazoan cells and therefore may not pick up subtle differences between the events occurring in unicellular organisms and multi-cellular organisms.In this review we discuss the markers most frequently used to analyze cell death in protozoan parasites, paying special attention to changes in cell morphology, mitochondrial activity, chromatin structure and plasma membrane structure/permeability. Regarding classical regulators/executors of apoptosis, we have reviewed the present knowledge of caspase-like and nuclease activities.

Productive HIV-1 infection of primary CD4+ T cells induces mitochondrial membrane permeabilization leading to a caspase-independent cell death.

We have explored in vitro the mechanism by which human immunodeficiency virus, type 1 (HIV-1) induces cell death of primary CD4+ T cells in conditions of productive infection. Although HIV-1 infection primed phytohemagglutinin-activated CD4+ T cells for death induced by anti-CD95 antibody, T cell death was not prevented by a CD95-Fc decoy receptor, nor by decoy receptors of other members of the TNFR family (TNFR1/R2, TRAILR1/R2/OPG, TRAMP) or by various blocking antibodies, suggesting that triggering of death receptors by their cognate ligands is not involved in HIV-induced CD4 T cell death. HIV-1 induced CD4 T cell shrinkage, cell surface exposure of phosphatidylserine, loss of mitochondrial membrane potential (Deltapsim), and mitochondrial release of cytochrome c and apoptosis-inducing factor. A typical apoptotic phenotype (nuclear chromatin condensation and fragmentation) only occurred in around half of the dying cells. Treatment with benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, a broad spectrum caspase inhibitor, prevented nuclear chromatin condensation and fragmentation in HIV-infected CD4+ T cells and in a cell-free system (in which nuclei were incubated with cytoplasmic extracts from the HIV-infected CD4+ T cells). Nevertheless, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone did not prevent mitochondrial membrane potential loss and cell death, suggesting that caspases are dispensable for HIV-mediated cell death. Our findings suggest a major role of the mitochondria in the process of CD4 T cell death induced by HIV, in which targeting of Bax to the mitochondria may be involved.

Synthesis of bone-like structured foams

Here we present a processing route to produce multi-structured ceramic foams based on the combination of particle-stabilized foams with polymeric sponges to produce positive and negative templating structures. Polyester sponges are infiltrated with freshly produced calcium aluminate alumina foams and upon sintering either positive templating structures are produced when wetting the sponges, or negative templating foams with a percolating pore network are obtained when completely filling the sponges. Additionally, by combining different layers of these particle-stabilized foam infiltrated sponges, various different structures can be produced, including sandwich structures, pore size gradients, and ceramic bone-like structures applying to different types of bone. The particle-stabilized foams used were in situ self-hardening calcium aluminate cement enriched alumina foams to obtain crack-free samples with pore interconnections and tailorable pore sizes.

Effect of a pathological scapular tilt after total shoulder arthroplasty.

Total shoulder arthroplasty (TSA) is an accepted and most successfully used treatment for different shoulder pathologies. Different risk factors for the failure of the prosthesis are known. A pathological scapular orientation, observed in elderly people or in patients suffering from neuromuscular diseases, could be a cause of failure, which has not been investigated yet. To test this hypothesis, a numerical musculoskeletal model of the glenohumeral joint was used to compare two TSA cases: a reference normal case and a case with a pathological anterior tilt of the scapula. An active abduction of 150° was simulated. Joint force, contact pattern, polyethylene and cement stress were evaluated for both cases. The pathological tilt slightly increased the joint force and the contact pressure, but also shifted the contact pattern. This eccentric contact increased the stress level within the polyethylene of the glenoid component and within the surrounding cement layer. This adverse effect occurred mainly during the first 60° of abduction. Therefore, a pathological orientation of the scapula may increase the risk of a failure of the cement layer around the glenoid component. These preliminary numerical results should be confirmed by a clinical study.

Anachronistic facies from a drowned Lower Triassic carbonate platform: Lower member of the Alwa Formation (Ba'id Exotic), Oman Mountains

- The lower member of the Alwa Formation (Lower Olenekian), found within the Ba'id Exotic in the Oman Mountains (Sultanate of Oman), consists of ammonoid-bearing, pelagic limestones that were deposited on an isolated, drowned carbonate platform on the Neotethyan Gondwana margin. The strata contain a variety of unusual carbonate textures and features, including thrombolites, Frutexites-bearing microbialites that contain synsedimentary cements, matrix-free breccias surrounded by isopachous calcite cement, and fissures and cavities filled with large botryoidal cements. Thrombolites are found throughout the study interval, and occur as 0.5-1.0 m thick lenses or beds that contain laterally laterally-linked stromatactis cavities. The Frutexites-bearing microbialites occur less frequently, and also form lenses or beds, up to 30 cm thick; the microbialites may be laminated, and often developed on hardgrounds. In addition, the Frutexites-bearing microbialites also contain synsedimentary calcite cement crusts and botryoids (typically <1 cm thick) that harbour layers or pockets of what appear to be bacterial sheaths and coccoids, and are indicative of biologically mediated precipitation of the cement bodies. Slumping following lithification led to fracturing of the limestone and the precipitation of large, botryoidal aragonite cements in fissures that cut across the primary fabric. Environmental conditions, specifically palaeoxygenation and the degree of calcium carbonate supersaturation, likely controlled whether the thrombolites (high level of calcium carbonate supersaturation associated with vertical mixing of water masses and dysoxic conditions) or Frutexites-bearing microbialites (low level of calcium carbonate supersaturation associated with anoxic conditions and deposition below a stable chemocline) formed. The results of this study point to continued environmental stress in the region during the Early Triassic that likely contributed to the uneven recovery from the Permian-Triassic mass extinction.

Effect of the Scapulo-Humeral Rhythm on Anatomical and Reverse Shoulder Prostheses

Introduction: Several studies have reported significant alteration of the scapula-humeral rythm after total shoulder arthroplasty. However, the biomechanical and clinical effects, particularly on implants lifespan, are still unknown. The goal of this study was to evaluate the biomechanical consequences of an altered scapula-humeral rhythm. Methods: A numerical musculoskeletal model of the shoulder was used. The model included the scapula, the humerus and 6 scapulohumeral muscles: middle, anterior, and posterior deltoid, supraspinatus, subscapularis and infraspinatus combined with teres minor. Arm motion and joint stability were achieved by muscles. The reverse and anatomic Aequalis prostheses (Tornier Inc) were inserted. Two scapula-humeral rhythms were considered for each prosthesis: a normal 2:1 rhythm, and an altered 1:2 rhythm. For the 4 configurations, a movement of abduction in the scapular plane was simulated. The gleno-humeral force and contact pattern, but also the stress in the polyethylene and cement were evaluated. Results: With the anatomical prosthesis, the gleno-humeral force increased of 23% for the altered rhythm, with a more eccentric (posterior and superior) contact. The contact pressure, polyethylene stress, and cement stress increased respectively by 20%, 48% and 64%. With the reverse prosthesis, the gleno-humeral force increased of 11% for an altered rhythm. There was nearly no effect on the contact pattern on the polyethylene component surface. Conclusion: The present study showed that alteration oft the scapula-humeral rythm induced biomechanical consequences which could preclude the long term survival of the glenoid implant of anatomic prostheses. However,an altered scapula-humeral rhythm, even severe, should not be a contra indication for the use of a reverse prosthesis. 

Total knee arthroplasty - a clinical and numerical study of the micromovements of the tibial implant

Introduction The importance of the micromovements in the mechanism of aseptic loosening is clinically difficult to evaluate. To complete the analysis of a series of total knee arthroplasties (TKA), we used a tridimensional numerical model to study the micromovements of the tibial implant.Material and Methods Fifty one patients (with 57 cemented Porous Coated Anatomic TKAs) were reviewed (mean follow-up 4.5 year). Radiolucency at the tibial bone-cement interface was sought on the AP radiographs and divided in 7 areas. The distribution of the radiolucency was then correlated with the axis of the lower limb as measured on the orthoradiograms.The tridimensional numerical model is based on the finite element method. It allowed the measurement of the cemented prosthetic tibial implant's displacements and the microvements generated at bone-ciment interface. A total load (2000 Newton) was applied at first vertically and asymetrically on the tibial plateau, thereby simulating an axial deviation of the lower limbs. The vector's posterior inclination then permitted the addition of a tangential component to the axial load. This type of effort is generated by complex biomechanical phenomena such as knee flexion.Results 81 per cent of the 57 knees had a radiolucent line of at least 1 mm, at one or more of the tibial cement-epiphysis jonctional areas. The distribution of these lucent lines showed that they came out more frequently at the periphery of the implant. The lucent lines appeared most often under the unloaded margin of the tibial plateau, when axial deviation of lower limbs was present.Numerical simulations showed that asymetrical loading on the tibial plateau induced a subsidence of the loaded margin (0-100 microns) and lifting off at the opposite border (0-70 microns). The postero-anterior tangential component induced an anterior displacement of the tibial implant (160-220 microns), and horizontal micromovements with non homogenous distribution at the bone-ciment interface (28-54 microns).Discussion Comparison of clinical and numerical results showed a relation between the development of radiolucent lines and the unloading of the tibial implant's margin. The deleterious effect of lower limbs' axial deviation is thereby proven. The irregular distribution of lucent lines under the tibial plateau was similar of the micromovements' repartition at the bone-cement interface when tangential forces were present. A causative relation between the two phenomenaes could not however be established.Numerical simulation is a truly useful method of study; it permits to calculate micromovements which are relative, non homogenous and of very low amplitude. However, comparative clinical studies remain as essential to ensure the credibility of results.

Fate of rubrospinal neurons after unilateral section of the cervical spinal cord in adult macaque monkeys: effects of an antibody treatment neutralizing Nogo-A.

The present study describes in primates the effects of a spinal cord injury on the number and size of the neurons in the magnocellular part of the red nucleus (RNm), the origin of the rubrospinal tract, and evaluates whether a neutralization of Nogo-A reduces the lesioned-induced degenerative processes observed in RNm. Two groups of monkeys were subjected to unilateral section of the spinal cord affecting the rubrospinal tract; one group was subsequently treated with an antibody neutralizing Nogo-A; the second group received a control antibody. Intact animals were also included in the study. Counting neurons stained with a monoclonal antibody recognizing non-phosphorylated epitopes on neurofilaments (SMI-32) indicated that their number in the contralesional RNm was consistently inferior to that in the ipsilesional RNm, in a proportion amounting up to 35%. The lesion also induced shrinkage of the soma of the neurons detected in the contralesional RNm. Infusing an anti-Nogo-A antibody at the site of the lesion did not increase the proportion of SMI-32 positive rubrospinal neurons in the contralesional RNm nor prevent shrinkage.