Vikram Deshpande

Consensus statement on the pathology of IgG4-related disease.

IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and—often but not always—elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4–7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4+ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.

Isotropic constitutive models for metallic foams

The yield behaviour of two aluminium alloy foams (Alporas and Duocel) has been investigated for a range of axisymmetric compressive stress states. The initial yield surface has been measured, and the evolution of the yield surface has been explored for uniaxial and hydrostatic stress paths. It is found that the hydrostatic yield strength is of similar magnitude to the uniaxial yield strength. The yield surfaces are of quadratic shape in the stress space of mean stress versus effective stress, and evolve without corner formation. Two phenomenological isotropic constitutive models for the plastic behaviour are proposed. The first is based on a geometrically self-similar yield surface while the second is more complex and allows for a change in shape of the yield surface due to differential hardening along the hydrostatic and deviatoric axes. Good agreement is observed between the experimentally measured stress versus strain responses and the predictions of the models.

Effective properties of the octet-truss lattice material

The effective mechanical properties of the octet-truss lattice structured material have been investigated both experimentally and theoretically. Analytical and FE calculations of the elastic properties and plastic yielding collapse surfaces are reported. The intervention of elastic buckling of the struts is also analysed in an approximate manner. Good agreement is found between the predictions of the strength and experimental observations from tests on the octet-truss material made from a casting aluminium alloy. Moreover, the strength and stiffness of the octet-truss material are stretching-dominated and compare favourably with the corresponding properties of metallic foams. Thus, the octet-truss lattice material can be considered as a promising alternative to metallic foams in lightweight structures.

Foam topology: bending versus stretching dominated architectures

Abstract Cellular solids can deform by either the bending or stretching of the cell walls. While most cellular solids are bending-dominated, those that are stretching-dominated are much more weight-efficient for structural applications. In this study we have investigated the topological criteria that dictate the deformation mechanism of a cellular solid by analysing the rigidity (or otherwise) of pin-jointed frameworks comprising inextensional struts. We show that the minimum node connectivity for a special class of lattice structured materials to be stretching-dominated is 6 for 2D foams and 12 for 3D foams. Similarly, sandwich plates comprising of truss cores faced with planar trusses require a minimum node connectivity of 9 to undergo stretching-dominated deformation for all loading states.

The Resistance of Clamped Sandwich Beams to Shock Loading

A systematic design procedure has been developed for analyzing the blast resistance of clamped sandwich beams. The structural response of the sandwich beam is split into three sequential steps: stage I is the one-dimensional fluid-structure interaction problem during the blast loading event, and results in a uniform velocity of the outer face sheet; during stage II the core crushes and the velocities of the faces and core become equalized by momentum sharing; stage III is the retardation phase over which the beam is brought to rest by plastic bending and stretching. The third-stage analytical procedure is used to obtain the dynamic response of a clamped sandwich beam to an imposed impulse. Performance charts for a wide range of sandwich core topologies are constructed for both air and water blast, with the monolithic beam taken as the reference case. These performance charts are used to determine the optimal geometry to maximize blast resistance for a given mass of sandwich beam. For the case of water blast, an order of magnitude improvement in blast resistance is achieved by employing sandwich construction, with the diamond-celled core providing the best blast performance. However, in air blast, sandwich construction gives only a moderate gain in blast resistance compared to monolithic construction.

High strain rate compressive behaviour of aluminium alloy foams

The high strain rate compressive behaviour of two cellular aluminium alloys (Alulight and Duocel) has been investigated using the split Hopkinson pressure bar and direct impact tests. It is found that the dynamic behaviour of these foams is very similar to their quasi-static behaviour. The plateau stress is almost insensitive to strain rate, for strain rates e5 up to 5000 s~1. Deformation is localised in weak bands in the Alulight foam but is spatially uniform for the Duocel foam, over the full range of strain rates 10~3 s~1)e5 ) 5000 s~1. ( 2000 Elsevier Science Ltd. All rights reserved.

Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations

John H. Stone, Arezou Khosroshahi, Vikram Deshpande, John K. C. Chan, J. Godfrey Heathcote, Rob Aalberse, Atsushi Azumi, Donald B. Bloch, William R. Brugge, Mollie N. Carruthers, Wah Cheuk, Lynn Cornell, Carlos Fernandez-Del Castillo, Judith A. Ferry, David Forcione, Gunter Kloppel, Daniel L. Hamilos, Terumi Kamisawa, Satomi Kasashima, Shigeyuki Kawa, Mitsuhiro Kawano, Yasufumi Masaki, Kenji Notohara, Kazuichi Okazaki, Ji Kon Ryu, Takako Saeki, Dushyant Sahani, Yasuharu Sato, Thomas Smyrk, James R. Stone, Masayuki Takahira, Hisanori Umehara, George Webster, Motohisa Yamamoto, Eunhee Yi, Tadashi Yoshino, Giuseppe Zamboni, Yoh Zen, and Suresh Chari

Collapse of truss core sandwich beams in 3-point bending

Abstract Sandwich beams, comprising a truss core and either solid or triangulated face-sheets, have been investment cast in an aluminium–silicon alloy and in silicon brass. The macroscopic effective stiffness and strength of the triangulated face-sheets and tetrahedral core are estimated by idealising them as pin-jointed assemblies; tests show that this approximation is adequate. Next, the collapse responses of these sandwich beams in 3-point bending are measured. Collapse is by four competing mechanisms: face-yield, face-wrinkling, indentation and core shear, with the active collapse mode dependent upon the beam geometry and yield strain of the material. Upper bound expressions for the collapse loads are given in terms of the effective properties of the faces and core of the sandwich beam; these upper bounds are in good agreement with the measured beam response, and are used to construct collapse mechanism maps with beam geometrical parameters as the axes. The maps are useful for selecting sandwich beams of minimum weight for a given structural load index. The optimisation reveals that truss core sandwich beams are significantly lighter than the competing concept of sandwich beams with a metallic foam core.

Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease

OBJECTIVE Patients with IgG4-related systemic disease (IgG4-RSD) frequently show an incomplete response to treatment with glucocorticoids and traditional disease-modifying antirheumatic drugs (DMARDs). B lymphocyte depletion is a therapeutic strategy known to be effective for pemphigus vulgaris, an autoimmune condition mediated by IgG4 autoantibodies. This study was performed to assess the clinical and serologic responses to B lymphocyte depletion therapy with rituximab in patients with IgG4-RSD. METHODS Four patients with IgG4-RSD were treated with 2 intravenous doses (1 gram each) of rituximab. Clinical improvement was assessed by monitoring the tapering/discontinuation of prednisone and DMARDs, and by measuring the serum concentrations of B lymphocytes, immunoglobulins, and IgG subclasses before and after therapy. RESULTS Clinical features of IgG4-RSD in these 4 patients included autoimmune pancreatitis, sclerosing cholangitis, lymphoplasmacytic aortitis, salivary gland involvement, orbital pseudotumor, and lacrimal gland enlargement. The 3 patients with elevated serum IgG and IgG4 levels at baseline had a mean IgG concentration of 2,003 mg/dl (normal range 600-1,500 mg/dl) and a mean IgG4 concentration of 2,160 mg/dl (normal range 8-140 mg/dl). Among these patients, the serum IgG4 concentrations declined by a mean of 65% within 2 months of rituximab administration. All 4 patients demonstrated striking clinical improvement within 1 month of the initiation of rituximab therapy, and tapering or discontinuation of their treatment with prednisone and DMARDs was achieved in all 4 patients. A decrease in IgG concentration was observed for the IgG4 subclass only. CONCLUSION Treatment with rituximab led to prompt clinical and serologic improvement in these patients with refractory IgG4-RSD, and is a viable treatment option for this condition. The decline in serum IgG4 concentrations was substantially steeper than that of the autoantibody concentrations in immune-mediated conditions in which rituximab is effective, such as in rheumatoid arthritis. In addition, the reduction in IgG-subclass levels appeared to be specific for IgG4. The swift improvement of IgG4-RSD suggests that rituximab achieves its effects in IgG4-RSD by depleting the pool of B lymphocytes that replenish short-lived IgG4-secreting plasma cells.

Rituximab for the Treatment of Igg4-related Disease: Lessons From 10 Consecutive Patients

AbstractPatients with IgG4-related disease (IgG4-RD) typically have elevated serum concentrations of IgG4 and share histopathologic features that are similar across affected organ(s). IgG4-RD patients frequently require prolonged treatment with glucocorticoids and are often unable to taper these medications. Traditional disease-modifying antirheumatic drugs (DMARDs) are generally ineffective. We assessed the clinical and serologic responses to B lymphocyte depletion therapy in 10 consecutive patients with steroid- and DMARD-refractory IgG4-RD.Ten patients with IgG4-RD were treated with rituximab (RTX) (2 infusions of 1000 mg, 15 days apart). Clinical improvement was assessed by monitoring the patient’s ability to taper prednisone to discontinuation and to stop DMARDs; by serial measurements of total IgG and IgG subclasses; and by follow-up radiologic assessments guided by the patient’s particular pattern of organ involvement. We also developed and retrospectively applied the IgG4-RD Disease Activity Index and Flare Tool.Organ involvement included the pancreas, biliary tree, aorta, salivary glands (submandibular and parotid), lacrimal glands, lymph nodes, thyroid gland, and retroperitoneum. Nine of 10 patients demonstrated striking clinical improvement within 1 month of starting RTX. One patient with advanced thyroid fibrosis associated with Riedel thyroiditis and a history of disease in multiple other organ systems did not have improvement in the thyroid gland, but the disease did not progress to involve new organs. All 10 patients were able to discontinue prednisone and DMARDs following RTX therapy. Significant decreases in IgG concentrations were observed for the IgG4 subclass only. Four patients were re-treated with RTX after 6 months because of either symptom recurrence and increasing IgG4 concentration at the time of peripheral B cell reconstitution (n = 2) or because of physician discretion (n = 2). Repeated courses of RTX maintained their effectiveness and resulted in further decreases in IgG4 concentrations. In patients who had an increased IgG4 concentration at the time of presentation, the level of serum IgG4 appeared to be a reliable measure of disease activity.IgG4-RD is an idiopathic, multiorgan inflammatory disease in which diverse organ manifestations are linked by characteristic histopathologic and immunohistochemical features. Treatment with RTX led to prompt clinical and serologic improvement in refractory IgG4-RD in all patients with active inflammation. Serial treatments with RTX may lead to progressive declines in serum IgG4 concentrations and better disease control. Serum IgG4 concentrations may remain low, and clinical disease activity may remain quiescent even after B cell reconstitution in a significant proportion of patients.