Effect of Co Substitution and Thermo-Magnetic Treatment on the Structure and Induced Magnetic Anisotropy of Fe84.5−xCoxNb5B8.5P2 Nanocrystalline Alloys

In the present work, we investigated in detail the thermal/crystallization behavior and magnetic properties of materials with Fe_84.5-xCo_xNb₅B_8.5P₂ (x = 0, 5, 10, 15 and 20 at.%) composition. The amorphous ribbons were manufactured on a semi-industrial scale by the melt-spinning technique. The subsequent nanocrystallization processes were carried out under different conditions (with/without magnetic field). The comprehensive studies have been carried out using differential scanning calorimetry, X-ray diffractometry, transmission electron microscopy, hysteresis loop analyses, vibrating sample magnetometry and Mössbauer spectroscopy. Moreover, the frequency (up to 300 kHz) dependence of power losses and permeability at a magnetic induction up to 0.9 T was investigated. On the basis of some of the results obtained, we calculated the values of the activation energies and the induced magnetic anisotropies. The X-ray diffraction results confirm the surface crystallization effect previously observed for phosphorous-containing alloys. The in situ microscopic observations of crystallization describe this process in detail in accordance with the calorimetry results. Furthermore, the effect of Co content on the phase composition and the influence of annealing in an external magnetic field on magnetic properties, including the orientation of the magnetic spins, have been studied using various magnetic techniques. Finally, nanocrystalline Fe_64.5Co₂₀Nb₅B_8.5P₂ cores were prepared after transverse thermo-magnetic heat treatment and installed in industrially available portable heating equipment.     

Safety and Feasibility of a Novel Dosing Regimen of Tirofiban Administered in Patients with Acute Myocardial Infarction with ST Elevation Before Primary Coronary Angioplasty: A Pilot Study

BACKGROUND: Intravenous glycoprotein GP IIb/IIIa receptor antagonists administered to patients with acute coronary syndromes limit platelet-dependent thrombus formation and vasoconstriction and lower the complication rate of PCI. The efficacy of glycoprotein IIb/IIIa inhibitors critically depends on appropriate suppression of platelet aggregation. A growing body of evidence indicates that regimen of tirofiban used in several recent trials may be suboptimal. We investigated if a novel regimen of dosage of tirofiban administered to patients with acute myocardial infarction with ST elevation (STEMI) before primary angioplasty is safe, feasible and whether such treatment improves coronary flow in infarct-related artery. METHODS: It was an open-label, non-randomized, prospective observational study. 253 consecutive patients with STEMI, qualified to PCI were included. 104 of patients (group 1) received heparin plus tirofiban at a novel regimen (10 microg/kg bolus, followed by 0.4 microg/kg/min for 30 min and then 0.1 microg/kg/min for 12-24 hours) and the remaining 149 of the patients (group 2) received a standard dose of heparin prior to PCI. Bleeding complications were recorded. The primary end point of the study was combined TIMI 1 + 2 + 3 grade flow at the time of first contrast medium injection during angiography for primary PCI. RESULTS: Heparin was administered 50.3 +/- 58.1 minutes (group 1) or 62.3 +/- 67.3 minutes (group 2) ( p = 0.205). Tirofiban was administered for an average of 14.5 +/- 14.4 minutes before TIMI assessment (group 1). In patients treated with heparin + tirofiban the rate of combined TIMI 1 + 2 + 3 coronary flow was higher (38.4% vs. 24.8%, p = 0.020) as compared to patients treated with heparin alone. The difference in the rate of TIMI > or = 2 coronary blood flow between the groups 1 and 2 (24.0% vs. 20.1%) has not reached statistical significance ( p = 0.459). At the same time the significant difference in the rate of TIMI 1 coronary blood flow between the groups 1 and 2 was noted (14.4 vs. 4.7%, p = 0.007). In hospital mortality in the groups 1 and 2 was similar (5.3 vs. 4.8%, p = 0.838). Significant difference was noted between the groups 1 and 2 with regard to minor bleeding complications (17.3 vs. 8.7%, p = 0.041). CONCLUSION: In patients undergoing primary angioplasty for acute myocardial infarction the novel regimen of tirofiban is well tolerated and feasible, and is associated with improvement in coronary blood flow in the infarct related artery. Larger studies assessing the effects of tirofiban on clinical outcomes of patients with AMI undergoing primary angioplasty seem worthwhile.     

Eosinophilic gastroenteritis and graft‐versus‐host disease induced by transmission of Norovirus with fecal microbiota transplant

Fecal microbiota transplantation (FMT) was performed to decolonize gastrointestinal tract from antibiotic‐resistant bacteria before allogeneic hematopoietic cells transplantation (alloHCT). AlloHCT was complicated by norovirus gastroenteritis, acute graft‐versus‐host disease, and eosinophilic pancolitis. Norovirus was identified in samples from FMT material. Symptoms resolved after steroids course and second norovirus‐free FMT from another donor.     

Microgravity culture condition reduces immunogenicity and improves function of pancreatic islets1

BACKGROUND: The failure of pancreatic islet allotransplants observed in almost all clinical attempts is related to poor initial islet function and allograft rejection. To remedy these problems we cultured islets in microgravity conditions to improve their function and to reduce their immunogenicity. METHODS: Fresh mouse islets or mouse islets cultured in stationary dishes or microgravity bioreactors were transplanted to streptozotocin-induced diabetic mouse recipients. RESULTS: Both allogeneic dish- or bioreactor-cultured islets survived more than 100 days compared with fresh allogeneic islets, which were rejected in less than 15 days. Islet titration studies revealed that 250 fresh or dish-cultured, but only 30 to 120 bioreactor-cultured, islets were necessary to produce euglycemia. Furthermore, glucose tolerance tests showed that bioreactor-cultured islets functioned better compared with fresh and dish-cultured islets on day 30 postgrafting. Immunostaining and transmission electron microscopy (TEM) analyses showed the gradual disappearance of dendritic cells in cultured islets compared with fresh islets. TEM revealed that the ultrastructure of islets from bioreactor, but not dish, appeared healthy and closely resembled fresh islets. Interestingly, TEM and scanning electron microscopy showed that only bioreactor-cultured islets developed unique and multiple nutritional channels between arrays of islet cells. TEM with colloidal lanthanum tracer revealed that only bioreactor islet cell cultures were devoid of tight junctional complexes, which may facilitate channel formation. CONCLUSION: Microgravity condition decreases immunogenicity and significantly improves the function of secretory cells.     

Phase I pharmacodynamic study of time and sequence dependency of hydroxyurea in combination with gemcitabine: a California Cancer Consortium Trial

Preclinical studies in our laboratory have demonstrated that prior exposure to hydroxyurea increases the percentage of cells in S phase, enhancing the cytotoxicity of subsequent gemcitabine treatment in human oropharyngeal KB cells. To evaluate the clinical implications of this time- and sequence-dependent potentiation, we performed a phase I trial of hydroxyurea given over 24 h followed by a 30-min infusion of gemcitabine in weeks 1 and 2 of a 3-week cycle. The dose of hydroxyurea was fixed at 500 mg orally every 6 h for four doses starting 24 h before each dose of gemcitabine. The initial dose level of gemcitabine was 250 mg/m(2) on days 2 and 9, and this was escalated stepwise to 1000 mg/m(2) on days 2 and 9. Gemcitabine pharmacokinetics were determined on days 2 and 9 of the first cycle. Of 27 patients enrolled (12 female, 15 male), 24 were evaluable for response and 23 were evaluable for toxicity. Their median age was 56 years (range 27-76 years). Tumor types included lung, head and neck, pancreas, breast, colon, prostate, stomach, ovary, esophagus, germ cell, thyroid, gallbladder, and unknown primary. A total of 80 cycles of treatment were completed. One patient (unknown primary) had an objective partial response lasting 21 months, and 12 patients had stable disease. All observed dose-limiting toxicities were related to myelosuppression. The gemcitabine maximum tolerated dose was established at 750 mg/m(2) on days 2 and 9. Hydroxyurea had no effect on the plasma pharmacokinetics of gemcitabine. These results suggest that hydroxyurea followed by gemcitabine can be safely administered and has activity on this schedule. We are presently developing a phase II trial of this regimen for patients with platinum-resistant head and neck cancer.     

A randomized phase II trial of the matrix metalloproteinase inhibitor BMS-275291 in hormone-refractory prostate cancer patients with bone metastases.

BACKGROUND: BMS-275291 is a selective matrix metalloproteinase inhibitor (MMPI) that does not inhibit sheddases implicated in the dose-limiting arthritis of older MMPIs. We conducted a randomized phase II trial of two doses of BMS-275291 (1,200 versus 2,400 mg) in hormone-refractory prostate cancer (HRPC) patients with bone metastases to probe for a dose-response relationship and to assess differential toxicities. Serial serum and urine specimens were collected to assess for markers of bone metabolism. METHODS: The primary end point was 4-month progression-free survival (PFS). Eligibility criteria included documentation of androgen-independent disease (including anti-androgen withdrawal), skeletal metastasis, adequate end-organ function and performance status, and no more than one prior chemotherapy regimen. Patients were randomized to 1,200 mg orally once daily (arm A) or 1,200 mg orally twice daily (arm B). Response was assessed every 56 days. RESULTS: Eighty patients were enrolled: 39 in arm A and 41 in arm B. There were no responders by prostate-specific antigen or measurable disease to treatment. Stable disease was noted at 8 weeks in 39% of patients in arm A and in 17% of patients in arm B. Progression of disease at 8 weeks was seen in 61% of patients in arm A versus 83% of patients in arm B. Median survival time was 21.6 months (95% confidence interval, 17.5; not reached), whereas median PFS time was 1.8 months (95% confidence interval 1.74; 2) for all patients. Patients in arm A had a median survival time that was not reached, whereas patients on arm B has a median survival time of 21 months (P = 0.2). PFS at 4 months favored arm A: 22% versus 10% (log-rank, P = 0.008). Grade 3 toxicities occurred in 5 (13%) patients in arm A and in 9 (22%) patients in arm B. Grade 4 toxicities were uncommon (only 4% of patients): one each of thrombosis, fatigue, and motor neuropathy was seen in the arm B. Bone marker studies showed that baseline serum levels of N-telopeptide, osteocalcin, procollagen I NH2-terminal propeptide, and PICP had prognostic significance for PFS and/or overall survival. CONCLUSIONS: Regardless of dose schedule, BMS-275291 was well tolerated in HRPC patients and had no dose-limiting arthritis. Toxicities differed modestly according to the dose schedule employed. As overall survival and PFS favored the once daily schedule, this dose schedule is recommended for future studies. Baseline markers of bone metabolism may have prognostic value in HRPC patients with bone metastases.     

The genetics of geometry

Although much progress has been made in understanding how gene expression patterns are established during development, much less is known about how these patterns are related to the growth of biological shapes. Here we describe conceptual and experimental approaches to bridging this gap, with particular reference to plant development where lack of cell movement simplifies matters. Growth and shape change in plants can be fully described with four types of regional parameter: growth rate, anisotropy, direction, and rotation. A key requirement is to understand how these parameters both influence and respond to the action of genes. This can be addressed by using mechanistic models that capture interactions among three components: regional identities, regionalizing morphogens, and polarizing morphogens. By incorporating these interactions within a growing framework, it is possible to generate shape changes and associated gene expression patterns according to particular hypotheses. The results can be compared with experimental observations of growth of normal and mutant forms, allowing further hypotheses and experiments to be formulated. We illustrate these principles with a study of snapdragon petal growth.     

Combination of paclitaxel and nitric oxide as a novel treatment for the reduction of restenosis

The combination of a nitric oxide (NO) donor and a paclitaxel-NO donor conjugate coated on a vascular stent was tested in a rabbit iliac artery model of stenosis as a potential therapy for restenosis. Paclitaxel was conjugated with a NO donor at the 7-position to give compound 7. An adamantane-based NO donor 14 was synthesized and combined with 7 to provide a burst of NO in the first few critical hours following injury to the vessel wall. Both 7 and 14 demonstrated antiproliferative activity (IC(50) = 20 nM and 15 microM, respectively) and antiplatelet activity (IC(50) = 10 and 1 microM, respectively). Stents were coated with a layer of a polymer containing test compounds. The total amount of NO eluted from the stents after a 6 h implantation in the rabbit iliac artery was 35%, 95%, and 69% of the original content for the stents coated with 7, 14, and the combination of 7 and 14, respectively. The antistenotic activity of 7 and 14 was determined in a 28-day rabbit model with two control groups (uncoated stents and polymer-coated stents) and two study groups (paclitaxel-coated stents and stents coated with the combination of 7 and 14). Polymer-coated stents caused inflammation and increased stenosis by 39% when compared to the uncoated stents. The stents coated with 7 plus 14 were as good as the uncoated stents, 41% better than the polymer-coated stents and 34% better than the paclitaxel-coated stents. These data indicate a beneficial effect of adding NO to an antiproliferative agent (paclitaxel) and suggest a potential therapeutic combination for the treatment of stenotic vessel disease.