Mutagenicity testing of 9-N-substituted adenines and their N-oxidation products.

Adenine together with certain 9-N-substituted derivatives such as 9-methyl, 9-benzyl, 9-benzhydryl, and 9-trityl were tested against Salmonella typhimurium strains TA97, TA98, and TA100 in the absence and presence of rat hepatic S9 prepared from Aroclor 1254 pretreated rats. All compounds were positive toward TA98 in the presence of the metabolic activating system, whereas they all lacked mutagenic activity in the absence of S9, and toward TA97 and TA100 with or without S9 when tested at 100 ng/plate. A similar pattern was observed for the corresponding 1-N-oxides. 6-Hydroxylaminopurine was not mutagenic toward TA100 at 100 ng/plate, whereas it was toxic toward TA97 and TA98 at this level. When tested at 1 ng/plate, hydroxylaminopurine was still toxic to TA98 but produced twice the spontaneous reversion rate to TA97 without metabolic activation. Surprisingly, 9-methyl-6-hydroxylaminopurine was only active toward TA98 in the presence of S9, whereas 9-benzyl-6-hydroxylaminopurine was highly active toward TA97 and TA100 in the absence of S9 and even more active in the presence of S9. This compound was inactive toward TA98 in the absence of S9. The results generally support the concept that nuclear N-oxidation of aminoazaheterocycles is a detoxication process, whereas N-hydroxylation of the exo amino group is a toxication reaction

Evaluation of fast spin echo MRI sequence for an MRI guided high intensity focused ultrasound system for in vivo rabbit liver ablation

The effectiveness of magnetic resonance imaging (MRI) to monitor thermal lesions created by High Intensity Focused Ultrasound (HIFU) in rabbit liver in vivo is investigated. The MRI sequences of T1-weighted, and T2-weighted fast spin echo (FSE) were evaluated. The main goal in this paper was to find the range of repetition time (TR) and range of echo time (TE) which maximizes the contrast to noise ratio (CNR). An ultrasonic transducer operating at 2 MHz was used, which is navigated using a positioning device. With T1W FSE the range of TR under which CNR is maximized ranges from 400 to 900 ms. The maximum contrast measured is approximately 25. With T2W FSE the range of TE that establishes maximum contrast is between 40 ms and 80 ms, with CNR of approximately 14. T1W FSE is much better than T2W FSE in detecting thermal lesions in liver. Both T1W and T2 W FSE were proven successful to image thermal lesions created by HIFU in rabbit liver in vivo

A Bayesian test for the appropriateness of a model in the biomagnetic inverse problem

This paper extends the work of Clarke [1] on the Bayesian foundations of the biomagnetic inverse problem. It derives expressions for the expectation and variance of the a posteriori source current probability distribution given a prior source current probability distribution, a source space weight function and a data set. The calculation of the variance enables the construction of a Bayesian test for the appropriateness of any source model that is chosen as the a priori infomation. The test is illustrated using both simulated (multi-dipole) data and the results of a study of early latency processing of images of human faces. [1] C.J.S. Clarke. Error estimates in the biomagnetic inverse problem. Inverse Problems, 10:77--86, 1994.Comment: 13 pages, 16 figures. Submitted to Inverse Problem

MRI monitoring of lesions created at temperature below the boiling point and of lesions created above the boiling point using high intensity focused ultrasound

Magnetic Resonance Imaging (MRI) was utilized to monitor lesions created at temperature below the boiling point and lesions created at temperature above the boiling point using High Intensity Focused Ultrasound (HIFU) in freshly excised kidney, liver and brain and in vivo rabbit kidney and brain. T2-weighted fast spin echo (FSE) was proven as an excellent MRI sequence that can detect lesions with temperature above the boiling point in kidney. This advantage is attributed to the significant difference in signal intensity between the cavity and the thermal lesion. In liver the MRI sequence of Proton Density is recommended to detect lesions above boiling. In brain T1-W FSE was the optimum pulse sequence to detect lesions of either type. In order to monitor the temperature elevation during a HIFU exposure, T1-weighted fast spoiled gradient (FSPGR) was used. The shape of the focal temperature distribution was uniform with the absence of boiling, whereas with an exposure affected by boiling, the temperature distribution could be of irregular shape, demonstrating the drastic effects taking place during boiling. In order to confirm that boiling occurred, the temperature was estimated using the widely used method of Proton Resonance Frequency (PRF) shift

Penetration of high intensity focused ultrasound in vitro and in vivo rabbit brain using MR imaging

In this paper magnetic resonance imaging (MRI) is investigated for monitoring the penetration of high intensity focused ultrasound (HIFU) ex vivo and in vivo rabbit brain. A single element spherically focused transducer of 5 cm diameter, focusing at 10 cm and operating at 2 MHz was used. A prototype MRI- compatible positioning device is described. MRI images were taken using fast spin echo (FSE). The length of the lesions in vivo rabbit brain was much higher than the length ex vivo, proving that the penetration in the ex vivo brain is limited by reflection due to trapped bubbles in the blood vessels

Neural Correlates of Induced Light Experience during Meditation: A Pilot Hyperscanning Study

Certain individuals during deep meditative states can transmitt and give out an aura or ‘light, which is perceived by others through some unknown connections, visual, telepathic or other. Despite various anecdotal, historical accounts of such induced light experience (ILE), its underlying neural mechanism is not known. In this pilot study, we investigated the neural correlates of ILE by simultaneously recording the EEGs of an expert Teacher, who is claimed to elicit ILE, and his Pupil (N=2) during joint sessions under various instructions, given separately to the Teacher (transmit/ do not transmit) and to the Pupil (receive/ do not receive). In a further condition both teacher and pupil wear opaque goggles during transmit/receive instruction, limiting the visual/outputinput. We observed a robust increase in the high frequency beta (12-30 Hz) and gamma oscillations (30-70 Hz) in the Teacher’s brain whenever he was instructed to transmit. Electric field tomography analysis localized these effects over several brain regions including the fusiform gyrus, angular gyrus and the cerebellum. Finally, we found that the Teacher’s and Pupil’s brain responses were synchronized, especially in the alpha band (8-12 Hz) during transmit/receive condition, and the information flow was directional, i.e. from the Teacher to the Pupil; interestingly, this enhanced interbrain synchrony disappeared with opaque goggles. These results were interpreted in terms of heightened internally selective attention as manifested by high frequency beta-gamma oscillations and of joint attention as manifested by interbrain alpha synchrony. Altogether, our results provide the first neuroscientific evidence underlying the phenomenological experience of induced light

Tourism policy and destination marketing in developing countries: the chain of influence

Tourism marketers including destination marketing organisations (DMOs) and international tour operators play a pivotal role in destination marketing, especially in creating destination images. These images, apparent in tourist brochures, are designed to influence tourist decision-making and behaviour. This paper proposes the concept of a “chain of influence” in destination marketing and image-making, suggesting that the content of marketing materials is influenced by the priorities of those who design these materials, e.g. tour operators and DMOs. A content analysis of 2,000 pictures from DMO and tour operator brochures revealed synergies and divergence between these marketers. The brochure content was then compared to the South African tourism policy, concluding that the dominant factor in the chain of influence in the South African context is in fact its organic image

The Unique Determination of Neuronal Currents in the Brain via Magnetoencephalography

The problem of determining the neuronal current inside the brain from measurements of the induced magnetic field outside the head is discussed under the assumption that the space occupied by the brain is approximately spherical. By inverting the Geselowitz equation, the part of the current which can be reconstructed from the measurements is precisely determined. This actually consists of only certain moments of one of the two functions specifying the tangential part of the current. The other function specifying the tangential part of the current as well as the radial part of the current are completely arbitrary. However, it is also shown that with the assumption of energy minimization, the current can be reconstructed uniquely. A numerical implementation of this unique reconstruction is also presented

Secukinumab demonstrated sustained retention, effectiveness and safety in a real-world setting in patients with moderate-to-severe plaque psoriasis: long-term results from an interim analysis of the SERENA study.

Randomized controlled trials of secukinumab have shown sustained efficacy and a favourable safety profile in multiple manifestations of psoriatic disease. To assess the long-term, real-world retention, effectiveness and safety of secukinumab in routine clinical practice for the treatment of moderate-to-severe plaque-type psoriasis (PsO). SERENA (CAIN457A3403) is a large, ongoing, longitudinal, observational study conducted at 438 sites and 19 countries for an expected duration of up to 5 years in adult patients with moderate-to-severe PsO, psoriatic arthritis and ankylosing spondylitis. Patients received ≥16 weeks of secukinumab treatment before enrolment. This interim analysis presents data from PsO patients, who were enrolled in the study between October-2016 and October-2018 and were observed for ≥2 years. In total, 1756 patients (67.3% male) with a mean age of 48.4 years and body mass index of 28.8 kg/m <sup>2</sup> were included in the analysis. The secukinumab treatment retention rates after 1, 2 and 3 years in the study were 88.0%, 76.4% and 60.5%, respectively. Of the 648 patients who discontinued the study, the most common reasons included lack of efficacy (42.6%), adverse event (17.4%), physician decision (12.2%) and subject decision (11.6%). Mean ± SD absolute PASI was 21.0 ± 13.0 at the start of treatment (n = 1,564). At baseline, the mean ± SD PASI score reduced to 2.6 ± 4.8 and remained low at Year 1 (2.3 ± 4.3), Year 2 (1.9 ± 3.6) and Year 3 (1.9 ± 3.5). The safety profile of secukinumab during the SERENA study was consistent with its known safety profile, with no new safety signals reported. Particularly, low rates of inflammatory bowel disease (0.3%; Incidence Rate [IR]:0.15), candida infections (3.1%; IR:1.43) and MACE (0.9%; IR:0.37) were observed. Secukinumab showed high treatment persistence, sustained effectiveness and a favourable safety profile up to 3 years of follow-up in the real-world population of PsO patients observed in SERENA