Propagation of fundamental Lamb modes along the non-principal axes of strain-stiffened soft compressible plates: A numerical investigation.

This paper numerically investigates the propagation of elastic plate waves along the non-principal directions in a prestretched compressible material described by the Gent model of hyperelasticity. We formulate the elastic tensor and the underlying wave equations in the Lagrangian space by employing the theory of nonlinear elasticity together with the linearized incremental equations. An extension of the Semi-Analytical Finite Element (SAFE) method is discussed for computing the dispersion characteristics of the two fundamental guided wave modes. The predictive capabilities of the numerical framework are established using the previously published data for a weakly nonlinear as well as hyperelastic material models. Using the numerical framework, we then bring out the effects of applied prestretch, orientation of the propagation direction, and material parameters on the dispersion characteristics of the fundamental Lamb modes. A limiting case of the neo-Hookean material model is first considered for elucidating such implicit dependencies, which are further highlighted by considering the strain-stiffening effect captured through the Gent material model. Our results indicate the existence of a threshold prestretch for which the Gent-type material can encounter a snap-through instability; leading to the change in the dispersion characteristics of the fundamental symmetric Lamb mode.

DC dynamic pull-in instability of a dielectric elastomer balloon: an energy-based approach.

This paper reports an energy-based method for the dynamic pull-in instability analysis of a spherical dielectric elastomer (DE) balloon subjected to a quasi-statically applied inflation pressure and a Heaviside step voltage across the balloon wall. The proposed technique relies on establishing the energy balance at the point of maximum stretch in an oscillation cycle, followed by the imposition of an instability condition for extracting the threshold parameters. The material models of the Ogden family are employed for describing the hyperelasticity of the balloon. The accuracy of the critical dynamic pull-in parameters is established by examining the saddle-node bifurcation in the transient response of the balloon obtained by integrating numerically the equation of motion, derived using the Euler-Lagrange equation. The parametric study brings out the effect of inflation pressure on the onset of the pull-in instability in the DE balloon. A quantitative comparison between the static and dynamic pull-in parameters at four different levels of the inflation pressure is presented. The results indicate that the dynamic pull-in instability gets triggered at electric fields that are lower than those corresponding to the static instability. The results of the present investigation can find potential use in the design and development of the balloon actuators subjected to transient loading. The method developed is versatile and can be used in the dynamic instability analysis of other conservative systems of interest.

Heparin enhances uptake of platelet factor 4/heparin complexes by monocytes and macrophages.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an iatrogenic complication of heparin therapy caused by antibodies to a self-antigen, platelet factor (4) and heparin. The reasons why antibodies form to PF4/heparin, but not to PF4 bound to other cellular glycosaminoglycans are poorly understood. OBJECTIVE: To investigate differences in cellular responses to cell-bound PF4 and PF4/heparin complexes, we studied the internalization of each by peripheral blood-derived monocytes, dendritic cells and neutrophils. METHODS AND RESULTS: Using unlabeled and fluorescently-labeled antigen and/or labeled monoclonal antibody to PF4/heparin complexes (KKO), we show that PF4/heparin complexes are taken up by monocytes in a heparin-dependent manner and are internalized by human monocytes and dendritic cells, but not by neutrophils. Complexes of PF4/low-molecular-weight heparin and complexes composed of heparin and murine PF4, protamine or lysozyme are internalized similarly, suggesting a common endocytic pathway. Uptake of complexes is mediated by macropinocytosis, as shown by inhibition using cytochalasin D and amiloride. Internalized complexes are transported intact to late endosomes, as indicated by co-staining of vesicles with KKO and lysosomal associated membrane protein-2 (LAMP-2). Lastly, we show that cellular uptake is accompanied by expression of MHCII and CD83 co-stimulatory molecules. CONCLUSIONS: Taken together, these studies establish a distinct role for heparin in enhancing antigen uptake and activation of the initial steps in the cellular immune response to PF4-containing complexes.

Platelets, glycoprotein Ib-IX, and von Willebrand factor are required for FeCl(3)-induced occlusive thrombus formation in the inferior vena cava of mice.

Venous thromboembolism is a leading cause of death from cardiovascular disease. Despite the importance of the glycoprotein (GP) Ib-IX/von Willebrand factor (vWF) axis in arterial thrombosis, its requirement in venous, not venule thrombosis in response to endothelial injury (not stenosis or stasis) is uncharacterized. GPIbα-vWF participation in FeCl(3)-induced thrombus formation was evaluated in the inferior vena cava (IVC). Stable, occlusive thrombus formation in response to FeCl(3)-induced injury of the IVC was studied. FeCl(3) (20% FeCl(3), 10 minutes)-induced occlusive thrombosis required platelets as confirmed by a lack of occlusion in thrombocytopenic mice, and stable occlusion in control animals. No IVC occlusion was observed using GPIbα-deficient animals, a model of the human Bernard-Soulier syndrome (BSS). Transgenic IL-4 R/GPIbα mice (lack murine GPIbα, but express the extracellular domain of the human interleukin (IL-4 receptor fused to the transmembrane and cytoplasmic domains of human GPIbα) were studied to determine if the absence of IVC occlusion in the BSS mouse was caused by GPIbα extracellular domain deficiency rather than platelet BSS phenotype associated abnormalities. As with GPIbα knock-out mice, no occlusion was observed in the IVC of IL-4 R/GPIbα mice. The IVC of vWF-deficient mice also failed to occlude in response to FeCl(3) treatment. The chimeric protein GPIbα(2V)-Fc prevented occlusion, demonstrating that GPIbα-vWF A1 domain interaction is required for FeCl(3)-induced stable thrombus formation in the IVC. Therefore, FeCl(3)-induced stable, occlusive thrombus formation in the IVC is platelet, and apparently GPIbα-vWF interaction dependent, despite the large diameter and low venous flow rate in the IVC.

Disruption of PF4/H multimolecular complex formation with a minimally anticoagulant heparin (ODSH).

Recent studies have shown that ultra-large complexes (ULCs) of platelet factor 4 (PF4) and heparin (H) play an essential role in the pathogenesis of heparin-induced thrombocytopenia (HIT), an immune-mediated disorder caused by PF4/H antibodies. Because antigenic PF4/H ULCs assemble through non-specific electrostatic interactions, we reasoned that disruption of charge-based interactions can modulate the immune response to antigen. We tested a minimally anticoagulant compound (2-O, 3-O desulfated heparin, ODSH) with preserved charge to disrupt PF4/H complex formation and immunogenicity. We show that ODSH disrupts complexes when added to pre-formed PF4/H ULCs and prevents ULC formation when incubated simultaneously with PF4 and UFH. In other studies, we show that excess ODSH reduces HIT antibody (Ab) binding in immunoassays and that PF4/ODSH complexes do not cross-react with HIT Abs. When ODSH and unfractionated heparin (UFH) are mixed at equimolar concentrations, we show that there is a negligible effect on amount of protamine required for heparin neutralisation and reduced immunogenicity of PF4/UFH in the presence of ODSH. Taken together, these studies suggest that ODSH can be used concurrently with UFH to disrupt PF4/H charge interactions and provides a novel strategy to reduce antibody mediated complications in HIT.

Islet-specific microRNAs in pancreas development, regeneration and diabetes.

Diabetes is a chronic and slowly progressive disease that is presently reaching epidemic proportions in several parts of the world. Multiple aspects including genetic and lifestyle changes have been identified as the key factors leading to the development of type 1 and type 2 diabetes. Although molecular mechanisms underlying the pathogenesis of diabetes remain unclear, recent discoveries in understanding post-transcriptional gene regulation by microRNAs (miRNAs) has opened a new area of research. MicroRNAs have been implicated as new players in pathogenesis as well as complications of diabetes. MiRNAs have been shown to be necessary not only during embryonic development of insulin-producing cells, transcription of (pro-)insulin gene and insulin secretion, but also in development of insulin resistance and diabetes. The present review summarizes the findings related to understanding the role of miRNAs in endocrine pancreas development, pancreas regeneration, islet function and diabetes.

Evaluation of the physiological significance of botrocetin/ von Willebrand factor in vitro signaling.

BACKGROUND: A signaling pathway is difficult, if not impossible, to elucidate in platelets using only in vivo studies. Likewise, the physiological significance of signaling information obtained exclusively from in vitro observations is unknown. Therefore, both in vitro and in vivo experiments are required to establish the physiological significance of a signaling pathway. OBJECTIVE: To evaluate the physiological significance of signaling data obtained from botrocetin (bt)/von Willebrand factor (VWF)-stimulated washed platelets. METHOD: Stable thrombus formation in response to FeCl(3)-induced injury of the mouse carotid artery was used to evaluate the physiological significance of signaling data obtained from bt/VWF-stimulated washed platelets. RESULTS: Syk, PLCgamma2, Galphaq and P2Y12, but not LAT, were found either to be required for or to affect stable thrombus formation. Prior in vitro studies had demonstrated that LAT is not required for bt/VWF-induced platelet aggregation in the presence of exogenous fibrinogen. These data provide the first demonstration of the in vivo role for these signaling molecules in GPIb-dependent/initiated signal transduction and are consistent with the signaling pathway deduced from in vitro studies of bt/VWF-stimulated washed platelets using metabolic inhibitors and knockout mice. CONCLUSION: The broad agreement between the in vitro and the in vivo results establish that bt/VWF stimulation of washed platelets can provide physiologically significant glycoprotein Ib-dependent/initiated signaling data.

Incorrectly aligned fly leads inside the ECG machine causing 'ischaemic' changes.

We describe a case in which a young woman was inappropriately diagnosed as having ischaemic heart disease after presenting with exertional neck pain and an abnormal ECG. Diffuse Q-wave and T-wave inversion changes were later attributed to erroneous placement of fly leads inside the ECG machine at a recent service. Clinicians should be aware of this uncommon cause of incorrect lead connections, which can result in unnecessary investigations and treatment.

Community involvement in planning and design for a rehabilition programme : A case of Latur Rehabilitation Programme

Shelter design and delivery is not only mere design or an architectural exercise but a pleasurable experience. However, planning and designing for rehabilitation programmes needs to be looked into through a social and sympathetic approach. In fact it requires integration of cultural and ethnic styles of the uprooted families into the planning and design of the new housing. It is always possible to conduct such exercises through participation of the beneficiaries in the normal designing process however, initiation of such a process for rehabilitation requires effort. This paper is a description of the case of Latur where the trauma stricken people, who refused to accept new housing provided by the NGOs and other donor organizations, readily accepted and moved into the housing provided by HUDCO. In the four villages adopted by HUDCO the people were involved in the planning process right from inception. Traditional living styles of the people were understood very well before conceptualizing the rehabilitation programme for the villagers. The clusters, the main entrance, the baithak and the open courtyard activity space were built into these designs, which were preferred to any other schemes in the affected towns and villages. (AU)

Can old people on oral anticoagulants be safely managed as out-patients?

Of 62 patients (mean age 75, range 65-92 years) referred to an out-patient anticoagulant clinic specifically for those aged 65 years or more, treatment was considered unsafe in only one patient and was discontinued. Minor bleeding which did not require a significant change in management was recorded on 25 (7%) of 381 clinic visits and one major haemorrhage occurred requiring emergency hospital admission. Anticoagulation was maintained within the therapeutic range on 284 (75%) visits. The results confirm that with appropriate out-patient care and supervision, the risks of oral anticoagulant therapy in the elderly need be no greater than in younger patients.

Significance of single serum urate estimations in acutely hospitalized elderly patients.

Clinical, pharmacological and biochemical correlates of hyperuricaemia were studied in 399 consecutive patients aged over 70 years admitted to hospital with acute medical illness. Hyperuricaemia was significantly related to renal impairment and to the use of diuretics, but to no other recognized associations of gout, including typical or atypical joint symptoms. 'Routine' measurement of serum uric acid alone or as a component of biochemical profiles in acute illness in the elderly appears unjustified, particularly since raised levels may encourage inappropriate use of urate-lowering therapy.

Eosinophilic colitis as a complication of the hypereosinophilic syndrome.

A patient with the hypereosinophilic syndrome complicated by a severe eosinophilic colitis is reported. The association has not previously been recorded.