Proteasome inhibition with bortezomib: an effective therapy for severe antibody mediated rejection after renal transplantation.

Antibody-mediated rejection (AMR) following renal transplantation is less responsive to conventional anti-rejection therapies. Plasmapheresis (PP), intravenous immunoglobulin (IVIg), rabbit antithymocyte globulin (rATG) and rituximab deplete immature B-cells but not mature plasma cells. The proteasome inhibitor bortezomib has activity against mature plasma cell, the source of damaging donor-specific antibody (DSA).We present the successful use of bortezomib in 2 patients who developed AMR following kidney transplantation. The first patient was a 54-year-old white female who received living-unrelated kidney transplantation from her husband. She developed severe AMR early after transplantation with rising DSA titers consistent with an anamnestic immune response by memory cells to the donor antigens. Renal function deteriorated despite treatment with pulse methylprednisolone (MP), PP and IVIg. After initiation of therapy with bortezomib, DSA titers became negative and serum creatinine returned to baseline with histological resolution of AMR. The second patient was a 19-year-old white male who received deceased donor kidney transplantation and developed AMR within 2 weeks, refractory to therapy with pulse MP, PP and IVIg with rising DSA. Bortezomib use resulted in disappearance of DSA and renal function improvement. Both patients tolerated the treatment well with stable renal function at last follow-up. The novel mechanisms of action and preliminary results with bortezomib are encouraging, but require larger studies and longer follow-up.

Quasi-static and dynamic investigation of an advanced high strength and corrosion resistant 10 % Cr nanocomposite martensitic steel.

The mechanical response of an advanced high strength and corrosion resistant 10 % Cr nanocomposite steel (ASTM A1035CS Grade 120) is measured under uniaxial tension and compression at the strain rates of 10-4 s-1, 10-2 s-1, 100 s-1, 700 s-1, and 3000 s-1. The experiments are performed at 22 °C as well as 80 °C to investigate the material behavior at the expected temperature rise due to adiabatic deformation at 15 % strain. Additionally, different compression-shear hat-shaped specimens are tested at quasi-static and dynamic strain rates to investigate the localization behavior of this material. The material exhibits small strain rate sensitivity (SRS) during quasi-static loading, but a pronounced SRS between quasi-static and dynamic strain rates. Tension-compression asymmetry is also observed at both temperatures. Experiments at 80 °C reveal a decrease in flow stress in both tension and compression indicating the material is sensitive to thermal softening due to adiabatic heating. Load-Unload-Reload (LUR) and strain rate jump experiments are performed to investigate the reasoning behind the approximate rate insensitivity of ASTM A1035CS steel during quasi-static strain rates. A new constitutive model is also developed using a novel rate dependent material model with a modified Hockett-Sherby (MHS) hardening model and incorporating Lode angle dependence to capture the tension-compression asymmetry. The model is also used to predict the LUR and strain rate jump experiments. Finally, reasoning behind the unique rate dependent thermo-mechanical behavior of ASTM A1035CS steel is discussed in regards to adiabatic heating, strain-partitioning, and phase transformation.

Quasi-static and dynamic response, and texture evolution of two overaged Al 7056 alloy plates in T761 and T721 tempers: Experiments and modeling.

The thermo-mechanical behavior and texture evolution of two overaged Al 7056 alloy plates, in T761 and T721 tempers, are measured over a wide range of strain rates (10‒4 - 3 × 103 s‒1) and temperatures (22-300 °C) under uniaxial tension and compression along the thickness direction, i.e. normal to the plate surface. A detailed study of the initial microstructure reveals an increase in precipitate size and decrease in density of precipitates, as the alloy is aged from the T761 to T721 temper; which in turn affects the flow stress and strain hardening behavior. Differences in flow strength and strain hardening rate, as well as tension-compression asymmetry in the two tempers, are apparent at the lower temperatures (22 °C & 100 °C) and decrease significantly at the higher temperatures (200 °C & 300 °C). Furthermore, initial texture measurements show a strong texture gradient along the normal direction (ND) of the plate. This texture gradient affects the ultimate stress insignificantly. However, it does have a considerable effect on the failure strains of specimens taken from different locations through the thickness. A transition from shear fracture at and below 200 °C to cup and cone fracture mode above 200 °C is observed in tension. Both tempers exhibit a positive strain rate sensitivity (SRS) that is dependent on temperature and strain rate. A sharp decrease in flow stress is found at 300 °C. The Khan-Liu (KL) model is modified to correlate with the measured thermo-mechanical responses of the two tempers over the studied, wide range of strain rates and temperatures. There is a close correlation between simulated and observed results.

Antilymphoid antibody preconditioning and tacrolimus monotherapy for pediatric kidney transplantation.

OBJECTIVE: Heavy post-transplant immunosuppression may contribute to long-term immunosuppression dependence by subverting tolerogenic mechanisms; thus, we sought to determine if this undesirable consequence could be mitigated by pretransplant lymphoid depletion and minimalistic post-transplant monotherapy. STUDY DESIGN: Lymphoid depletion in 17 unselected pediatric recipients of live (n = 14) or deceased donor kidneys (n = 3) was accomplished with antithymocyte globulin (ATG) (n = 8) or alemtuzumab (n = 9). Tacrolimus was begun post-transplantation with subsequent lengthening of intervals between doses (spaced weaning). Maintenance immunosuppression, morbidity, graft function, and patient/graft survival were collated. RESULTS: Steroids were added temporarily to treat rejection in two patients (both ATG subgroup) or to treat hemolytic anemia in two others. After 16 to 31 months (mean 22), patient and graft survival was 100% and 94%, respectively. The only graft loss was in a nonweaned noncompliant recipient. In the other 16, serum creatinine was 0.85 +/- 0.35 mg/dL and creatinine clearance was 90.8 +/- 22.1 mL/1.73 m2. All 16 patients are on monotherapy (15 tacrolimus, one sirolimus), and 14 receive every other day or 3 times per week doses. There were no wound or other infections. Two patients developed insulin-dependent diabetes. CONCLUSION: The strategy of lymphoid depletion and minimum post-transplant immunosuppression appears safe and effective for pediatric kidney recipients.