Abstract

Development of Cell-processing Systems for Human Stem Cells (Neural Stem Cells, Mesenchymal Stem Cells, and iPS Cells) for Regenerative Medicine

Yonehiro Kanemura

Regenerative medicine using human stem cells is one of the newest and most promising fields for treating various intractable diseases and damaged organs. For clinical applications, choosing which human stem cells to use, i.e. according to tissue of origin and progenitor type, is a critical issue. Many preclinical studies indicate that the transplantation of neural stem/progenitor cells (NSPCs), which are somatic stem cells, holds promise for treating various neurological diseases. We found that ABCB1, a member of the ATP-binding cassette (ABC) transporter superfamily, is predominantly expressed in immature human fetal NSPCs, and thus could be used as a phenotypic marker to investigate and monitor NSPCs in culture. Therefore, ABCB1 may be useful in quality-control strategies for human NSPCs. We also identified a useful substrate for supporting the growth and pluripotency of human ES and iPS cells, PCM-DM: the pericellular matrix (PCM) prepared from human decidua-derived mesenchymal cells (DMCs), which we isolated from human placenta. Furthermore, new re-programming techniques for generating iPS cells should greatly contribute to custom-designed cell therapies using pluripotent stem cells. We have successfully derived human iPS cells from DMCs. Although these iPS cells would be allogeneic, they are considered ideal for clinical applications. We hope these findings will promote the development of cell-processing systems for human allogeneic stem cells for clinical use in regenerative medicine applications.

Diagnostic and Treatment of Otolith Disorders

Dietmar Basta

Some years ago little was known about the symptoms, diagnostic methods and treatment of otolith disorders. The postural control in otolith disorders is highly reduced during stance and gait tasks. This is especially true if the proprioceptive and/or visual inputs are reduced. Patients with otolith disorders use the trunk sway to ensure postural control during different senso-motoric conditions. The diagnostic methods for the analysis of otolith function were much improved over the last decade. The gold standard for examining utricular function is the excentric rotation and for the saccular function the vestibular evoked myogenic potentials (VEMP). For the application of VEMPs in clinical practice it is necessary to determine all parameters, which influence the latencies and amplitude of the potential. Thus normative values were calculated for VEMP - latencies and - amplitudes with respect to age, gender, stimulus design and tonic neck muscle activity. By using the equation developed in this work, a quantitative evaluation of saccular function was possible for the first time. Since otolith disorders are difficult to treat a new therapeutic approach was developed to enhance the central vestibular compensation. This rehabilitation training reduced the trunk sway of the patients very effectively by applying a non-vestibular neurofeedback signal.

The Progress of Myeloma Treatment for Patients with Comorbidity

Meletios A. Dimopoulos

Over the last decade the outcome of patients with symptomatic multiple myeloma has improved. This is due to the introduction of three novel agents in the management of this disease: Thalidomide, bortezomib and lenalidomide. When single agent bortezomib is administered to patients with refractory or relapsed multiple myeloma, at least a partial response occurs in 43% and the subsequent median time to progression is 6.2 months and median overall survival is 30 months. These outcomes are improved when liposomal doxorubicin are added to bortezomib. Bortezomib-based combinations are being used with increasing frequency for the treatment of newly diagnosed symptomatic patients with multiple myeloma. More specifically, when the combination of bortezomib, melphalan and prednisone is administered to elderly patients ineligible for high dose-therapy, at least a partial response occurs in 71% (including complete response in 30%), the median time to progression is 24 months and the three year overall survival is 72%. Combination of bortezomib with dexamethasone with or without thalidomide are being frequently used in younger patients as an induction regimen when stem cell collection is planned. Furthermore, bortezomib is the agent choice when myeloma patients present or develop renal impairment. This agent is not only well tolerated and active in such patients but it can also reserve renal impairment in at least 50% of them. Bortezomib-based regimens are active in patients with adverse cytogenetic features. Finally there is accumulating evidence to indicate that bortezomib may have an anabolic affect on bone formation.

Low-dose Aspirin and the GI Tract

Loren A. Laine

Low-dose aspirin (75-325 mg daily) is used for primary prevention of cardiovascular events (i.e., patients without established cardiovascular disease) and secondary prevention (patients with established cardiovascular disease). Low-dose aspirin is documented to decrease myocardial infarctions, strokes, and mortality when used for secondary prevention. In trials of primary prevention, myocardial infarctions are decreased but strokes and mortality are not significantly reduced. Therefore, primary prevention should only be employed in patients with relatively high cardiovascular risk to ensure that the cardiovascular benefit outweighs the bleeding risk (e.g., > 10% risk of coronary heart disease over 10 years). The incidence of gastroduodenal ulcers at endoscopy with low-dose aspirin in most double-blind trials is 5 - 7% over 12 - 26 weeks-much lower than the incidence with standard doses of other traditional NSAIDs. Use of low-dose aspirin significantly increases major GI bleeding, with relative risk of 2.1 (95% CI, 1.6-2.7) in a meta-analysis of randomized trials. Factors that may increase the relative risk of GI bleeding include prior history of ulcers or GI bleeding, corticosteroid use, anticoagulant therapy, and addition of a non-aspirin NSAID. Enteric coating of low-dose aspirin does not decrease the risk of GI bleeding. Although data are mixed, increasing the aspirin dose within the low-dose range (from 75 to 325mg) is not clearly documented to increase GI bleeding. Randomized double-blind trials showed that proton pump inhibitors (PPIs) and H₂-receptor antagonists significantly decrease ulcers at endoscopy in low-dose aspirin users. PPIs also decrease recurrent ulcer bleeding with low-dose aspirin in high-risk patients who presented with bleeding ulcers while on aspirin therapy. When clopidogrel is combined with low-dose aspirin, the relative risk of GI bleeding appears to increase by approximately 80-100% compared to aspirin alone. Preliminary analysis of a prematurely-terminated randomized double-blind trial revealed a significantly lower rate of a composite GI endpoint (overt and occult GI bleeding, symptomatic gastroduodenal ulcers and erosions) with PPI than with placebo in patients taking aspirin plus clopidogrel. Current U.S. consensus recommendations suggest that low-dose aspirin users with GI risk factors (e.g., history of ulcer or GI bleeding, concomitant anti-platelet or anticoagulant therapy) receive a proton pump inhibitor to reduce GI bleeding.