A clinical instrument for multi-element in vivo analysis by prompt, delayed and cyclic neutron activation using 252Cf

The design and construction of a versatile clinical instrument for multi-element in vivo neutron activation analysis of major and minor body elements is described. A 200 micrograms (4 GBq) 252Cf neutron source is stored below ground level and pneumatically propelled to one of two irradiation ports. These deliver collimated beams of fast neutrons either to a localised volume such as the liver or kidney, or across the width of a patient for a head-to-toe scanning whole-body measurement. The source control system allows selection of either a continuous or cyclic mode of activation. The instrument is intended primarily for measurement, by the prompt-gamma technique, of total and partial body calcium, total body nitrogen and partial body cadmium. The potential of the instrument for determination of these three elements has been established. Phantom results suggest that total body calcium can be measured with a precision of +/- 2.6% (CV) for an average whole-body skin dose equivalent of 6.4 mSv; total body nitrogen with a precision of +/- 2.0% for an average whole-body skin dose equivalent of less than 0.4 mSv; and a detection limit (2 SD of the background) of 2.4 mg of cadmium in the kidney has been obtained for a radiation dose equivalent to the skin of 3 mSv (QF = 10). The suitability of this instrument for the measurement of other elements is also discussed.     

A two-way scanning method for total body in vivo neutron activation analysis.

When determining the total body content of many elements by neutron activation analysis, irradiation and whole body counting by scanning along the length of the body has significant advantages. A neutron source of lower output and a whole body counter using smaller detectors and shielding (than otherwise needed) can provide a high, uniform response for many elements throughout the body. This was previously achieved by making the speed and direction of scanning identical in irradiation and counting (one-way scanning). A simple theoretical model for scanned irradiation and counting is described. The model is used to show that a scanning regime in which both scanning directions are used (two-way scanning) can provide acceptably uniform response for elements having induced activities of a wide range of half-life. This is supported by measurements made using an existing scanning facility for total body in vivo neutron activation analysis. The two-way scanning regime offers the advantages of increased patient comfort, simpler operation and more efficient use of the time available for counting induced activity.     

Influence of industrialization on trace element concentration in human lungs]

Introduction: People who spend their entire lives in highly industrialized regions are in danger of accumulating trace elements by inhalation as a result of the increased amounts of factory-produced smoke. In order to test the environmentally accumulated trace elements in lungs, lung samples of patients who lived their entire lives in the industrial area of Duisburg were compared with those of patients from the less industrialized areas of Cologne and surroundings. Material and Method: Five patients were studied who lived in Duisburg and died at 50-68 years but not primarily as a result of lung diseases. From each patient five samples of the left lung were removed at autopsy. Lungs from 18 patients who died in Cologne were also examined. From each of the latter 2 samples were removed from the left lung. All samples were studied by means of neutron activation analysis and the following elements analysed: Co, Fe, Rb, Se, Cr, Cs, Sb, Sc, Zn and Al. The Al-concentration was analysed only in patients aged 50-68 years. Results: The values of the non-essential Sc, Al and Cs and of the essential trace elements Co were found to be appreciably higher in the samples from Duisburg than in those from Cologne. Sc in the samples from the highly industrialized area was increased up to a factor of 100, Cs, Al and Co to a factor of 10. In the lungs of adults in Duisburg, aged 50-68 years, the concentration of Sc was more than 1,000 times greater than in lungs of children in Cologne, aged 0-10 years. In all samples from Duisburg, the rare element Eu was detectable by means of neutron activation analysis but could not be detected in a sample from Cologne. Discussion: It is likely that the different uptakes of trace elements in the lungs depend on correspondingly different concentrations of the elements in the air. The extensive accumulation, especially of the non-essential elements, in the lungs should be an incentive to examine possible detrimental effects on human health in the future. The element Sc which was strikingly accumulated in the lungs and which can be easily measured by neutron activation analysis might be used as a standard for estimating the extent of environmental pollution.     

Neutron activation of holmium poly(L-lactic acid) microspheres for hepatic arterial radioembolization: a validation study

Poly(L-lactic acid) microspheres loaded with holmium-166 acetylacetonate (¹⁶⁶Ho-PLLA-MS) are a novel microdevice for intra-arterial radioembolization in patients with unresectable liver malignancies. The neutron activation in a nuclear reactor, in particular the gamma heating, damages the ¹⁶⁶Ho-PLLA-MS. The degree of damage is dependent on the irradiation characteristics and irradiation time in a particular reactor facility. The aim of this study was to standardize and objectively validate the activation procedure in a particular reactor. The methods included light- and scanning electron microscopy (SEM), particle size analysis, differential scanning calorimetry, viscometry, thermal neutron flux measurements and energy deposition calculations. Seven hours-neutron irradiation results in sufficient specific activity of the ¹⁶⁶Ho-PLLA-MS while structural integrity is preserved. Neutron flux measurements and energy deposition calculations are required in the screening of other nuclear reactors. For the evaluation of microsphere quality, light microscopy, SEM and particle size analysis are appropriate techniques.     

Neutron activation analysis for copper in biological material applied to Wilson''s disease

A method for the neutron activation analysis of copper in biological material is described and applied to the diagnosis and management of four cases of Wilson's disease. Results obtained for serum and urine are in agreement with values obtained by established colorimetric techniques. The method described can estimate 10(-9) g. copper to within 10% and this sensitivity has allowed the determination of copper from biopsy material such as liver, spleen, hair, and nail.     

Tissue copper determinations by neutron activation analysis

A method is described for the handling of tissue samples for copper determination by neutron activation analysis. The results obtained for normal liver copper estimations compared favourably with results obtained by conventional methods.     

Dosimetric characterization of the irradiation cavity for accelerator-based in vivo neutron activation analysis

A neutron irradiation cavity for in vivo activation analysis has been characterized to estimate its dosimetric specifications. The cavity is defined to confine irradiation to the hand and modifies the neutron spectrum produced by a low energy accelerator neutron source to optimize activation per dose. Neutron and gamma-ray dose rates were measured with the microdosimetric technique using a tissue-equivalent proportional counter at the hand irradiation site and inside the hand access hole. For the outside of the cavity, a spherical neutron dose equivalent meter and a Farmer dosemeter were employed instead due to the low intensity of the radiation field. The maximum dose equivalent rate at the outside of the cavity was 2.94 microSv/100 microA min, which is lower by a factor of 1/2260 than the dose rate at the hand irradiation position. The local dose contributions from a hand, an arm and the rest of a body to the effective dose rate were estimated to be 1.73, 0.782 and 2.94 microSv/100 microA min, respectively. For the standard irradiation protocol of the in vivo hand activation, 300 microA min, an effective dose of 16.3 microSv would be delivered.     

Nuclear methods to characterize biomaterials

Techniques using X-rays are often used to study biomaterials fields. However, when one is interested by quantitative and very sensitive measurements, it is valuable to develop nuclear instruments and methods, in addition and complement with others. Fast neutron activation is appropriate for non-destructive analysis. Thermal neutron activation can evaluate trace elements as a reference. Proton-induced X-rays emission is applied to cartography of heavy elements. If necessary, proton-induced gamma-rays emission and charged particles scattering are suitable for evaluation and cartography of light elements. Radioactivated nuclei and labelled molecules can tag element transfers and biofunctionality. In our work, these methods are related to biomaterials field.     

Apparatus for the measurement of total body nitrogen using prompt neutron activation analysis with californium-252

Details of clinical apparatus designed for the measurement of total body nitrogen (as an indicator of body protein), suitable for the critically ill, intensive-care patient are presented. Californium-252 radio-isotopic neutron sources are used, enabling a nitrogen measurement by prompt neutron activation analysis to be made in 40 min with a precision of +/- 3.2% for a whole body dose equivalent of 0.145 mSv. The advantages of Californium-252 over alternative neutron sources are discussed. A comparison between two irradiation/detection geometries is made, leading to an explanation of the geometry adopted for the apparatus. The choice of construction and shielding materials to reduce the count rate at the detectors and consequently to reduce the pile-up contribution to the nitrogen background is discussed. Salient features of the gamma ray spectroscopy system to reduce spectral distortion from pulse pile-up are presented.     

Chronic immune activation is a distinguishing feature of liver and PBMC gene signatures from HCV/HIV coinfected patients and may contribute to hepatic fibrogenesis

Hepatitis C virus/human immunodeficiency virus (HCV/HIV) coinfected patients demonstrate accelerated progression to severe liver injury in comparison to HCV monoinfected patients, although the underlying mechanisms are unclear owing to infection of separate tissue compartments with two distinct viral pathogens. Microarray analysis of paired liver biopsy and peripheral blood mononuclear cell (PBMC) specimens from HCV/HIV coinfected and HCV monoinfected patients identified a gene expression signature associated with increased inflammation and immune activation that was present only in liver and PBMC samples from coinfected patients. We also identified in these samples liver- and PBMC-specific signatures enriched with fibrogenic/hepatic stellate activation and proinflammatory genes, respectively. Finally, Bayesian networks were constructed by assimilating these data with existing data from liver and PBMC samples from other cohorts, augmenting enrichment of biologically important pathways and further indicating that chronic immune activation in HCV/HIV coinfection may exacerbate liver disease progression in coinfected patients.     

Increased bromide levels in serum and hair during lithium treatment

The concentration of bromide was measured by neutron activation analysis in samples of serum from 32 patients on maintenance lithium carbonate and from 32 age- and sex-matched controls. Whole blood and hair samples were also taken for analysis from a number of patients and controls. Bromide levels were found to be significantly higher in serum and hair of patients on lithium carbonate than in controls. The possible effects of this increase and the mechanisms causing it are discussed.     

Thermal neutron irradiation field design for boron neutron capture therapy of human explanted liver

The selective uptake of boron by tumors compared to that by healthy tissue makes boron neutron capture therapy (BNCT) an extremely advantageous technique for the treatment of tumors that affect a whole vital organ. An example is represented by colon adenocarcinoma metastases invading the liver, often resulting in a fatal outcome, even if surgical resection of the primary tumor is successful. BNCT can be performed by irradiating the explanted organ in a suitable neutron field. In the thermal column of the Triga Mark II reactor at Pavia University, a facility was created for this purpose and used for the irradiation of explanted human livers. The neutron field distribution inside the organ was studied both experimentally and by means of the Monte Carlo N-particle transport code (MCNP). The liver was modeled as a spherical segment in MCNP and a hepatic-equivalent solution was used as an experimental phantom. In the as-built facility, the ratio between maximum and minimum flux values inside the phantom ((phi(max)/phi(min)) was 3.8; this value can be lowered to 2.3 by rotating the liver during the irradiation. In this study, the authors proposed a new facility configuration to achieve a uniform thermal neutron flux distribution in the liver. They showed that a phi(max)/phi(min) ratio of 1.4 could be obtained without the need for organ rotation. Flux distributions and dose volume histograms were reported for different graphite configurations.     

Study of the relative dose-response of BANG-3 polymer gel dosimeters in epithermal neutron irradiation

Polymer gels have been reported as a new, potential tool for dosimetry in mixed neutron-gamma radiation fields. In this work, BANG-3 (MGS Research Inc.) gel vials from three production batches were irradiated with 6 MV photons of a Varian Clinac 2100 C linear accelerator and with the epithermal neutron beam of the Finnish boron neutron capture therapy (BNCT) facility at the FiR 1 nuclear reactor. The gel is tissue equivalent in main elemental composition and density and its T2 relaxation time is dependent on the absorbed dose. The T2 relaxation time map of the irradiated gel vials was measured with a 1.5 T magnetic resonance (MR) scanner using spin echo sequence. The absorbed doses of neutron irradiation were calculated using DORT computer code, and the accuracy of the calculational model was verified by measuring gamma ray dose rate with thermoluminescent dosimeters and 55Mn(n,gamma) activation reaction rate with activation detectors. The response of the BANG-3 gel dosimeter for total absorbed dose in the neutron irradiation was linear, and the magnitude of the response relative to the response in the photon irradiation was observed to vary between different gel batches. The results support the potential of polymer gels in BNCT dosimetry, especially for the verification of two- or three-dimensional dose distributions.     

A feasibility study of in vivo 14-MeV neutron activation analysis using the associated particle technique

The feasibility of using the time correlated associated particle technique for in vivo 14-MeV neutron activation analysis has been investigated. Gamma rays following neutron inelastic scattering with nitrogen, carbon, and oxygen have been measured with a 12.5 x 10-cm NaI (T1) detector. The results have been scaled to a proposed facility comprising four such detectors past which the subject would be scanned. Based on counting statistics, the precision of estimation of these elements has been determined to be 2.1%, 1.0%, and 1.1%, respectively, for experimental measurements on a sample containing physiological concentrations of the major body elements. The average body dose level would be restricted to 0.3 mSv.     

Quantification of manganese in human hand bones: a feasibility study

Manganese is both an essential element to human health and also toxic when humans are exposed to excessive levels, particularly by means of inhalation.Biological monitoring of manganese exposure is problematic. It is subject to homeostasis; levels in blood (or serum/plasma) reflect only the most recent exposure and rapidly return to within normal ranges, even when there has been a temporary excursion in response to exposure. In this context, we have been developing a non-invasive technique for measurement of manganese stored in bone, using in vivo neutron activation analysis. Following preliminary feasibility studies, the technique has been enhanced by two significant infrastructure advances. A specially designed irradiation facility serves to maximize the activation of manganese with respect to the dose of ionizing radiation. Secondly, an array of eight NaI(Tl) crystals provides a detection system with very close to 4 pi geometry. This feasibility study, using neutron activation analysis to measure manganese in the bones of the hand, takes two features into account. Firstly, there is considerable magnesium present in the bone and this produces a spectral interference with the manganese. The 26 Mg(n,gamma)27 Mg reaction produces gamma -rays of 0.843 MeV from the decay of 27 Mg, which interfere with the 0.847 MeV gamma -rays from the decay of 56 Mn,produced by the 55 Mn(n,gamma)56 Mn reaction. Secondly, this work provides estimates of the levels of manganese to be expected in referent subjects. A revised estimate has been made from the most recent literature to explore the potential of the technique as a suitable means of screening patients and people exposed to excessive amounts of Mn who could develop many-fold increased levels of Mn in bones as demonstrated through various animal studies. This report presents the enhancements to the neutron activation system, by which manganese can be measured, which resulted in a detection limit in the hand of human subjects of 1.6 microg/g Ca. It also provides a revised estimate of expected referent levels of manganese in bone, now estimated to be 0.63 microg/g Ca and highlights the extent to which technical improvements will be required to further extend the application of the technique for in vivo measurements in non-exposed human subjects.     

Trace elements in manic depressive psychosis

The concentrations of 16 elements (Al, Ba, Br, Ca, Cl, Cu, I, Pb, Mg, Mn, Mo, Rb, Se, Na, S and Ti) were estimated by neutron activation analysis in samples of hair, whole blood, serum and urine from normal controls, from patients suffering from mania and depression and from patients who had recovered from mania and from depression. Significant differences between groups were shown but apart from molybdenum, no element showed a significant change in more than one tissue. The differences in molybdenum concentrations appear to be of potential interest but the results must be interpreted with caution.     

Controllability of depth dose distribution for neutron capture therapy at the Heavy Water Neutron Irradiation Facility of Kyoto University Research Reactor

The updating construction of the Heavy Water Neutron Irradiation Facility of the Kyoto University Research Reactor has been performed from November 1995 to March 1996 mainly for the improvement in neutron capture therapy. On the performance, the neutron irradiation modes with the variable energy spectra from almost pure thermal to epi-thermal neutrons became available by the control of the heavy-water thickness in the spectrum shifter and by the open-and-close of the cadmium and boral thermal neutron filters. The depth distributions of thermal, epi-thermal and fast neutron fluxes were measured by activation method using gold and indium, and the depth distributions of gamma-ray absorbed dose rate were measured using thermo-luminescent dosimeter of beryllium oxide for the several irradiation modes. From these measured data, the controllability of the depth dose distribution using the spectrum shifter and the thermal neutron filters was confirmed.     

Measurement of total body chlorine by prompt gamma in vivo neutron activation analysis

A method of measuring total body chlorine (TBCl) by prompt gamma in vivo neutron activation analysis is described which depends on the same NaI(Tl) spectra used for determinations of total body nitrogen. From these spectra counts ratios of chlorine to hydrogen are derived and TBCl is determined using a model of body composition which depends on measured body weight, total body water (by tritium dilution) and protein (6.25 X nitrogen) as well as estimated body minerals and glycogen. The precision of the method based on scanning an anthropomorphic phantom is at present only approximately 9% (SD), for a patient dose equivalent of less than 0.30 mSv. Spectra collected from 67 normal volunteers (32 male, 35 female) yielded mean values of TBCl of 72 +/- 19 (SD) g in males and 53.6 +/- 15 g in females, in broad agreement with values reported by workers using delayed gamma methods. Results are also presented for two human cadavers analysed both by neutron activation and by conventional chemical analysis; the ratios of TBCl (neutron activation) to TBCl (chemical) were 0.980 +/- 0.028 (SEM) and 0.91 +/- 0.09. Finally, it is suggested that an improvement in precision will be achieved by increasing the scanning time (thereby increasing the radiation dose equivalent) and by adding two more detectors.     

A fundamental study on hyper-thermal neutrons for neutron capture therapy

The utilization of hyper-thermal neutrons, which have an energy spectrum with a Maxwellian distribution at a higher temperature than room temperature (300 K), was studied in order to improve the thermal neutron flux distribution at depth in a living body for neutron capture therapy. Simulation calculations were carried out using a Monte Carlo code 'MCNP-V3' in order to investigate the characteristics of hyper-thermal neutrons, i.e. (i) depth dependence of the neutron energy spectrum, and (ii) depth distribution of the reaction rate in a water phantom for materials with 1/v neutron absorption. It is confirmed that hyper-thermal neutron irradiation can improve the thermal neutron flux distribution in the deeper areas in a living body compared with thermal neutron irradiation. When hyper-thermal neutrons with a 3000 K Maxwellian distribution are incident on a body, the reaction rates of 1/v materials such as 14N, 10B etc are about twice that observed for incident thermal neutrons at 300 K, at a depth of 5 cm. The limit of the treatable depth for tumours having 30 ppm 10B is expected to be about 1.5 cm greater by utilizing hyper-thermal neutrons at 3000 K compared with the incidence of thermal neutrons at 300 K.     

Calibration and evaluation of a system of total body in vivo activation analysis using 14 MeV neutrons.

A system has been established for determining the total body contents of calcium, phosphorus, sodium, chlorine and nitrogen by neutron activation analysis using sealed-tube neutron generators and a shadow-shield whole-body counter. The system was calibrated using three anthropomorphic phantoms of different sizes, filled with various mixtures of the activatable elements in amounts similar to those in man. The reproducibility determined from replicate measurements, was on average +/- 2.9% (SD). The average uncertainty in absolute measurements was estimated to be +/- 4.2% (68% confidence interval).