SKIN DOSE, EFFECTIVE DOSE AND RELATED RISK IN TRANSCATHETER AORTIC VALVE IMPLANTATION (TAVI) PROCEDURES: IS THE CANCER RISK ACCEPTABLE FOR YOUNGER PATIENTS?

The aim of this study was to estimate conversion coefficients for maximum entrance skin dose (MESD) and effective dose (E) for patients undergoing transcatheter aortic valve implantation (TAVI) and to evaluate the risk of exposure-induced cancer death (REID) for prospectively younger patients. Effective doses and risks were estimated for 22 patients using PCXMC whereas MESDs were estimated for a sub-group of 15 patients using Gafchromic film. The estimated conversion coefficients for skin dose [CCS = MESD/dose-area product (DAP)] and E (CCE = E/DAP) were 9.7±1.5 and 0.24±0.02 mSv/Gy cm(2), respectively. The REID ranged from 1:9900 to 1:1400 and by decreasing the age of examination to 40-50 y of age, the REID increased with a factor of 2 for females and 1.5 for males. The organ at risk was the lung. Currently, the patient population is elderly with radiation-induced skin injuries as the main risk. The risk of cancer induction should additionally be considered if younger patient populations are to be treated.

Phase equilibria and formation of vesicles of dioleoylphosphatidylcholine in glycerol/water mixtures.

The lipid 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) forms a lamellar liquid crystalline phase (L alpha) in arbitrary mixtures of glycerol and water. The phase has been characterized by means of X-ray diffraction, 31P-NMR spectroscopy and differential scanning calorimetry (DSC). In the L alpha state, and for DOPC concentrations greater than 50% (w/w), the thickness of the lipid bilayer decreases, while the area of the polar head group increases with increasing glycerol concentration. The phase transition from gel to L alpha state occurs in the range of 240 to 260 K. Contrary to a previous (McDaniel, R.V., McIntosh, T.J. and Simon, S.A. (1983) Biochim. Biophys. Acta 731, 97) study of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) we find that in the gel state, the thickness of the DOPC lipid bilayer is greater than that in the L alpha state. This suggests that in the gel state, the lipid acyl chains of DOPC are in extended configuration. The lamellar phase reaches its maximum swelling at about 50% (w/w) of DOPC. At lower DOPC concentrations a two-phase system is formed where the lamellar phase exists in equilibrium with excess of solvent. Unilamellar vesicles can be prepared from a diluted suspension of the lamellar phase either by using the sonicator or extruder technique. We show this by means of 31P-NMR, EPR and fluorescence spectroscopy. The mean radius of the vesicles, prepared by a sonicator, has been determined at different glycerol/water mixtures. It is found to decrease continuously from 100 A at 100% water to a minimum of 75 A at about 50% water in the solvent mixture. By further decreasing the water content in the solution, the radius rapidly increases, and a mean radius of 450 A is estimated at a water content of 10%. The rotational relaxation times of a fluorescent probe and two EPR spin probes, solubilized in DOPC vesicles, have been measured at different glycerol/water mixtures. It is found that the rotational rates are always much slower in the systems containing glycerol.

Temperature variation in newborn babies: importance of physical contact with the mother.

BACKGROUND: Hypothermia is a major cause of deterioration and death in the neonatal period. Temperature deviations are key signs of illness. OBJECTIVE: To determine normal patterns of temperature variation in newborn babies and the influence of external factors. METHODS: Abdominal and foot skin temperature were continuously recorded in 27 healthy full term babies during the first two days of life and related to the care situation-that is, whether the baby was with the mother or in its cot. The recordings were made using no wires to avoid interference with the care of the neonate. Ambient temperature was close to 23 degrees C during the study period. RESULTS: Mean rectal and abdominal and foot skin temperature were lower on day 1 than day 2. The foot skin temperature was directly related to the care situation, being significantly higher when the baby was with the mother. The abdominal skin temperature was much less influenced by external factors. When the neonates were with their mothers, the mean difference between rectal temperature and abdominal skin temperature was 0.2 degrees C compared with a mean difference between rectal temperature and foot skin temperature of 1.5 degrees C, indicating a positive heat balance. In the cot the corresponding temperature differences were 0.7 degrees C and 7.5 degrees C. A temperature difference between rectal and foot skin temperature of 7-8 degrees C indicates a heat loss close to the maximum for which a neonate can compensate (about 70 W/m2). CONCLUSION: This study emphasises the importance of close physical contact with the mothers for temperature regulation during the first few postnatal days.

Skin dose alarm levels in cardiac angiography procedures: is a single DAP value sufficient?

Maximum estimated skin doses to patients undergoing coronary angiography procedures were obtained using radiographic slow film and diode dosemeters. Conversion factors of maximum entrance skin dose versus dose-area product (MESD/DAP) for diagnostic (coronary angiography (CA); 20 patients; 2 operators) and interventional procedures (percutaneous transluminal coronary angiography (PTCA); 10 patients; 1 operator) were 4.3 (mean value of 10 CA; operator A), 3.5 (mean value of 10 CA; operator B) and 9.7 (mean value of 10 PTCA; operator B) mGy(Gycm2)(-1), respectively. The results emphasise a need for both operator- and procedure-specific conversion factors. Compared with a single, global factor for all cardiac procedures and/or operators that is commonly applied today, such a refinement is expected to improve the accuracy in skin dose estimations from these procedures. Consequently, reference DAP values used in the clinic to define patients who could suffer from a radiation induced skin injury following a cardiac procedure, should be defined for each operator/procedure. The film technique was found to be superior to the diode in defining conversion factors in this study, and allowed for a rapid and accurate estimation of MESD for each patient. With appropriate positioning of the diode, a combined film/diode technique has a potential use in the training of new angiography operators. The patient body mass index (BMI) value was a good indicator of the variation in average lung dose (critical organ) between patients. The highest lung dose/DAP value was obtained for normal sized patients (BMI: 19-26), and was close to 1.5 mGy(Gycm2)(-1) with both CA and PTCA procedures.

APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells.

Two main causes of platinum resistance are mutation in the tumor suppressor gene TP53 and drug-induced increase in intracellular glutathione concentration. Mutations in TP53 occur in about 50% of human tumors. APR-246 (PRIMA-1(MET)) is the first clinical-stage compound that reactivates mutant p53 and induces apoptosis. APR-246 is a prodrug that is converted to the active compound methylene quinuclidinone (MQ), a Michael acceptor that binds to cysteine residues in mutant p53 and restores its wild-type conformation. Here, we show that MQ also binds to cysteine in glutathione, thus decreasing intracellular free glutathione concentration. We also show that treatment with APR-246 completely restores the cisplatin and doxorubicin sensitivity to p53-mutant drug-resistant ovarian cancer cells. We propose that this unique ability of APR-246/MQ to bind to cysteines in both mutant p53 and glutathione has a key role in the resensitization as well as in the outstanding synergistic effects observed with APR-246 in combination with platinum compounds in ovarian cancer cell lines and primary cancer cells. However, MQ binding to cysteines in other targets, for example, thioredoxin reductase, may contribute as well. Strong synergy was also observed with the DNA-damaging drugs doxorubicin and gemcitabine, while additive effects were found with the taxane docetaxel. Our results provide a strong rationale for the ongoing clinical study with APR-246 in combination with platinum-based therapy in patients with p53-mutant recurrent high-grade serous (HGS) ovarian cancer. More than 96% of these patients carry TP53 mutations. Combined treatment with APR-246 and platinum or other DNA-damaging drugs could allow dramatically improved therapy of a wide range of therapy refractory p53 mutant tumors.

Distribution of muscle degeneration in Welander distal myopathy--a magnetic resonance imaging and muscle biopsy study.

Seven patients with Welander distal myopathy were subjected to magnetic resonance imaging (MRI) of the lower extremity, and muscle biopsies of the tibialis anterior, soleus and vastus lateralis muscles. MRI revealed abnormalities in both the anterior and posterior compartments of the lower leg in three of the patients, and in only the posterior compartment in the rest of the patients. No MRI abnormalities were found in either the proximal muscles of the leg or in the peroneal or posterior tibial muscle groups. Affected muscles had T1- and T2-values indicating a replacement of muscle fibres with fat tissue. Muscle biopsies showed pathological changes varying from slight to severe in tibialis anterior and soleus muscles in all patients. No muscle fibre abnormalities were seen in the vastus lateralis muscle in any of the patients. In accordance with earlier reports from patients with Welander distal myopathy, there was muscle degeneration of tibialis anterior muscles corresponding to the weakness of dorsal extension of the feet, but also degeneration in the muscles of the posterior compartment. The patients did not, however, show any clinical signs of weakness related to posterior muscle groups. There is no evidence of involvement of proximal muscles of the leg clinically, with MRI or in muscle biopsies.

Three-dimensional dose mapping from gamma knife treatment using a dosimeter gel and MR-imaging.

A new method has been investigated for the mapping of dose distributions in three dimensions delivered by the Leksell gamma knife. The irradiation unit is used to selectively treat small volumes in the brain with single high doses of ionising radiation--a treatment procedure known as radiosurgery. The dosimetry method investigated utilises a dosimeter gel consisting of ferrous sulphate solution and agarose which is, prior to irradiation, loaded into a cavity in a spherical phantom. Chemical changes induced in the gel by the radiation are measured by means of an MR-scanner. This imaging method permits rapid evaluation of the dose distribution in an irradiated volume. It thus offers a potential verification of individual radiation intracranial target treatment regimes as well as quality assurance measurements, assuming that the precision and accuracy of the dose mapping are adequate. The dose and its distribution registered by the gel dosimeter, in this initial experiment, are in good agreement with corresponding computed data obtained with the KULA treatment planning system of the gamma knife. The gel has thus the potential of being an attractive alternative dose mapping method to those used at present in radiosurgery, i.e. radiographic film and small ionisation chambers. The precision of the dosimeter gel is, however, not yet sufficient high to be used as a basic dosimetry system for the gamma knife.

Reducing noise damage by using a mid-frequency sound conditioning stimulus.

Sound conditioning guinea pigs to a 6.3 kHz tone at 78 dB SPL for either 13 or 24 days provides significant physiological (auditory brain stem responses, ABR; and distortion product otoacoustic emissions, DPOAE) and morphological (cochleograms) protection against a subsequent traumatic exposure (6.3 kHz, 100 dB SPL for 24 h) delivered 2 h after sound conditioning. Threshold shifts (ABR, DPOAE) were significantly reduced and the degree of hair cell loss was minimal. When a 1 week pause was given between the end of the sound conditioning and the traumatic exposure, protection was still observed, but to a lesser degree. These findings demonstrate that mid-frequency sound conditioning protects against noise trauma and that the protective effect is maintained for at least 1 week.

Medial olivocochlear efferent terminals are protected by sound conditioning.

Synaptophysin immunoreactivity was used as a marker for the olivocochlear efferent system that innervates the outer hair cells of the cochlea. An intense noise exposure at either 6.3 kHz or 1.0 kHz caused a significant reduction in anti-synaptophysin immunoreactivity within the 8-6 mm or 14-11 mm distance from the round window, respectively. In the region of the main lesion, the reduction in synaptophysin immunoreactivity for both the 6.3 and 1.0 kHz exposures correlated well with outer hair cell loss. In regions peripheral to the main lesion, some remnants of efferent nerve endings could remain even when their associated outer hair cells were missing. Pre-treatment with a low level sound conditioner (either at 6.3 tone or 1.0 kHz) effectively reduced the efferent and outer hair cell pathology induced by the 6.3 and 1.0 kHz intense noise exposures, respectively. The results demonstrate the feasibility of using anti-synaptophysin immunoreactivity as an effective means of quantifying pathological alterations to the medial cochlear efferent terminals throughout the cochlea. Furthermore, the results show that sound conditioning significantly reduces damage to the efferent terminals.

Resolution of biexponential transverse relaxation in magnetic resonance imaging.

The accuracy in measurements of mono- and biexponential transverse relaxation processes with an MRI unit (0.5 T) was studied with a binary phantom. Comparison with spectrometer measurements (0.5 T) demonstrated that the imager underestimated the T2 values for monoexponential processes. Numerical resolution of biexponential processes also yielded underestimated relaxation times, but the resolution of a slow, constant component from faster components was relatively precise and consistent, provided the T2 ratio was above 2.5 in the T2 range 200-800 ms for a spin-echo sequence with 32 echoes. The effects of signal-averaging, strength of slice-selective gradient, single- versus multi-slice mode and repetition time were of little importance. In coronal slices a spurious biexponentiality occurred occasionally from monoexponential sources. The influence of stochastic noise was of minor importance compared to the effect of systematic noise.

MR imaging of absorbed dose distributions for radiotherapy using ferrous sulphate gels.

The measurement of absorbed dose distributions using dosemeter gel and magnetic resonance imaging (MRI) in a standard geometry has been investigated. Absorbed depth-dose curves and profiles measured with this new technique show good agreement with corresponding measurements using diodes. This was proven in a 60Co beam as well as an electron beam. The dosemeter gel is made of agarose and ferrous sulphate solution. The dose response is linear (r = 0.9996) in the investigated dose interval, 0-40 Gy. The sensitivity is a factor of about six higher compared to ordinary ferrous sulphate solution, known as 'Fricke'. This is a true 3D dose measurement technique which will have a number of applications in radiation therapy, since it is possible to mould the gel to arbitrary geometries, mix different radiation qualities and integrate the absorbed dose from different kinds of fields.

Improvements in absorbed dose measurements for external radiation therapy using ferrous dosimeter gel and MR imaging (FeMRI).

A ferrous gel, based on ferrous (Fe) sulphate and agarose, was used with a clinical magnetic resonance imaging (MRI) scanner to obtain relative dose distribution data from therapeutic photon and electron beams. The FeMRI gel was scanned using a new MRI acquisition protocol optimized for T1 measurements. Thorough comparisons with silicon semiconductor detector and ionization chamber measurements, as well as with Monte Carlo calculations, were performed in order to quantify the improvements obtained using FeMRI for dose estimations. Most of the relative doses measured with FeMRI were within 2% of the doses measured with other methods. The larger discrepancies (2-4%) found at shallow depths are discussed. The uncertainty in relative dose measurements using FeMRI was significantly improved compared with previously reported results (5-10%, one standard deviation, 1 SD), and is today between 1.6% and 3.3% (depending on dose level, 2 SD). This corresponds to an improvement in the minimum detectable dose (3 SD above background) from approximately 2 Gy to better than 0.6 Gy. The results obtained in this study emphasize the importance of obtaining basic FeMRI dose data before the method is extended to complicated treatment regimes.

Morphological and functional preservation of the outer hair cells from noise trauma by sound conditioning.

Guinea pigs were sound conditioned to a low-level, long-term pure tone stimulus (1 kHz, 81 dB SPL, 24 days) before exposure to a traumatic noise (1 kHz, 105 dB SPL, 72 h). Auditory brainstem response thresholds and distortion product otoacoustic emissions were obtained at selected frequencies before sound conditioning and at day 1, 5, 10, and 15 during sound conditioning as well as on the final 24th day. Auditory brainstem responses at 1 and 2 kHz were not affected at any time during sound conditioning. The amplitude of the distortion product otoacoustic emission showed minor alterations (below 10 dB) at selected frequencies only during the initial stages (day 1, 5, and 10) of sound conditioning in some, but not all the animals. Distortion product amplitudes were similar to control values on the 15th and 24th day of conditioning. Surface preparations of the organ of Corti did not reveal any significant hair cell loss induced by sound conditioning. The effect of a traumatic exposure (1 kHz, 105 dB SPL, 72 h) on a control group and a sound conditioned group was determined. The distortion product otoacoustic emission amplitude measured 4 weeks after the cessation of the traumatic exposure revealed significant differences. The amplitude of the distortion product otoacoustic emission for the control group was depressed at all tested frequencies and at lower frequencies (2.8, 2.1, and 1.75 kHz) the emissions did not show an increase in response to increases in intensity, of the primaries. The sound conditioned group showed increases in distortion product amplitude with increases in the intensity of the primaries for all tested frequencies and statistically significant reductions from the pre-exposure values were not found. Surface preparations from the control group indicated that the traumatic noise exposure affected nearly 100% of the outer hair cells around the 14 mm distance from the round window. The sound conditioned group showed a significantly less (50%) outer hair cell loss than the control group. The sound conditioned group illustrated an altered pattern of damage after subsequent noise trauma. There were two distinct regions of outer hair cell loss, one being around the 16 mm distance and the other around the 12 mm distance from the round window. These results imply that the intrinsic properties of the outer hair cells and/or the organ of Corti have been altered by sound conditioning.

Characterization of hearing in an X,0 'Turner mouse'.

Turner's syndrome is due to total (45,X) or partial (mosaicism) loss of one X-chromosome. The main features are short stature, ovarian dysgenesis with no estrogen production and infertility. In addition to ear and hearing disorders, middle ear problems including acute/serous otitis media and chronic middle ear disease are frequent. Sensorineural hearing loss is often seen with a dip in the mid-frequencies and also an early high frequency loss. In this study, middle-and inner-ear pathology was characterized using physiological and morphological techniques in a 'Turner mouse' that has been generated with the chromosomal aberration X,0. Otitis media was found in some of these X,0 animals, a symptom that is seldom found in control animals. The auditory brainstem responses (ABR) of the Turner mouse showed a progressive hearing loss in the high frequency region that exceeded the normal age-related hearing loss of control mice and increased latencies of the first ABR wave. Outer hair cell loss was apparent in the cochlear basal turn of Turner mice. Decreases in the amplitude of distortion product otoacoustic emissions were correlated with the loss of ABR threshold sensitivity. These results indicate that hearing problems in the Turner mouse seems to be of cochlear origin with an eighth nerve component. This Turner mouse model appears to have ear and hearing problems quite similar to humans and can therefore be used as a model to determine the auditory pathology underlying this syndrome.

Effects of trabecular bone on marrow relaxation in the tibia.

The effects of bone on marrow relaxation in the trabecular volume of the most proximal 3 cm in the left tibia were studied with a RF-spoiled gradient echo MRI protocol on a 1.0 T MR unit. The MR measurements were performed on six healthy volunteers, and repeated within one month in order to assess the precision of the method. In the same subjects, the area bone mineral density (BMD, g/cm2) was measured at the left proximal femur using dual-energy X-ray absorptiometry. The calcaneus of the same side was examined with quantitative ultrasound. The marrow T2* relaxation deviated from a mono-exponential decay, and resembled the decay of subcutaneous fat. The shape of the relaxation curve reflected the presence of several spectral components in bone marrow, and was further influenced by the amount and structure of the surrounding trabecular bone. The bone marrow decays showed substantially reduced inter-subject variability after normalisation of the marrow data fit parameters to corresponding values for s.c. fat. This suggests the use of an internal adipose tissue reference in order to correct for diet-related variations of marrow T2* estimates. The mean relative precision of the MR measurements was between 5% and 10% depending on the data fit model. Moderate-to-strong correlations between DXA BMD indices in the proximal femur and MR parameters were found (r(max)=-0.96; p < 0.01), while ultrasound-derived measures of bone strength measured on the calcaneus demonstrated significantly weaker correlations to the MR parameters (r(max)=-0.78; p > 0.05). The method employed in this study showed reasonable precision and a moderate to good correlation compared to other bone parameters derived at the same extremity, and is a promising tool for the use on patients.

MRI measurements of the dependence on T1 of the echo amplitudes using a multiple spin-echo scheme.

Analytical calculations using the Bloch formalism were performed to assess the dependence on T1 of the echo amplitudes for the Phase-Alternating Phase-Shift (PHAPS) multiple spin-echo protocol. Measurements in a 0.5 T MR imaging unit were performed to ratify the analytical results. Especially for low T2 values, the echo amplitudes were erroneous, with an increasing contribution from stimulated echo components with increasing T1. Apart from affecting T2 estimates, stimulated echoes generated a non-monoexponential signal decay of the echo trains. The results confirmed previous simulation studies as regards the dependence on T1 of T2 estimates from PHAPS.

Dependence on T1 of the echo amplitudes from multiple spin-echo sequences with equidistant echoes: simulation studies.

Transverse relaxation times were estimated from numerical simulations on spin systems using multi-echo spin-echo MRI protocols. The influence of T1 on the echo amplitudes via stimulated echo components was studied. The resulting effects on T2 estimates from the Carr-Purcell (CP), Carr-Purcell-Meiboom-Gill (CPMG), and Phase-Alternating-Phase-Shift (PHAPS; combination of CP and CPMG), multiple echo schemes were examined. Protocols with either spatially selective or nonselective refocusing pulses were studied. An intravoxel static field inhomogeneity of 0.1, 1, and 10 ppm was stimulated. The dependence on T1 of the T2 estimates was notable for T1 values below approximately 800 msec for all protocols. The PHAPS scheme provided rather accurate, but underestimated, T2 values when selective refocusing was used. With nonselective refocusing, PHAPS T2 values were overestimated and demonstrated a pronounced dependence on magnetic field inhomogeneity. In general, long T2 values were erroneous with the PHAPS protocol. The results indicate that a CPMG protocol structure provides a more robust method for T2 estimations than the PHAPS protocol.

Properties of the phase-alternating phase-shift (PHAPS) multiple spin-echo protocol in MRI: a study of the effects of imperfect RF pulses.

The effects of imperfect radiofrequency (RF) pulses on the echo amplitudes from the Carr-Purcell (CP), Carr-Purcell-Meiboom-Gill (CPMG), and the PHase-Alternating Phase-Shift (PHAPS; combination of CP and CPMG) multiple spin-echo schemes were studied. Properties of the PHAPS scheme for transverse relaxation time measurements was emphasized. Numerical simulations on non-relaxing spin systems were performed to assess the properties of selective (damped sinc shaped) and nonselective refocusing pulses in terms of effective spatial selectivity and generation of secondary echo signal. Analytical solutions of the Bloch equations were applied to study the generation and propagation of stimulated echo signal caused by nonideal 180 degrees phase reversals, and the results were used to analyse the numerical simulations in terms of primary and stimulated echo components. Finally, the simulated echo train patterns from the different MSE schemes were compared with MR imaging measurements. It was found that the underestimation of T2 values by the PHAPS protocol with selective refocusing pulses is mainly an effect of an "artificial" echo amplitude decay in the CP scheme, while the CPMG scheme produces a typical even-odd echo pattern (different from corresponding echo patterns in conventional high resolution NMR). Both effects are related to the flip angle error and phase dispersion along the slice selection direction from selective RF pulses, and are not significantly influenced by stimulated echo interference for nonrelaxing spin systems. However, the presence of stimulated echoes at the time of the primary echoes implies a dependence on T1 of the PHAPS echo amplitudes. In the CPMG protocol, different gradient schemes have been implemented to defocus stimulated echoes. However, the results indicate that there exists stimulated components that will not be affected by such gradients, and that the optimization of the RF refocusing pulses then remain the main objective.

[Alcohol-induced cognitive impairment is reversible. Neuropsychological tests but not MRT show improvement after abstinence]. / Alkoholinducerad kognitiv påverkan kan gå i regress. Neuropsykologiska test men inte MRT visar förbättring efter abstinens.

Of alcoholic patients who underwent MRI (magnetic resonance imaging) of the brain and neuropsychological tests shortly after discontinuation of heavy drinking, a subgroup underwent repeat MRI scans and neuropsychological assessment one year later. The reduction in drinking habits was associated with cognitive improvement but no significant difference in MRI variables including T1-relaxation time.