Synthesis methods to prepare single- and multi-core iron oxide nanoparticles for biomedical applications.

We review current synthetic routes to magnetic iron oxide nanoparticles for biomedical applications. We classify the different approaches used depending on their ability to generate magnetic particles that are either single-core (containing only one magnetic core, i.e. a single domain nanocrystal) or multi-core (containing several magnetic cores, i.e. single domain nanocrystals). The synthesis of single-core magnetic nanoparticles requires the use of surfactants during the particle generation, and careful control of the particle coating to prevent aggregation. Special attention has to be paid to avoid the presence of any toxic reagents after the synthesis if biomedical applications are intended. Several approaches exist to obtain multi-core particles based on the coating of particle aggregates; nevertheless, the production of multi-core particles with good control of the number of magnetic cores per particle, and of the degree of polydispersity of the core sizes, is still a difficult task. The control of the structure of the particles is of great relevance for biomedical applications as it has a major influence on the magnetic properties of the materials.

Identification of 1-butyl-3-(1-(4-methyl)naphthoyl)indole in a herbal mixture.

Besides the cannabinoid mimetic JWH-073, a novel 4 methylnaphthoyl homologue of JWH-073 was detected in a herbal mixture. The structure of the compound was elucidated after thin layer chromatographic enrichment from the herbal mixture by nuclear magnetic resonance (NMR) and gas chromatographic mass spectrometric (GC-MS) analysis. The paper outlines data after GC-MS, liquid chromatography mass spectrometry (LC-MS) and NMR spectroscopy, and describes the structure elucidation.

Characterization of pentoxyverine metabolites in urine using GC/MS after intoxication with Silomat cough drops.

A nearly two and a half year old boy was hospitalized after showing symptoms of disorientation and hallucination. The parents remembered the child playing with a bottle of Silomat cough drops, so that an intoxication was taken into consideration. After liquid/liquid extraction of a urine sample collected in hospital, the underivatized and the acetylated extracts were analyzed by gas chromatography-mass spectrometry (GC/MS) using electron ionization (EI) as well as chemical ionization (CI). In the urine sample high amounts of pentoxyverine (carbetapentane) and several of its metabolites, e.g., different hydrolyzed, desalkylated and ring-hydroxylated products have been identified. The correlation of the results, the observed symptoms, and the access to the Silomat cough drops reveal an intoxication after ingestion of an unknown amount of the antitussive pentoxyverine. Corresponding EI- and CI-GC/MS spectra are presented characterizing the structure of its metabolites.

Differentiation of regioisomeric ring-substituted fluorophenethylamines with product ion spectrometry.

The electron ionization (EI) of aromatic ring-substituted isomers gives virtual identical mass spectra which seriously affects their analysis. Especially regioisomeric meta- and para-ring-substituted compounds cannot show any ortho-effect reactions making their differentiation by mass spectrometry impossible. Furthermore o-, m- and p-substituted compounds can only be separated insufficiently by chromatography due to their very similar retention that do not allow univocal identification. Product ion mass spectrometry has proved to be a useful tool to differentiate structurally closely related fluorophenethylamines even in the case of the meta- and para-isomers. A series of N-alkylated o-, m- and p-fluoroamphetamines and 1-(4-fluorophenyl)butan-2-amines have been synthesized in microscale and studied by product ion spectrometry. The combination of chemical ionization (CI) and product ion spectrometry of hydrogen fluoride loss ions [M+H-HF](+) allows a univocal differentiation of all studied fluoro-substituted phenethylamines without prior derivatization. This method with submicrogram detection limits provides great advantages for the differentiation between aromatic regioisomeric fluorophenethylamine designer drugs where other methods such as nuclear magnetic resonance (NMR) spectrometry lack sufficient sensitivity or might fail because complex mixtures have to be analyzed.

Influence of press-fit parameters on the primary stability of uncemented femoral resurfacing implants.

Primary stability is essential to the success of uncemented prostheses. It is strongly influenced by implantation technique, implant design and bone quality. The goal of this study was to investigate the effect of press-fit parameters on the primary stability of uncemented femoral head resurfacing prostheses. An in vitro study with human specimens and prototype implants (nominal radial interference 170 and 420 microm) was used to investigate the effect of interference on primary stability. A finite element model was used to assess the influence of interference, friction between implant and bone, and bone quality. Primary stability was represented by the torque capacity of the implant. The model predicted increasing stability with actual interference, bone quality and friction coefficient; plastic deformation of the bone began at interferences of less than 100 microm. Experimentally, however, stability was not related to interference. This may be due to abrasion or the collapse of trabecular bone structures at higher interferences, which could not be captured by the model. High nominal interferences as tested experimentally appear unlikely to result in improved stability clinically. An implantation force of about 2,500 N was estimated to be sufficient to achieve a torque capacity of about 30 N m with a small interference (70 microm).

Migration and cyclic motion of a new short-stemmed hip prosthesis--a biomechanical in vitro study.

BACKGROUND: Uncemented, short-stemmed hip prostheses have been developed to reduce the risk of stress shielding and to preserve femural bone stock. The long-term success of these implants is yet uncertain. Prerequisite for osseointegration is sufficient primary stability. In this study the cyclic motion and migration patterns of a new short-stemmed hip implant were compared with those for two clinically successful shaft prostheses. METHODS: The prostheses were implanted in paired fresh human femura and loaded dynamically (gait cycle) with increasing load (max 2,100 N) up to 15,000 cycles. Relative displacements between prosthesis and bone were recorded using a 3D-video analysis system. FINDINGS: The short stem displayed a biphasic migration pattern with stabilisation at maximum load. Initial migration was predominantly into varus and was greater than that for the shaft prostheses. Failure occurred in cases of poor bone quality and malpositioning. Cyclic motion of the short prosthesis was less than that for the shaft prostheses. Surface finish showed no effect. System stiffness for the new stem was lower than for the shaft prostheses. INTERPRETATION: The new stem tended to migrate initially more than the shaft prostheses, but stabilised when cortical contact was achieved or the cancellous bone was compacted sufficiently. Bone quality and correct positioning were important factors for the short stem. The lower cyclic motion of the new stem should be favourable for bony ingrowth. The lower system bending stiffness with the new implant indicated a more physiological loading of the bone and should thereby reduce the effects of stress shielding.

Biomechanics of a new short-stemmed uncemented hip prosthesis: An in-vitro study in human bone.

The migration pattern, cyclic motion, system stiffness and failure load of a new short-stemmed hip prosthesis were compared to a clinically successful shaft prosthesis during the initial loading phase. The influence of implant-sizing on mechanical stability was also investigated for the new stem, in particular with relation to the bone quality. Prostheses were implanted in paired human femora and loaded cyclically up to 3515 cycles. Relative displacements between prosthesis and bone were measured using a 3D-camera and reflective marker system. Migration of the new stem was predominantly into varus and was higher than for the shaft prosthesis. The test set-up was proposed to simulate a worst-case loading scenario since muscle forces, which tend to reduce bone deformation, were not simulated. It could therefore be expected that clinical migration of the implants would be less pronounced than that observed in this study. Cyclic motion for the new stem was similar to that for the clinically successful shaft prosthesis, suggesting that bone ingrowth could be expected for the new stem. No significant difference in fracture load was observed between the implants. The system stiffness with the new stem was lower than for the shaft prosthesis, indicating more physiological load transfer. Smaller implant sizing with 'cancellous' fixation seems favourable, as it led to similar migration and smaller cyclic motion values than with 'cortical' fixation. A trend for higher cyclic motion and migration was observed in femora with poor bone quality. Hence, sufficiently good bone stock is necessary, when implanting the new short-stemmed prosthesis.

Role of p53 mutations, protein function and DNA damage for the radiosensitivity of human tumour cells.

PURPOSE: The tumour suppressor protein p53 is considered to have an impact on the radiosensitivity of tumour cells. However, this concept does not easily translate to the tumour sensitivity in the clinics. The aim of the present study was to determine whether a functional or dysfunctional p53 is associated with a sensitive or resistant phenotype. It was further studied whether DNA damage might be an additive factor by which p53 has impact on cell survival. MATERIALS AND METHODS: Nine human tumour cell lines were studied for p53 mutation by direct sequencing of exons 4-9. Regulation of p53 and p21(cip1/waf1) protein was assessed by immunoblotting and cell cycle effects by combining 5-bromodeoxyuridine incorporation and flow cytometry. RESULTS AND CONCLUSION: Three strains (RT112, Du145, SCC4451) were found to have a missense-mutation in the core domain and one did not express p53 at all (HeLa), presumably due to HPV18 infection. Immunoblots of these cells showed neither a regulated p53 nor p21 expression. The cells did not arrest in G1 phase after X-irradiation but did arrest in G2/M. All cells expressing wild-type protein (LNCaP, T47D-B8, MCF-7 and sublines BB and Bus) showed an intact p53 and p21 regulation and a modest arrest in both G1 and G2/M. Thus, in contrast to other studies, all tumour cells investigated showed either a typical p53wt or mutant (mut) pattern. Protein function was compared with cell survival and DNA damage, as assessed previously. p53 wild-type cells were on average 1.3-times (n.s.) more radiosensitive than mutant cells, but there was a considerable overlap between both groups. Further, the 1.3-fold enhanced resistance of cells lacking wild-type p53 was paralleled by a 1.3-fold lower number of induced double-strand breaks. The results suggest that p53 could have impact on chromatin compaction and thus effect DNA damage induction and radiosensitivity of tumour cells.

Fatal intoxication with a decalcifying agent containing formic acid.

A fatality caused by ingestion of a decalcifying agent containing formic acid is reported. Quantitative analysis of formic acid in the form of its methyl ester was performed in different body fluids and organ samples using head-space gas chromatography with flame ionization detection. The blood taken at the time of admission to hospital had a concentration of 370.3 microg/ml, which declined to 13.9 microg/ml after 6.5 h of haemodialysis. Post-mortem concentrations were 855.4 microg/ml (heart blood), 2,712 microg/ml (gastric contents), 1128 microg/ml (haemorrhagic fluid from abdominal cavity), 3,051 microg/ml (bile), 2,664 microg/ml (contents of small intestine), 442.7 microg/g (liver) and 542.3 microg/g (kidney). The most important morphological findings for differentiating between oral and respiratory ingestion were ulceration of the oropharynx and the oesophagus as well as extensive necrotic lesions in the stomach and the duodenum without perforation. Death was caused by massive acidosis, haemolysis, bleeding complications, hepatic and renal failure. Toxicological and morphological findings revealed that a considerable amount of formic acid had been ingested orally with a suicidal intention.

Biocompatible magnetic polymer carriers for in vivo radionuclide delivery.

The magnetic guidance of antiplastic and antibacterial agents as well as x-ray and MRI contrast substances in vivo by means of magnetic particles has been attempted repeatedly during the last 2 decades with more or less success. When using microparticles, the circulation time in the blood, the biodistribution, and to a greater or lesser extent, the specific targeting are determined by the uniformity of size, chemical composition, surface modification, and the electric surface charge. The electrophoretic mobility is an important parameter for the prediction of the usefulness of the prepared particle, modified by chemical and biological molecules. For its success, radionuclide therapy depends on the critical relationship between the amount of radioactive isotopes in the target tissue and in critical normal tissue. Because the implementation of radioimmunotherapy for the treatment of cancer has proven to be considerably more difficult than initially anticipated, we propose the use of magnetic nanospheres for the well directed delivery of radionuclides to a tumor after the intravenous administration of the biodegradable colloidal suspension.