Impact of Short-Range Forces on Defect Production from High-Energy Collisions.

Primary radiation damage formation in solid materials typically involves collisions between atoms that have up to a few hundred keV of kinetic energy. During these collisions, the distance between two colliding atoms can approach 0.05 nm. At such small atomic separations, force fields fitted to equilibrium properties tend to significantly underestimate the potential energy of the colliding dimer. To enable molecular dynamics simulations of high-energy collisions, it is common practice to use a screened Coulomb force field to describe the interactions and to smoothly join this to the equilibrium force field at a suitable interatomic spacing. However, there is no accepted standard method for choosing the parameters used in the joining process, and our results prove that defect production is sensitive to how the force fields are linked. A new procedure is presented that involves the use of ab initio calculations to determine the magnitude and spatial dependence of the pair interactions at intermediate distances, along with systematic criteria for choosing the joining parameters. Results are presented for the case of nickel, which demonstrate the use and validity of the procedure.

Electron-phonon coupling in Ni-based binary alloys with application to displacement cascade modeling.

Energy transfer between lattice atoms and electrons is an important channel of energy dissipation during displacement cascade evolution in irradiated materials. On the assumption of small atomic displacements, the intensity of this transfer is controlled by the strength of electron-phonon (el-ph) coupling. The el-ph coupling in concentrated Ni-based alloys was calculated using electronic structure results obtained within the coherent potential approximation. It was found that Ni0.5Fe0.5, Ni0.5Co0.5 and Ni0.5Pd0.5 are ordered ferromagnetically, whereas Ni0.5Cr0.5 is nonmagnetic. Since the magnetism in these alloys has a Stoner-type origin, the magnetic ordering is accompanied by a decrease of electronic density of states at the Fermi level, which in turn reduces the el-ph coupling. Thus, the el-ph coupling values for all alloys are approximately 50% smaller in the magnetic state than for the same alloy in a nonmagnetic state. As the temperature increases, the calculated coupling initially increases. After passing the Curie temperature, the coupling decreases. The rate of decrease is controlled by the shape of the density of states above the Fermi level. Introducing a two-temperature model based on these parameters in 10 keV molecular dynamics cascade simulation increases defect production by 10-20% in the alloys under consideration.

The influence of transition metal solutes on the dislocation core structure and values of the Peierls stress and barrier in tungsten.

Several transition metals were examined to evaluate their potential for improving the ductility of tungsten. The dislocation core structure and Peierls stress and barrier of 1/2<111> screw dislocations in binary tungsten-transition metal alloys (W(1-x)TM(x)) were investigated using density functional theory calculations. The periodic quadrupole approach was applied to model the structure of the 1/2<111> dislocation. Alloying with transition metals was modeled using the virtual crystal approximation and the applicability of this approach was assessed by calculating the equilibrium lattice parameter and elastic constants of the tungsten alloys. Reasonable agreement was obtained with experimental data and with results obtained from the conventional supercell approach. Increasing the concentration of a transition metal from the VIIIA group, i.e. the elements in columns headed by Fe, Co and Ni, leads to reduction of the C' elastic constant and increase of the elastic anisotropy A = C(44)/C'. Alloying W with a group VIIIA transition metal changes the structure of the dislocation core from symmetric to asymmetric, similarly to results obtained for W(1-x)Re(x) alloys in the earlier work of Romaner et al (2010 Phys. Rev. Lett. 104 195503). In addition to a change in the core symmetry, the values of the Peierls stress and barrier are reduced. The latter effect could lead to increased ductility in a tungsten-based alloy. Our results demonstrate that alloying with any of the transition metals from the VIIIA group should have a similar effect to alloying with Re.

Pharmacokinetic study of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies.

S-CKD602 is a pegylated liposomal formulation of CKD-602. This study is the first to evaluate the factors affecting the high interpatient variability in the pharmacokinetic disposition of S-CKD602. S-CKD602 was administered intravenously (i.v.) every 3 weeks as part of a phase I study. Pharmacokinetics studies of the liposomal encapsulated and released CKD-602 in plasma were performed. The pharmacokinetic variability of S-CKD602 is associated with both linear and nonlinear clearances. Patients > or =60 years of age have a 2.7-fold higher exposure of S-CKD602 as compared with patients <60 years of age (P = 0.02). Patients with a lean body composition have a higher plasma exposure of S-CKD602 (P = 0.02). Patients who have received prior therapy with pegylated liposomal doxorubicin (PLD) have a 2.2-fold higher exposure of S-CKD602 as compared with patients who have not received PLD (P = 0.045). Prolonged exposure of the encapsulated drug in plasma over 1-2 weeks provides significant pharmacologic advantages. The high interpatient variability in the pharmacokinetic disposition of S-CKD602 was associated with age, body composition, saturable clearance, and prior PLD therapy.

Magnetic interactions influence the properties of helium defects in iron.

Density functional theory calculations of He defect properties in iron have shown an unexpected influence of magnetism arising from the defect's electronic structure. In contrast with previous work that neglected such effects, the results indicate that the tetrahedral position is energetically more favorable for the He interstitial than the octahedral site. This may have significant implications for He clustering and bubble nucleation, which will impact material performance in future fusion reactors. These results provide the basis for development of improved atomistic models.

Minocycline-induced pericardial effusion.

OBJECTIVE: To describe a reversible hypersensitivity reaction characterized by pericardial effusion and acute mixed liver injury in a woman treated with minocycline. CASE SUMMARY: A 39-year-old white woman developed dyspnea and chest pain with pericardial effusion on echocardiography approximately 20 days after starting minocycline treatment. Additional manifestations consisted of eosinophilia and liver injury. No lung, skin, or joint involvement was noted; antinuclear antibody testing was negative. DISCUSSION: Minocycline has been associated with rare but severe hypersensitivity reactions and autoimmune disorders, generally involving the lungs, skin, or joints. We observed a patient with an unusual minocycline-induced reaction with pericardial effusion and acute mixed liver injury. The number of spontaneously reported cases in national and international databases indicates that minocycline-induced pericardial effusion is very rare as a main clinical manifestation. CONCLUSIONS: Clinicians should be aware of the possibility of pericardial effusion without lung, skin, or joint involvement as an adverse effect of minocycline.

[Fluoroquinolones as etiology of tendinopathy]. / Fluoroquinolone als Ursache von Tendinopathien.

Tendinopathies as a result of fluoroquinolone therapy represent a new clinical entity. We report on tendinitis and tendon rupture in six fluoroquinolone treated patients of our outpatient and dialysis service between 1995 and 1997. The most important risk factors for tendinopathies were renal failure in all cases, glucocorticosteroid therapy in five patients, secondary hyperparathyroidism in three patients, advanced age in two patients, and diabetes mellitus in another patient. Latency periods of 2 to 60 days between onset of fluoroquinolone therapy and emergence of symptoms suggest significant involvement of these agents and are compatible with previously published case reports. Therefore, care should be used in prescribing fluoroquinolones to older renal transplant or hemodialysis patients with additional risk factors for tendinopathies. These drugs should be stopped when symptoms of tendinitis occur, particularly to prevent tendon rupture. The incidence of fluoroquinolone induced tendinopathies in patients without renal diseases is unknown.

[Retrospective study of drug-induced agranulocytosis in hospitalized patients in Geneva and comparison with cases reported to IOCM]. / Etude rétrospective des cas d'agranulocytose médicamenteuse hospitalisés à Genève et comparaison avec les cas notifiés à l'OICM.

In a retrospective study, 19 cases classified as idiosyncratic drug-induced agranulocytosis were found among 162 files of patients hospitalized in internal medicine clinics of the university hospital where this diagnosis had been coded. This would give an estimated incidence of 2.6 cases per million inhabitants per year for the Geneva area. In most cases several drugs were implicated in causation of the episodes. Suspected drugs were those commonly reported in the literature, but also some drugs which might already have been taken to treat infectious complications of agranulocytosis. A comparison of the Geneva cases with those notified to the Swiss Intercantonal Office for the Control of Medicines reveals a similar profile of involved drugs.

Omeprazole-induced hepatotoxicity? A case report.

CASE REPORT: We observed a serious symptomatic hepatocellular liver injury in an 85-year-old man treated with omeprazole for many years. Peak values for AST, ALT and AP were 1542 U/l (normal range 14-50), 1236 U/l (11-60) and 154 U/l (30-125) respectively. Abdominal CT scan was normal and viral serologic testing was negative. Omeprazole was discontinued and liver enzymes normalized in 12 days. The patient was known to suffer from ischemic heart disease and had had a myocardial infarction 6 months previously. He was reexposed to omeprazole and the level of liver enzymes rose again and normalized after stopping omeprazole. Despite the improvement of his liver function, the patient died 5 days later due to chronic congestive heart failure. DISCUSSION: Five cases of omeprazole-induced liver injury have been reported to the Swiss Drug Regulatory Agency since 1990, among them two of cholestatic hepatitis and one of hepatic failure. The WHO Data Base has collected 13,630 ADRs related to omeprazole, with more than 80 cases of hepatitis, 60 of jaundice and about 40 of cholestatic hepatitis. In contrast, only one case of severe symptomatic hepatotoxicity is described in the literature. Clinical studies reported minimal increase of liver enzymes only, in 1-5% of cases. CONCLUSION: This case with reexposure, together with those reported internationally, suggests that hepatitis is a possible but obviously rare complication of omeprazole treatment.

[Liver injury caused by coumarin anticoagulants: experience of the IKS (Intercanton Monitoring Station) and the SANZ (Swiss Center for Drug Monitoring)]. / Leberschäden durch Coumarin-Antikoagulantien: Erfahrungen der IKS und der SANZ.

Drug-induced liver diseases are potentially avoidable. Hepatotoxic drugs can mimic virtually any form of liver disease. Among all voluntary adverse drug reaction reports to central registries, 4-7% refer to drug-induced liver diseases. We analyze all cases of coumarin-induced hepatic injuries reported on a voluntary basis to the Swiss Drug Monitoring Centre (SANZ) and the Pharmacovigilance Centre (IKS) from 1981 to 1995. During this period the SANZ collected 9720 reports, 674 of which (6.9%) referred to the liver and the biliary tract. In only 11 reports an oral anticoagulant was involved. In 8 cases we assumed at least a possible causal relationship. 2 more cases were reported directly to the IKS. Among these 10 cases 7 were related to phenprocoumon and 3 to acenocoumarol. In 4 cases elevated concentrations of liver enzymes were measured 2-7 days after the beginning of therapy. In the remaining 6 cases the clinical picture was so severe that the patients had to be hospitalized. These 10 cases are discussed and compared with the cases published in the literature. According to our data, hepatic disorders induced by coumarin-anti-coagulants are rare. If hepatitis is diagnosed in a patient treated with oral anticoagulants, the differential diagnosis of a coumarin-induced hepatic injury has to be considered. Crossreactions between the coumarin derivatives phenprocoumon and acenocoumarol are possible.

The efficacy of recombinant human granulocyte colony-stimulating factor and recombinant human granulocyte macrophage colony-stimulating factor in permitting the administration of higher doses of cyclophosphamide in a doxorubicin-cyclophosphamide combination. An NSABP pilot study in patients with metastatic or high-risk primary breast cancer. National Surgical Adjuvant Breast and Bowel Project.

Colony-stimulating factors (CSFs) shorten the duration of myelosuppression following chemotherapy and, thus, allow the administration of higher doses. This study evaluates the efficacy of granulocyte macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) in allowing administration of high-dose cyclophosphamide in combination with doxorubicin. Ninety women with metastatic, locally advanced, or high-risk (> or = 10 positive nodes) breast cancer and no prior anthracycline treatment were given doxorubicin (60 mg/m2) with progressively increased doses of cyclophosphamide (1,200 mg/m2, 1,800 mg/m2, and 2,400 mg/m2). The first 60 patients received GM-CSF; the remaining 30, G-CSF. The maximum tolerated dose was not reached with 2,400 mg/m2 of cyclophosphamide. When compared to GM-CSF, G-CSF significantly reduced the duration of granulocytopenia (P < .001). No differences in duration of thrombocytopenia were noted. The results were not sufficiently consistent to indicate a trend toward reduction in rates of febrile neutropenia with one CSF versus the other. However, patients who received G-CSF were hospitalized less frequently than those receiving GM-CSF. With CSFs, high-dose cyclophosphamide in combination with doxorubicin can be safely administered on an outpatient basis. A shorter duration of granulocytopenia resulted from the use of G-CSF than from GM-CSF.

The impact of therapy with filgrastim (recombinant granulocyte colony-stimulating factor) on the health care costs associated with cancer chemotherapy.

The objective of the study was to estimate the net impact on health resource utilisation of using recombinant granulocyte colony-stimulating factor (filgrastim) following myelosuppressive chemotherapy. Cost minimisation of the study medication in a randomised, double-blind, placebo-controlled clinical trial was conducted in teaching institutions and affiliated community hospitals participating in a clinical trial. 68 patients with small cell lung cancer undergoing cyclophosphamide, doxorubicin and etoposide chemotherapy were randomised to blinded placebo or filgrastim study medication at three or 14 clinical trials sites. The patients received daily subcutaneous injections of filgrastim or placebo, initiated 24 h after chemotherapy and continued until the neutrophil count exceeded 10,000 x 10(6)/l after the time of the expected nadir. Differences in total charges, costs and Medicare payments between treatment groups were the main outcomes measured. Compared to placebo patients, filgrastim-treated patients had significantly fewer and less resource-intensive hospitalisations. After accounting for filgrastim purchase and administration, the charge model predicts overall savings from filgrastim use in a clinical setting in which the risk of febrile neutropenia is high for patients not receiving filgrastim. The Medicare and cost models predict only a partial recapture of the cost of filgrastim therapy. The health care resources impact of filgrastim was sensitive to the risk of hospitalisation with febrile neutropenia, and to the perspective chosen for measuring resource utilisation (charges, costs or Medicare payments). The adjunctive use of filgrastim following myelosuppressive chemotherapy leads to partial or complete recapture of the cost of purchasing and administering the product.

Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer.

BACKGROUND: Neutropenia and infection are major dose-limiting side effects of chemotherapy. Previous studies have suggested that recombinant methionyl granulocyte colony-stimulating factor (G-CSF) can reduce chemotherapy-related neutropenia in patients with cancer. We conducted a randomized clinical trial to test this hypothesis and the clinical implications. METHODS: Patients with small-cell lung cancer were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of recombinant methionyl G-CSF to study the incidence of infection as manifested by fever with neutropenia (absolute neutrophil count, less than 1.0 x 10(9) per liter, with a temperature greater than or equal to 38.2 degrees C) resulting from up to six cycles of chemotherapy with cyclophosphamide, doxorubicin, and etoposide. The patients were randomly assigned to receive either placebo or G-CSF, with treatment beginning on day 4 and continuing through day 17 of a 21-day cycle. RESULTS: The safety of the study treatment could be evaluated in 207 of the 211 patients assigned to either drug, and its efficacy in 199. At least one episode of fever with neutropenia occurred in 77 percent of the placebo group, as compared with 40 percent of the G-CSF group (P less than 0.001). Over all cycles of chemotherapy, the median duration of grade IV neutropenia (absolute neutrophil count, less than 0.5 x 10(9) per liter) was six days with placebo as compared with one day with G-CSF. During cycles of blinded treatment, the number of days of treatment with intravenous antibiotics, the number of days of hospitalization, and the incidence of confirmed infections were reduced by approximately 50 percent when G-CSF was given, as compared with placebo. Mild-to-moderate medullary bone pain occurred in 20 percent of the patients receiving G-CSF. CONCLUSIONS: The use of G-CSF as an adjunct to chemotherapy in patients with small-cell cancer of the lung was well tolerated and led to reductions in the incidence of fever with neutropenia and culture-confirmed infections; in the incidence, duration, and severity of grade IV neutropenia; and in the total number of days of treatment with intravenous antibiotics and days of hospitalization.

Use of granulocyte-macrophage colony-stimulating factor in patients with malignancy and bone marrow failure.

Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered to 10 patients with refractory malignancies, 2 patients who had myelodysplastic syndromes with severe neutropenia and to a patient who had delayed marrow recovery after 3 cycles of therapy for acute leukemia. A marked neutropenia and monocytopenia was observed within 5 min after an i.v. injection of GM-CSF. This persisted for 1-2 h and seemed related to activation of an adhesive glycoprotein (MO1) on the surface of these cells. With continued daily i.v. administration of GM-CSF, all patients with refractory malignancies developed a striking leukocytosis. Total leukocyte counts reached 75,000/microliters within 2 weeks of treatment. This was due to an increase in band and segmented neutrophils, eosinophils and monocytes. Accelerated myelopoiesis required the continuous presence of GM-CSF; with pump failure for 24 h or discontinuation after 14 days, leukocyte counts returned to normal levels in 24-48 h. GM-CSF also increased myelopoiesis in the patients with myelodysplastic syndromes or following anti-leukemic treatment. These observations suggest that this growth factor should prove a useful adjunct in the treatment of patients with malignancies and bone marrow failure.