High frequency components of tracheal sound are emphasized during prolonged flow limitation.

A nasal pressure transducer, which is used to study nocturnal airflow, also provides information about the inspiratory flow waveform. A round flow shape is presented during normal breathing. A flattened, non-round shape is found during hypopneas and it can also appear in prolonged episodes. The significance of this prolonged flow limitation is still not established. A tracheal sound spectrum has been analyzed further in order to achieve additional information about breathing during sleep. Increased sound frequencies over 500 Hz have been connected to obstruction of the upper airway. The aim of the present study was to examine the tracheal sound signal content of prolonged flow limitation and to find out whether prolonged flow limitation would consist of abundant high frequency activity. Sleep recordings of 36 consecutive patients were examined. The tracheal sound spectral analysis was performed on 10 min episodes of prolonged flow limitation, normal breathing and periodic apnea-hypopnea breathing. The highest total spectral amplitude, implicating loudest sounds, occurred during flow-limited breathing which also presented loudest sounds in all frequency bands above 100 Hz. In addition, the tracheal sound signal during flow-limited breathing constituted proportionally more high frequency activities compared to normal breathing and even periodic apnea-hypopnea breathing.

Diffuse sleep spindles show similar frequency in central and frontopolar positions.

The objective of the present work was to examine fronto-central spindle frequency. A previously validated spindle detector, providing an electroencephalographic (EEG) amplitude independent spindle detection, was used to detect bilateral sleep spindles from sleep EEG recordings of ten healthy subjects with a time resolution of 0.33-s. A bilateral spindle detected centrally and frontopolarly simultaneously is called here a diffuse spindle. A bilateral spindle detected only frontopolarly or centrally at a given time is called a pure frontopolar and a pure central spindle, respectively. Spindle frequency was obtained with zero-padded discrete Fourier transform (DFT). Waveform phase angle of diffuse spindles was also examined. A total of 1230 diffuse spindles and 5316 pure central and 2595 pure frontopolar spindles were detected. The difference of median spindle frequency between central and frontopolar brain positions was clearly smaller in diffuse spindles than in pure spindles. Moreover, 34% of the diffuse spindles showed a similar frequency in central and frontopolar locations. This figure was up to 50.9% when including the 700 diffuse spindles fulfilling a strict anteroposterior (AP) timing criteria. The timing criteria selection in diffuse spindle analysis is a new functionality, enabled by the present spindle analysis method. Diffuse spindles showed coherent spindle oscillation in a large fronto-central area. Pure frontopolar spindles might be special cases of diffuse spindles, both of them seem to be generated in the nucleus medialis dorsalis (NMD) of the thalamus.

Detection of compressed tracheal sound patterns with large amplitude variation during sleep.

The objective of the present work was to develop automated methods for the compressed tracheal breathing sound analysis. Overnight tracheal breathing sound was recorded from ten apnoea patients. From each patient, three different types of tracheal sound deflection pattern, each of 10 min duration, were visually scored, viewing the compressed tracheal sound curve. Among them, high deflection patterns are of special interest due to the possible correlation with apnoea-hypopnoea sequences. Three methods were developed to detect patterns with high deflection, utilizing nonlinear filtering in local characterization of tracheal sounds. Method one comprises of local signal maximum, the second method of its local range, and the third of its relative range. The three methods provided 80% sensitivity with 57, 91 and 93% specificity, respectively. Method three provided an amplitude-independent approach. The nonlinear filtering based methods developed here offer effective means for analysing tracheal sounds of sleep-disordered breathing.

Ionization chamber radial response deconvolution in megavoltage photon beam.

The aim of this paper is to study a radial response model as a method, to correct output factor results gathered with ionization chambers of different size and shape in cone collimated RT fields. An enhanced version of a non-parametric super-resolution deconvolution method able to model a radial response function of a small cylinder symmetric ionization chamber is described and demonstrated. The radial response of four ionization chambers with different geometry and radius are estimated using 6 MV photon beam in water at the isocentre plane. Finally the validity of the estimates is tested by applying the response functions to the output factor measurements of 4-20 mm conical collimators. The enhanced method is demonstrated by obtaining the response function characteristics with a spatial uncertainty smaller than 0.1 mm when the distance from chamber axis is larger than 0.5 mm. In all studied ionization chambers, a significant local response maximum is found close to the air cavity boundary. The agreement between the output factor results of different chambers is promising, the largest difference (max-min) in output factor is 4% obtained for the smallest 4 mm cone size.

Fast voxel-level dosimetry for (177)Lu labelled peptide treatments.

In peptide receptor radionuclide therapy (PRRT), voxel-level radiation absorbed dose calculations can be performed using several different methods. Each method has it strengths and weaknesses; however, Monte Carlo (MC) simulation is presently considered the most accurate method at providing absorbed dose distributions. Unfortunately MC simulation is time-consuming and often impractical to carry out in a clinical practice. In this work, a fast semi-Monte Carlo (sMC) absorbed dose calculation method for (177)Lu PRRT dosimetry is presented. The sMC method is based on a local electron absorption assumption and fast photon MC simulations. The sMC method is compared against full MC simulation code built on PENELOPE (vxlPen) using digital phantoms to assess the accuracy of these assumptions.Due to the local electron absorption assumption of sMC, the potential errors in cross-fire dose from electrons and photons emitted by (177)Lu were first evaluated using an ellipsoidal kidney model by comparing vxlPen and sMC. The photon cross-fire dose from background to kidney and kidney to background with varying kidney-to-background activity concentration ratios were calculated. In addition, kidney to kidney photon and electron cross-dose with different kidney to kidney distances were studied. Second, extended cardiac-torso (XCAT) phantoms were created with liver lesions and with realistic activity distributions and tissue densities. The XCAT phantoms were used to simulate SPECT projections and 3D activity distribution images were reconstructed using an OSEM algorithm. Image-based dose rate distributions were calculated using vxlPen and sMC. Total doses and dose rate volume histograms (DrVH) produced by the two methods were compared.The photon cross-fire dose from the kidney increased the background's absorbed dose by 5% or more up to 5.8 cm distance with 20 : 1 kidney to background activity concentration ratio. On the other hand, the photon cross-fire dose from the background to the kidney volume was negligible. The vxlPen results showed that the cross fire dose between two similar kidney volumes relative to the source kidney's self-dose were 0.5% and 0.02% for photon and electrons, respectively, when source and target kidneys were modelled next to each other. The photon cross-dose decreased as function of distance, and electron doses were zero at distances larger than 4 mm. The difference between sMC and vxlPen kidney total doses in the XCAT phantom study was -0.4% while the electron dose DrVHs were identical between the methods. There was a systematic 5% difference in photon doses in soft tissue between the codes due to different simulations parameters. However, the photons produced only 4% of the kidney's total dose, thus the difference was not considered significant for total dose calculations.The comparison studies show that the absorbed doses calculated using the sMC differ only slightly from dedicated MC simulator results, while the dose estimates can be obtained in a fraction of the dedicated simulator's calculation time. Results imply that there is no need for electron MC simulation for (177)Lu absorption calculations with current SPECT systems. However, the photon cross-fire dose should be taken into account in healthy tissues, which have a relatively low uptake especially in cases where there are high uptake volumes are nearby.

The addition of entropy-based regularity parameters improves sleep stage classification based on heart rate variability.

The work considers automatic sleep stage classification, based on heart rate variability (HRV) analysis, with a focus on the distinction of wakefulness (WAKE) from sleep and rapid eye movement (REM) from non-REM (NREM) sleep. A set of 20 automatically annotated one-night polysomnographic recordings was considered, and artificial neural networks were selected for classification. For each inter-heartbeat (RR) series, beside features previously presented in literature, we introduced a set of four parameters related to signal regularity. RR series of three different lengths were considered (corresponding to 2, 6, and 10 successive epochs, 30 s each, in the same sleep stage). Two sets of only four features captured 99 % of the data variance in each classification problem, and both of them contained one of the new regularity features proposed. The accuracy of classification for REM versus NREM (68.4 %, 2 epochs; 83.8 %, 10 epochs) was higher than when distinguishing WAKE versus SLEEP (67.6 %, 2 epochs; 71.3 %, 10 epochs). Also, the reliability parameter (Cohens's Kappa) was higher (0.68 and 0.45, respectively). Sleep staging classification based on HRV was still less precise than other staging methods, employing a larger variety of signals collected during polysomnographic studies. However, cheap and unobtrusive HRV-only sleep classification proved sufficiently precise for a wide range of applications.

Gene therapy using antisense oligodeoxynucleotides labeled with Auger-emitting radionuclides.

Antisense oligomers may be used as a vehicle for carrying a radiation source into a specific location inside a tumor cell. The effects of radioactive-labeled oligodeoxynucleotides (ODNs) may have both direct antisense inhibition and radiation. Thus far, the use of radioactive ODNs has been limited mostly to clinical biokinetic studies. Therapeutic possibilities remain unknown if the basic question of the optimal source of radiation is unanswered. We have shown previously that oligonucleotide therapy can be effective theoretically with the internally labeled ODN phosphorothioates 32P, 33P, and 35S. Here, we expand the selection of radionuclides; we calculated in vivo subcellular tissue distribution for ODN phosphorothioates using the decay characteristics of several beta- and Auger-emitting radionuclides: 32P, 35S, 51Cr, 67Ga, 111In, (1114m)In, 123I, 125I, 131I, and 201Tl. The absorbed nuclear doses of these radiolabeled oligonucleotides were estimated in different cellular dimensions using the subcellular biodistribution data for two oligonucleotides (ISIS 2105 and ISIS 2922). Our results indicate that Auger-emitter isotopes do not give higher absorbed cell nuclear doses than the isotopes suitable for internal labeling of ODN phosphorothioates. However, the biological difference is difficult to estimate. The best isotope for subcellular targeting was 35S, which gives the smallest variation of nuclear dose in the different cell dimensions we studied (nuclear diameter, 6-16 microm; cellular diameter, 12-20 microm). Therefore, we conclude that in oligonucleotide radiotherapy, nuclear targets should be treated with short-range beta-emitters (35S or 33P) that are suitable for the internal labeling of oligonucleotides unless the relative biological effectiveness of Auger-emitters could be remarkably improved. Dual labeling with 32P and 35S may provide therapeutic benefits when treating smaller and larger targets simultaneously. Further in vivo development, especially with 33P and 35S labels for ODNs, is strongly indicated.

Radiation-induced changes in human brain metabolites as studied by 1H nuclear magnetic resonance spectroscopy in vivo.

PURPOSE: External radiation therapy for brain tumors exposes healthy areas of brain to considerable doses of radiation. This may cause cognitive and psychological impairment, which indicate neuronal dysfunction. 1H-magnetic resonance spectroscopy (MRS) was used to study brain metabolites in the adjacent regions 0.5-13 years after exposure to therapeutic irradiation. METHODS AND MATERIALS: Eight patients with irradiated brain tumors were examined by means of in vivo 1H-MRS using a point-resolved spectroscopy (PRESS) sequence with echo times of 60 or 270 ms. The metabolites were quantified by using brain water concentration as internal reference. The volume of interest (VOI) was positioned in irradiated brain areas excluding, however, scar and recurrent tumor. The respective radiation doses were measured based on radiation therapy plans, simulator films, and localization MR images. RESULTS: The concentration of the neuron-specific metabolite N-acetyl-L-aspartate (NAA) was 13.2 +/- 1.4 mmol/l in controls, whereas it was reduced in the brains of treated patients to 8.6 +/- 0.9 mmol/l (total radiation dose 59-62 Gy). Concentrations of creatine and choline-containing compounds were unchanged. The T2 of water was longer in irradiated than in unexposed brain areas. CONCLUSION: Therapeutic brain irradiation causes neuronal damage, which is reflected by reduction of N-acetyl-L-aspartate (NAA) concentrations. 1H-MRS could serve clinically as a means of evaluating adverse effects in the central nervous system, enabling intervention and rehabilitation.

Relative output factors of asymmetric megavoltage beams.

A new method for calculating output factors of asymmetric therapy fields is presented. The method uses the output factors of symmetric fields, as well as off-axis ratios measured in air, to calculate the output factor for an arbitrary asymmetric field. Calculations have been checked by measurements in four photon beams (4-18 MV) of three different linear accelerators. The accuracy between the theory and the measurements is generally better than 1%. According to the preliminary results the method may also be suitable for megavoltage electron beams.

ICRU reference points and maximum doses of rectum and bladder in intracavitary radiotherapy.

The absorbed doses in the reference points of the rectum and bladder defined by ICRU report 38 for reporting intracavitary radiotherapy were compared with the calculated maximum doses of these organs. The calculations were validated by a thermoluminescent probe. A good correlation between the doses at the reference points and the calculated maximum doses was found.

A dielectric method for measuring early and late reactions in irradiated human skin.

BACKGROUND AND PURPOSE: To measure the dielectric constant of irradiated human skin in order to test the feasibility of the dielectric measurements in the quantitation of acute and late radiation reactions. MATERIALS AND METHODS: The dielectric constant of irradiated breast skin was measured at an electromagnetic frequency of 300 MHz in 21 patients during postmastectomy radiotherapy. The measurements were performed with an open-ended coaxial line reflection method. The irradiation technique consisted of an anterior photon field to the lymph nodes and a matched electron field to the chest wall using conventional fractionation of five fractions/week to 50 Gy. Fourteen out of the 21 patients were remeasured 2 years later and the skin was palpated for subcutaneous fibrosis. RESULTS: At 5 weeks the dielectric constant had decreased by 31 and 39% for the investigated skin sites of the photon and electron fields, respectively. There was a statistically significant inverse correlation between the mean dielectric constant and the clinical score of erythema. An unexpected finding was a decrease of the dielectric constant of the contralateral healthy skin during radiotherapy. Two years later a statistically significant positive correlation was found between the dielectric constant at the irradiated skin sites and the clinical score of subcutaneous fibrosis. CONCLUSIONS: Dielectric measurements non-invasively yield quantitative information concerning radiation-induced skin reactions.

Phase I trial on sms-D70 somatostatin analogue in advanced prostate and renal cell cancer.

Plasma concentrations and tolerability of a novel somatostatin analogue sms-D70 were studied in patients with metastatic hormone-resistant prostate cancer (HRPC) or metastatic renal cell cancer. To overcome the limitations of the octapeptides having affinity only to somatostatin receptor subtypes 2 and 5, HRPC expressing mainly somatostatin receptors 1 and 4, a somatostatin derivative based on the natural somatostatin having affinity to all five somatostatin receptor subtypes, was developed. The in vivo stability of this dextran-conjugated derivative, somatostatin-D70, was confirmed previously in animal studies, and the nanomolar "panaffinity" has been shown in in vitro receptor binding studies on cell lines transfected with the somatostatin receptor genes. Sms-D70 was given with subcutaneous injection once a week at dose levels of 5, 10, 20, 35, and 50 mg. For pharmacokinetic studies, sms-D70 was labeled with 131I. Fourteen patients were treated, of whom 10 had prostate and 4 renal cell cancer. The kinetic data revealed high stability with a long half-life in the blood. The drug was well tolerated, and no grade 4 (WHO) toxicity was observed. The maximal tolerated dose could not be established due to the lack of dose-limiting toxicities. Objective PSA responses were not recorded in these heavily treated patients, but subjective stabilization of pain was observed and urinary symptoms were alleviated in four patients. Three patients with metastatic HRPC received 5-10-mg intravenous injections of sms-D70 once weekly for 4-14 months on a compassionate use basis. In all cases, serum PSA values decreased more than 50% from the pretreatment level, but these results are difficult to interpret due to concomitant treatments given to these patients. In conclusion, sms-D70 was well tolerated in the treatment of metastatic prostate and renal cell cancer, but no responses were found in these heavily treated patients.

Ionizing radiation induces expression of immediate early genes in the rat brain.

In situ hybridization histochemistry and immunocytochemistry were used to examine whether therapeutic ionizing radiation induces expression of immediate early genes in the rat brain. One hour following a single dose of 2 or 15 Gy the expression of c-fos and zif-268 but not of c-jun mRNAs was induced in a scattered cell population in the lateral striatum, whereas in the piriform cortex the expression of zif-268 mRNA was decreased. Other brain regions did not show consistent changes in the mRNA levels. Three hours after radiation the mRNA levels had returned to normal. Immunocytochemistry showed the number of c-Fos and Jun-B-positive neurones to be increased in the striatum and slightly increased in the frontoparietal cortex 1 and 3 h after radiation. The results show that a subpopulation of neurones is sensitive to ionizing radiation at the clinically relevant dose of 2 Gy and that the neuronal response to this irradiation involves altered expression of genes encoding for transcription factors.

Radiation therapy for breast cancer and clonal chromosome translocations: a fluorescence in situ hybridization study.

The frequency of chromosomal translocations was analyzed in skin fibroblast cell cultures derived from irradiated and nonirradiated skin biopsies from five cases of breast adenocarcinoma in women, who had undergone radiotherapy after surgery. The study was performed at the first annual check-up. Chromosomal in situ suppression (CISS) hybridization was performed using metaphase nonisotopic fluorescence in situ hybridization (FISH) with library probes specific for chromosomes 1, 2, 3, 4, 5, 7, 8, 13, 19, and 20. The results showed that the frequency of clonal translocations in metaphases obtained from irradiated areas was significantly higher than in metaphases from the nonirradiated tissue samples.

Modelling of the dielectric properties of normal and irradiated skin.

We have shown that irradiation changes the dielectric properties of human skin at radiofrequencies. Both the dielectric constant and the conductivity of the irradiated skin decrease, especially at low frequencies. The experimental data were analysed using two bioelectric models. Relevant dielectric parameters were determined by curve fitting. The dielectric relaxation of the radiation-induced acute or late reaction of the skin occurred at higher frequencies than with normal or non-irradiated skin, while the static conductivity and static dielectric constant of the irradiated skin decreased. We conclude that bioelectric modelling provides a useful tool in the evaluation of cellular changes in irradiated skin.

Components op the flood-field uniformity index in a gamma camera.

The flood-field uniformity index has been investigated as a function of the total number of counts and the image matrix size. The analysis showed the dependence of the NEMA integral uniformity index on the counting statistics. A linear model to determine the noise-free component of the uniformity index that was applied successfully to the experimental data is presented. In addition, the heterogeneity of the integral uniformity index IU presented as a function of image matrix size m fits well to the fractal equation IU(m)/IU(1) = mD-1 with the fractal dimension D = 1.34. This result shows that the uniformity index could be handled as a fractal quantity.

Imaging lobular breast carcinoma: comparison of synchrotron radiation DEI-CT technique with clinical CT, mammography and histology.

Different modalities for imaging cancer-bearing breast tissue samples are described and compared. The images include clinical mammograms and computed tomography (CT) images, CT images with partly coherent synchrotron radiation (SR), and CT and radiography images taken with SR using the diffraction enhanced imaging (DEI) method. The images are evaluated by a radiologist and compared with histopathological examination of the samples. Two cases of lobular carcinoma are studied in detail. The indications of cancer are very weak or invisible in the conventional images, but the morphological changes due to invasion of cancer become pronounced in the images taken by the DEI method. The strands penetrating adipose tissue are seen clearly in the DEI-CT images, and the histopathology confirms that some strands contain the so-called 'Indian file' formations of cancer cells. The radiation dose is carefully measured for each of the imaging modalities. The mean glandular dose (MGD) for 50% glandular breast tissue is about 1 mGy in conventional mammography and less than 0.25 mGy in projection DEI, while in the clinical CT imaging the MGD is very high, about 45 mGy. The entrance dose of 95 mGy in DEI-CT imaging gives rise to an MGD of 40 mGy, but the dose may be reduced by an order of magnitude, because the contrast is very large in most images.

Small-angle x-ray scattering studies of human breast tissue samples.

Small-angle x-ray scattering (SAXS) patterns are recorded from thin breast tissue samples containing healthy and cancerous regions. The SAXS patterns are compared with histo-pathological observations. The information available from SAXS is reviewed, and a model for scattering from collagen is presented. Scattering patterns of collagen at regions far from the tumours are essentially different from those at tumours. The axial period of collagen fibrils is 65.0 +/- 0.1 nm in healthy regions, and 0.3 nm larger in cancer-invaded regions. The average intensity of scattering from cancerous regions is an order of magnitude higher than the intensity from healthy regions. This is interpreted to arise from an increase of the specific surface area of the scatterers, which is due to a disruption of the molecular and supra-molecular structures in cancerous regions and invasion of new types of cells. The differences of the SAXS patterns are large and distinctive enough to suggest that these phenomena may be utilized in mammography.

Analysis of depth profiling data obtained by confocal Raman microspectroscopy.

The nominal depth resolution achieved in confocal Raman microscopy is on the order of a few micrometers. Often, however, the depth resolution is decreased by light refraction at the sample surface. The problem can be avoided with the use of an immersion objective and index matching oils. Through this intervention the instrument point-spread function (PSF) can be assumed to be independent of the depth of focus in the sample, and spatially invariant depth profiles can be acquired. In this work the instrument PSF was determined by measuring a depth profile of a thick uniform sample and calculating the first derivative of the depth profile curve. The first-derivative method was also used to determine sample thickness. Convolution with the PSF makes it possible to simulate the behavior of the instrument with different sample functions. It is also possible to use the instrument PSF to deconvolve depth-profiling data. Deconvolution reduces the blurring effect of the instrument and increases the depth resolution. Deconvolution can also be used in analysis of the sample surface position and in layer structure analysis. In this paper we show how the convolution integral can be used with the immersion sampling technique to determine the PSF and how the sample thickness can be determined.

Absorbed dose estimates for 131I-labelled monoclonal antibody therapy in patients with intraperitoneal pseudomyxoma.

Seven patients with intraperitoneal pseudomyxoma originating from the appendix (4 cases) and from the ovary (3 cases) were treated with radioimmunotherapy. During the therapy, nine infusions of 3.0-4.2 GBq of 131I-labelled B72.3 monoclonal antibody were administered. We developed three-dimensional dose calculation software that can utilize activity maps based on SPET images to calculate the absorbed dose distribution using point source kernels. The dose calculation program was employed to calculate absorbed doses to various organs. The calculated dose distributions enable us to evaluate the variation in dose within the organs, which is normally not available using approaches based on geometric models. The patient-specific absorbed dose calculations were compared with doses based on a model that uses photon S-factors derived from a standard phantom. The compared doses agreed well on average, but in some organs showed large discrepancies.