Vitamin D treatment of senescence accelerated mice (SAM-P/6) induces several regulators of stromal cell plasticity

In an attempt to understand the regulation of bone marrow multipotential cells plasticity in vivo, we treated 4-month-old SAM-P/6 mice with a constant infusion of either 18 pmol/24 h of 1,25(OH)₂D₃ or vehicle alone for 6 weeks. In vehicle treated animals 78% ± 4 adipose volume vs. total volume was stained positive with oil red O as compared to only 32 ± 3% in 1,25(OH)₂D₃treated animals (P < 0.001). Furthermore, we aimed to identify the changes in gene expression induced by 1,25(OH)₂D₃in bone marrow cells by analyzing a set of 5440 genes in the NIA 15K Mouse cDNA microarray. Overall, a coordinated regulation of genes which both stimulate osteoblastogenesis and inhibit adipogenesis was observed in 1,25(OH)₂D₃-treated mice when compared to vehicle treated mice. In summary, this study illustrates the anti-adipogenic effect of 1,25(OH)₂D₃in bone cells and identifies some of the possible key signals involved in bone cell plasticity.     

Plasma therapy in thrombotic thrombocytopenic purpura: review of the literature and the Bern experience in a subgroup of patients with severe acquired ADAMTS-13 deficiency

Based on clinical studies daily plasma exchange (PE) has become the first-choice therapy for thrombotic thrombocytopenic purpura (TTP) since 1991. Recent findings may explain its effectiveness, which particularly may include supply of ADAMTS-13 and removal of anti-ADAMTS-13 autoantibodies and unusually large von Willebrand factor (VWF) multimers. The most preferable PE regimens as well as replacement fluids are discussed and treatment-related adverse reactions are summarized. Proposals for a potential reduction of their frequency and for improvement of treatment efficiency are given. These suggestions are partially based on the experience of our institution in adult patients with severe ADAMTS-13 deficiency (<5% activity), and include (1) continuous calcium-gluconate infusion during PE in order to reduce citrate-related adverse reactions; (2) the evaluation of solvent/detergent-treated (S/D) plasma as replacement fluid in order to reduce adverse events due to fresh frozen plasma (FFP); (3) the evaluation of immunoadsorption in order to increase procedural efficiency in autoantibody removal; and (4) the substitution of ADAMTS-13 by means of recombinant drug instead of plasma.     

von Willebrand factor-cleaving protease (ADAMTS-13) activity determination in the diagnosis of thrombotic microangiopathies: the Swiss experience

Severe deficiency of von Willebrand factor (VWF)-cleaving protease (ADAMTS-13) activity (<5% of normal) is a specific finding for acute idiopathic thrombotic thrombocytopenic purpura (TTP), a disorder that presents as thrombocytopenia, microangiopathic hemolytic anemia, and often organ dysfunction such as neurological disturbances or renal failure, and fever. Between January 2001 and July 2003, ADAMTS-13 activity was determined in plasma samples of 396 consecutive patients referred to our laboratory for diagnostic purposes. Plasma samples with ADAMTS-13 activity less than 5% were in addition tested for the presence of inhibitory antibodies. Patients were assigned to 10 predefined clinical categories according to information provided by the referring clinician: thrombotic microangiopathy (TMA) not further specified; neoplasia- or chemotherapy-associated TMA; TMA following hematopoietic stem cell transplantation; TMA with additional/alternative disorder; idiopathic TTP; hemolytic-uremic syndrome (HUS) not specified; HUS with diarrhea prodrome (D+HUS); atypical HUS; other hematological disorder; and no clinical information available. Severe ADAMTS-13 deficiency was found in 69 (17%) patients, including 42 with acquired idiopathic TTP, either at initial presentation or at relapse, 14 with confirmed or suspected hereditary TTP, 10 with TMA not further specified, two with neoplasia- or chemotherapy-associated TMA, and one in continued clinical remission 3.4 years after splenectomy for plasma-refractory TTP. Forty-three (62%) patients with ADAMTS-13 activity less than 5% displayed inhibitory antibodies. Severe ADAMTS-13 deficiency was found in 60% of patients diagnosed with acute idiopathic TTP, but in none of 130 patients diagnosed with HUS or in any of the 14 patients with hematopoietic stem cell transplantation-associated TMA. Thus, plasma ADAMTS-13 activity less than 5% does not identify all patients clinically diagnosed with TTP, and severe ADAMTS-13 deficiency is not invariably associated with clinical manifestations of microvascular platelet clumping.     

Leflunomide

Leflunomide is a low-molecular weight, synthetic, oral agent specifically developed for immunosuppression. Because of activity in animal models, leflunomide was tested in rheumatoid arthritis(RA). These investigations have demonstrated that leflunomide reduces the clinical symptoms and signs of RA, improves health related quality of life, and retards structural damage. Leflunomide has been evaluated in RA patients as monotherapy and in combination with methotrexate. Close monitoring for adverse events with particular attention for monitoring liver enzymes for hepatic toxicity is important during treatment with leflunomide.     

Advanced gastric cancer: a new combined surgical and oncological approach

Forty-two patients with advanced gastric carcinoma underwent chemotherapy in accordance with the FAMTX protocol. Complete tumor remission was achieved in 7%, and partial remission in 29% of the patients. In this group 6 patients (tumor stage: T3-4, N 2-3, M X-1) underwent a second-look operation after chemotherapy either to confirm the complete remission or the resect the remaining tumor mass. The mean follow-up time of these 6 patients is 22 (8-55) months; 4 are still in complete remission 8 to 55 months after the first operation. It is concluded that even in advanced stages of gastric carcinomas a more aggressive approach involving a combination of surgical and chemotherapeutic treatment improves the survival time of these patients.     

Adjuvant treatment of pancreatic carcinoma in a clinically adapted mouse resection model.

BACKGROUND: The high rate of local recurrence after radical resection of pancreatic adenocarcinoma fosters intensive efforts to develop new approaches for adjuvant treatment. The established animal models show significant limitations in simulating an adjuvant therapeutic setting. For optimal approximation to the clinical situation we therefore improved a murine orthotopic human xenotransplantation model. METHODS: Subtotal pancreatectomy in mice was performed after orthotopic inoculation of human pancreatic cancer cells and manifestation of solid tumours. The natural course of disease, tumour growth and metastases were analysed. Gemcitabine as a cytotoxic drug was tested in vitro on the cell line used in this model and the effect of adjuvant treatment with gemcitabine in vivo was investigated. RESULTS: All tumour-resected animals showed local recurrence. Organ metastases occurred in 67% in resected compared to 25% of non-resected animals. Gemcitabine in vitro was ineffective, but as adjuvant monotherapy resulted in a highly significant reduction of tumour weight and metastatic events. CONCLUSION: Subtotal pancreatectomy for xenotransplanted pancreatic cancer in SCID beige mice is feasible. Due to high rates of local recurrence and increased organ metastases, this model offers a relevant option for preclinical adjuvant testing, especially as in vitro and in vivo effects of cytotoxic drugs differ enormously.