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PubMed2005

Bayesian analysis of the neuromagnetic inverse problem with l(p)-norm priors.

Magnetoencephalography (MEG) allows millisecond-scale non-invasive measurement of magnetic fields generated by neural currents in the brain. However, localization of the underlying current sources is ambiguous due to the so-called inverse problem. The most widely used source localization methods (i.e., minimum-norm and minimum-current estimates (MNE and MCE) and equivalent current dipole (ECD) fitting) require ad hoc determination of the cortical current distribution (l(2)-, l(1)-norm priors and point-sized dipolar, respectively). In this article, we perform a Bayesian analysis of the MEG inverse problem with l(p)-norm priors for the current sources. This way, we circumvent the arbitrary choice between l(1)- and l(2)-norm prior, which is instead rendered automatically based on the data. By obtaining numerical samples from the joint posterior probability distribution of the source current parameters and model hyperparameters (such as the l(p)-norm order p) using Markov chain Monte Carlo (MCMC) methods, we calculated the spatial inverse estimates as expectation values of the source current parameters integrated over the hyperparameters. Real MEG data and simulated (known) source currents with realistic MRI-based cortical geometry and 306-channel MEG sensor array were used. While the proposed model is sensitive to source space discretization size and computationally rather heavy, it is mathematically straightforward, thus allowing incorporation of, for instance, a priori functional magnetic resonance imaging (fMRI) information.

Adult↗
PubMed2006

A verifiable solution to the MEG inverse problem.

Magnetoencephalography (MEG) is a non-invasive brain imaging technique with the potential for very high temporal and spatial resolution of neuronal activity. The main stumbling block for the technique has been that the estimation of a neuronal current distribution, based on sensor data outside the head, is an inverse problem with an infinity of possible solutions. Many inversion techniques exist, all using different a-priori assumptions in order to reduce the number of possible solutions. Although all techniques can be thoroughly tested in simulation, implicit in the simulations are the experimenter's own assumptions about realistic brain function. To date, the only way to test the validity of inversions based on real MEG data has been through direct surgical validation, or through comparison with invasive primate data. In this work, we constructed a null hypothesis that the reconstruction of neuronal activity contains no information on the distribution of the cortical grey matter. To test this, we repeatedly compared rotated sections of grey matter with a beamformer estimate of neuronal activity to generate a distribution of mutual information values. The significance of the comparison between the un-rotated anatomical information and the electrical estimate was subsequently assessed against this distribution. We found that there was significant (P < 0.05) anatomical information contained in the beamformer images across a number of frequency bands. Based on the limited data presented here, we can say that the assumptions behind the beamformer algorithm are not unreasonable for the visual-motor task investigated.

Brain↗
PubMed2005

Ankle eversion torque response to sudden ankle inversion Torque response in unbraced, braced, and pre-activated situations.

In 13 young ankle stable subjects, ankle eversion torque and peroneal EMG were simultaneously recorded in response to sudden ankle inversion. The eversion torque response was bi-phasic. The initial development of torque, which was responsible for 30% of the maximal eversion torque response, was observed 135 ms after the start of platform rotation and correlated well with the onset of the automatic postural peroneal EMG response. The remaining eversion torque response commenced after 305 ms, strongly correlating with the onset of the peroneal long latency voluntary EMG activity. With the ankle unbraced, 66% of the maximal torque level was reached in 326 ms. While braced, the same torque magnitude was reached using 230 ms (p<0.02), and pre-activation of the peroneal muscles allowed the subjects to reach the same level of torque in 89 ms (p<0.0005). Prior to the study, a common reaction pattern to sudden inversion was expected in an ankle stable population, but review of the eversion torque and EMG data from the 13 subjects revealed three different voluntary reaction patterns: 10 subjects showed an efficient activation of evertor muscles; two subjects stiffened their ankles with activation of both in- and evertor muscles; and one subject showed a marginal voluntary activation of the ankle evertors. The results of the study indicate that the reaction to sudden ankle inversion is not solely automatic. The main part of the torque response is voluntarily mediated and inter-individual differences in strategy seem to exist in healthy subjects.

Adult↗
PubMed2004

Voluntary exercise augments acute effects of CB1-receptor inverse agonist on body weight loss in obese and lean mice.

Cannabinoid CB1 receptor (CB1R) inverse agonists reduce appetite and body weight (BW) gain in various species. Exercise is thought to be a natural reward process and the cannabinoid system is also believed to influence reward. We tested the hypothesis that voluntary exercise would augment the effects of AM251, a CB1R inverse agonist, on food intake (FI) and BW loss in murine genetic models of obesity. ob/ob, agouti yellow (A(y)), and lean C57BL/6J mice were treated via oral gavage with vehicle or AM251 (1, 3, or 10 mg/kg) 1 h before the dark cycle. The suppressive effects of 3 and 10 mg/kg AM251 on overnight FI, BW gain, and water intake (WI) were significant in ob/ob mice. In contrast, in A(y) mice, 10 mg/kg AM251 decreased FI and BW gain while it did not influence WI. Food consumption of ob/ob and A(y) mice, as evidenced by feeding frequency (FF) and feeding duration (FD), was reduced by AM251 for 4-6 h. AM251 at these doses had no impact on the appetitive behavior or BW gain of lean mice. After a 1-week wash-out period, mice were given running wheels in their home cages. With running wheel exercise, lean and obese mice exhibited increased sensitivity to AM251. Low voluntary wheel running activity of ob/ob mice precluded detection of combined effects of AM251 and exercise in this genetic model of obesity. Lean and agouti mice given AM251 combined with exercise lost a greater amount of BW than with AM251 alone. Our data suggest that voluntary exercise can enhance CB1R inverse agonist effects on appetite and BW loss in both lean and agouti obese mice.

Animals↗
PubMed2004

A comparison of forward and inverse planned conformal, multi segment and intensity modulated radiotherapy for the treatment of prostate and pelvic nodes.

BACKGROUND AND PURPOSE: Full inverse planned intensity modulated radiotherapy (IMRT) may be indicated to treat concave targets like prostate and pelvic nodes, because concave dose distributions cannot be generated with conformal radiotherapy (CRT). We investigated whether this concave dose distribution can be produced using simplified forward planned multi segment radiotherapy (MSRT). PATIENTS AND METHODS: CRT, MSRT and IMRT dose distributions were calculated and compared for five patients treated in our current IMRT prostate and pelvic node dose escalation trial. The same beam arrangement was used for CRT, MSRT and IMRT, increasing the number of segments. The MSRT concave dose distribution was realised regarding left and right pelvic nodes as two separate targets. The IMRT dose distribution had been used to treat the patients using a step and shoot delivery. RESULTS: Contrary to CRT, forward planned MSRT concave dose distributions had improved target coverage at lower or equivalent bowel doses than inverse planned IMRT. The five MSRT beams had a maximum of three segments per beam. Both lateral beams had two segments to deliver the two dose levels to prostate and nodes. The posterior field needed a third segment to avoid using a central block. The two anterior oblique beams needed a third segment to account for the different beam weighting because the nodes were irradiated partially using four and partially using five beams. Inverse planned IMRT used up to 15 segments in any one beam, with an average of 11.4 per beam. CONCLUSIONS: Concave dose distributions for prostate and pelvic node treatment were generated using forward planned multi segment techniques. The plans met clinical constraints used in our IMRT protocol. MSRT presented a significant advantage over both CRT and IMRT.

Humans↗
PubMed2004

Influence of dose point and inverse optimization on interstitial cervical and oropharyngeal carcinoma brachytherapy.

BACKGROUND AND PURPOSE: Evaluation of the use of optimization methods in interstitial cervical and oropharyngeal brachytherapy; evaluation of the conformal index (COIN) and the natural dose ratio (NDR) to quantify the implant quality. MATERIAL AND METHODS: CT-based dose distributions were obtained for seven implants according to the Paris system. CT-based implants were used to assess the dose point and inverse optimization methods. To compare the results of these planning methods, the coverage index (CI), normal tissue irradiation (NTI), and the protection of organs at risk (OARs) were evaluated using cumulative dose volume histograms (CDVH). RESULTS: In regular cervical implants, a CI of 94 and 96%; a NTI of 35 and 28% resulted for non-optimized and optimized implants, respectively. In irregular cervical implants, a CI of 88, 96, and 90%; a NTI of 44, 37, and 44% resulted for non-optimized, dose point optimized, and inverse optimized implants, respectively. Compared to the non-optimized implants; both optimization methods resulted in better protection for the bladder wall. As for the protection of the rectal wall, only the inverse optimization gave a better result. In oropharyngeal implants, a better CI resulted after dose point optimization. Irradiation of the contralateral parotid were improved after both optimization methods. The maximum change in COIN that could have been achieved by optimization was 3%, as CI and NTI increased similarly. For the same value of COIN, an underdosage of PTV was avoided by the optimization methods as NDR increased from 0.86 to 1.01. CONCLUSION: CT-based optimized implant allows conformation of the dose distribution to the PTV while sparing normal tissue and organs at risk. COIN and NDR should be used together to evaluate both doses to normal tissue and organs at risk, and an under- or overdose inside the PTV.

Brachytherapy↗
PubMed2005

Anatomy-based inverse planning dose optimization in HDR prostate implant: a toxicity study.

BACKGROUND AND PURPOSE: The aim of this study is to evaluate the acute and late complications in patients who have received HDR implant boost using inverse planning, and to determine dose volume correlations. PATIENTS AND METHODS: Between September 1999 and October 2002, 44 patients with locally advanced prostate cancer (PSA>/=10 ng/ml, and/or Gleason score>/=7, and/or Stage T2c or higher) were treated with 40-45 Gy external pelvic field followed by 2--3 fraction of inverse-planned HDR implant boost (6--9.5 Gy /fraction). Median follow-up time was 1.7 years with 81.8% of patients who had at least 12 months of follow up (range 8.6--42.5. Acute and late morbidity data were collected and graded according to RTOG criteria. Questionnaires were used to collect prostate related measures of quality of life, and international prostate symptom score (IPSS) before and after treatment. Dose-volume histograms for prostate, urethra, bladder, penis bulb and rectum were analyzed. RESULTS: The median patient age was 64 years. Of these, 32% were in the high risk group, and 61% in the intermediate risk group. 3 patients (7%) had no adverse prognostic factors. A single grade 3 GU acute toxicity was reported but no grade 3--4 acute GI toxicity. No grade 3--4 late GU or GI toxicity was reported. Acute (late) grade 2 urinary and rectal symptoms were reported in 31.8 (11.4%) and 4.6% (4.6%) of patients, respectively. A trend for predicting acute GU toxicity is seen for total HDR dose of more than 18 Gy (OR=3.6, 95%CI=[0.96--13.5], P=0.058). The evolution of toxicity is presented for acute and late GU/GI toxicity. Erectile dysfunction occurs in approximately 27% of patients who were not on hormonal deprivation, but may be taking sildenafil. The IPSS peaked on averaged 6 weeks post-implant and returned to the baseline at a median of 6 months. CONCLUSIONS: Inverse-planned HDR brachytherapy is a viable option to deliver higher dose to the prostate as a boost without increasing GU or rectal complication. Further HDR dose escalation to the prostate is feasible.

Adenocarcinoma↗
PubMed2006

Comparison of forward planning with automated inverse planning for three-dimensional conformal radiotherapy of non-small cell lung cancer without IMRT.

The forward and inverse treatment plans of 10 patients with lung cancer were compared in terms of PTV coverage, sparing of normal lung and time required to generate a plan. The inverse planning produced as good treatment plans as an experienced dosimetrist with considerable reduction in staff time. When translated to other complex sites, inverse non-IMRT planning may have considerable impact on manpower requirements.

Algorithms↗
PubMed2006

Recent developments in constitutive receptor activity and inverse agonism, and their potential for GPCR drug discovery.

The concept of constitutively active G-protein-coupled receptors is now firmly rooted in receptor pharmacology. Many independent research groups have contributed to its acceptance since its introduction by Costa and Herz in 1989. This concept necessitated a revised ligand classification, and a new category of inverse agonists was introduced alongside existing agonist and antagonist ligands. Initially, it was hoped that new therapeutic modalities would become available. However, the drug industry has not adopted inverse agonism as a design criterion and instead accepted that some compounds emerge as (neutral) antagonists in compound screening, whereas other compounds possess inverse agonistic activity. In this article, we summarize aspects of the impact of constitutive activity on the drug-discovery process: for example, its use in orphan receptor assays, its link with pharmacogenetics and genomics, and its relevance for currently marketed drugs.

Alternative Splicing↗
PubMed2005

Sensitivity analysis of an inverse procedure for determination of elastic coefficients for strong anisotropy.

The elastic coefficients of anisotropic solids are often evaluated from measurements of phase or group velocities of ultrasonic bulk waves by the usage of inverse optimizing procedures. This paper discusses the effects of various factors on such procedures results for transversely isotropic solids with considerably strong anisotropy. First, the inverse determination of all elastic coefficients of unidirectional CFRP composite is briefly outlined. Then the results of the optimization are treated as exact values and the sensitivity of the optimizing process versus main considered sources of inaccuracies is analyzed. Results of extensive simulations are presented to illustrate the effect of input data distortion, input data incompleteness, and geometrical conversion from experimentally obtained group velocities into corresponding phase velocities used as input data for the optimizing procedure. The paper takes note of how information about the elastic coefficients can be extracted from the different segments of the phase velocity surface. The stability versus input data distortion for inversion from group velocities and phase velocities is compared and the importance of reliable geometrical converting from group into phase velocities is illustrated. An novel method for geometrical conversion of distorted group velocity data into corresponding phase velocities based on affine combinations of low-order polynomials is presented and compared with piecewise or high-order polynomial fitting.

Anisotropy↗
PubMed2005

A model-based inverse method for positioning scatterers in a cladded component inspected by ultrasonic waves.

Nondestructive methods aim at detecting, locating and identifying defects. Inversion of ultrasonic measurements obtained by inspecting a steel component of regular geometry with an immersed transducer leads to accurate location of defects. When the component is cladded, the irregular geometry of the surface and the anisotropic nature of the cladding material lead to aberrations of the radiated field (e.g., beam distortions, splitting and defocusing, these varying with the transducer scanning position). As a consequence, defect location may be inaccurate and defects (e.g., cracks) sizing impossible. In the present paper, a model-based inverse method is developed to solve this problem. It relies on the time-dependent simulation of ultrasonic propagation in this material of complex geometry and structure, in order to determine a set of probable positions for the defect at the origin of the measured ultrasonic echo-structure. The most probable position is determined by minimizing a cost-function of likeness between the simulated and measured ultrasonic images. The overall scheme shall generally apply to inverse measured ultrasonic echo-structures as soon as the simulation of the forward problem is tractable. To validate the method, examples of application are given dealing with actual measurements obtained in the real configuration of pressure vessel inspection.

Journal Article↗
PubMed2006

Elasticity reconstruction for ultrasound elastography using a radial compression: an inverse approach.

To reduce the inherent mechanical artifacts in the strain images, many groups have investigated solutions to the inverse problem in elastography. However, in prostate elastography or intravascular elastography where the compression direction is radial, the inverse problem has not been studied thoroughly. In this paper, an iterative approach is proposed to reconstruct tissue elasticity for ultrasound elastography using a radial compression. The method is based upon the stress-strain relations in the polar coordinates. Computer simulations in an intravascular model are performed to illustrate the feasibility of this method in reducing the mechanical artifacts of the strain images. The reconstructed elasticity error and the contrast-transfer efficiency (CTE) as a function of the iteration number show that the inverse approach converges with a few iterations.

Algorithms↗
PubMed2004

Impact of 'ome' analyses on inverse metabolic engineering.

Genome-wide or large-scale methodologies employed in functional genomics such as DNA sequencing, transcription profiling, proteomics, and metabolite profiling have become important tools in many metabolic engineering strategies. These techniques allow the identification of genetic differences and insight into their cellular effects. In the field of inverse metabolic engineering mapping of differences between strains with different degree of a certain desired phenotype and subsequent identification of factors conferring that phenotype are an essential part. Therefore, the tools of functional genomics in particular have the potential to promote and expand inverse metabolic engineering. Here, we review the use of functional genomics methods in inverse metabolic engineering, examples are presented, and we discuss the identification of targets for metabolic engineering with low fold changes using these techniques.

Animals↗
PubMed2003

Penetrating corneal transplant with inadvertent corneal button inversion.

PURPOSE: To report a penetrating corneal transplant in which there was inadvertent inversion of the corneal button. DESIGN: Interventional case report. METHODS: A 48-year-old man with lattice corneal dystrophy had a third penetrating keratoplasty in the right eye 3 years after the second procedure and 2 years following renal transplantation. RESULTS: Histologic examination of the corneal button from the second penetrating keratoplasty disclosed inadvertent corneal graft inversion. Survival epithelium from the donor in the anterior chamber may be explained by the ocular anterior chamber-associated immune deviation or by the patient's systemic cyclosporine A (CsA) treatment after renal transplantation. CONCLUSIONS: Histologically proven corneal button inversion is a rare cause of corneal graft failure.

Cornea↗
PubMed1997

Phosphatidylcholine-fatty acid membranes: effects of headgroup hydration on the phase behaviour and structural parameters of the gel and inverse hexagonal (H(II)) phases.

The phase behaviour and structural parameters of a homologous series of saturated diacyl phosphatidylcholine/fatty acid 1:2 (mol/mol) mixtures having chain lengths from C12 to C20 were studied by X-ray diffraction and calorimetry, as a function of water content. The chain-melting transition temperatures of the 1:2 PC/FA mixtures are found to be largely independent of the degree of hydration. For all chain lengths, the tilted L(beta') and rippled P(beta') gel phases of the pure PC component are replaced by an untilted L(beta) gel phase in the 1:2 PC/FA mixtures. This gel phase swells considerably upon hydration, with a limiting water layer thickness in the range 18-24 A, depending on the chain length. However, unlike pure phospholipid systems, the lateral chain packing within the gel phase bilayers is essentially identical in both the dry and the fully hydrated states. The fluid bilayer L(alpha) phase is suppressed in the 1:2 mixtures, being replaced by inverse non-lamellar phases for all chain lengths greater than C12, and at all levels of hydration. For chain lengths of C16 and greater, the inverse hexagonal H(II) phase is formed directly upon chain melting, at all water contents. For the shorter chain length mixtures, the behaviour is more complex, with the H(II) phase forming at low hydration, but with bicontinuous cubic phases appearing at higher levels of hydration. The implications of these surprising results are explored, in terms of the effective hydrophilicity of the associated PC and FA headgroups and the packing within the interfacial region. We suggest that the presence of the fatty acids significantly alters the lateral stress profile across the lipid monolayer in the fluid state, compared to that of the corresponding pure PC system, such that inverse phases, where the interface bends towards the water, become strongly favoured. Furthermore, for short chain lengths, packing constraints favour the formation of phases with negative interfacial Gaussian curvature, such as the bicontinuous cubic phases, rather than the H(II) phase, which has more severe chain packing frustration.

Calorimetry↗
PubMed2000

Inverse agonist properties of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A) and 1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxyl ic acid phenylamide (CP-272871) for the CB(1) cannabinoid receptor.

Two subtypes of cannabinoid receptors are currently recognized, CB(1), found in brain and neuronal cells, and CB(2), found in spleen and immune cells. We have characterized 1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxyl ic acid phenylamide (CP-272871) as a novel aryl pyrazole antagonist for the CB(1) receptor. CP-272871 competed for binding of the cannabinoid agonist (3)H-labeled (-)-3-[2-hydroxy-4-(1, 1-dimethylheptyl)-phenyl]-4-[3-hydroxypropyl]cyclohexan-1-ol ([(3)H]CP-55940) at the CB(1) receptor in rat brain membranes with a K(d) value 20-fold greater than that of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A). CP-272871 also competed for binding with the aminoalkylindole agonist (3)H-labeled (R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]1, 4-benzoxazin-6-yl](1-naphthyl)methanone ([(3)H]WIN-55212-2), as well as the aryl pyrazole antagonist [(3)H]SR141716A. Inverse agonist as well as antagonist properties were observed for both SR141716A and CP-272871 in signal transduction assays in biological preparations in which the CB(1) receptor is endogenously expressed. SR141716A augmented secretin-stimulated cyclic AMP (cAMP) accumulation in intact N18TG2 neuroblastoma cells, and this response was reversed by the agonist desacetyllevonantradol. CP-272871 antagonized desacetyllevonantradol-mediated inhibition of adenylyl cyclase in N18TG2 membranes, and increased adenylyl cyclase activity in the absence of agonist. SR141716A and CP-272871 antagonized desacetyllevonantradol-stimulated (35)S-labeled guanosine-5'-O-(gamma-thio)-triphosphate ([(35)S]GTPgammaS) binding to brain membrane G-proteins, and decreased basal [(35)S]GTPgammaS binding to G-proteins. K(+) enhanced CP-272871 and SR141716A inverse agonist activity compared with Na(+) or NMDG(+) in the assay. These results demonstrated that the aryl pyrazoles SR141716A and CP-272871 behave as antagonists and as inverse agonists in G-protein-mediated signal transduction in preparations of endogenously expressed CB(1) receptors.

Animals↗
PubMed1998

Effect of clofibrate on the chiral inversion of ibuprofen in healthy volunteers.

OBJECTIVES: To determine the influence of the hypolipidemic drug clofibrate on the stereoselective metabolism of ibuprofen in humans. METHODS: Healthy male subjects (n = 12) ingested a dose of 400 mg pseudoracemic ibuprofen (200 mg R-ibuprofen, 160 mg S-ibuprofen, and 40 mg 13C-S-ibuprofen) on two occasions after either pretreatment with clofibrate (2 gm/day over 1 week) or no pretreatment in a randomized order. RESULTS: When subjects were pretreated with clofibrate, clearances of R-ibuprofen and 13C-S-ibuprofen increased significantly from 55.0 and 66.4 ml/min to 186.2 and 106.7 ml/min (p < 0.01), respectively. This increase was similarly reflected in the clearance by inversion of R-ibuprofen (control, 36.0 ml/min; treated, 118.8 ml/min; p < 0.01), as well as in the clearance by noninversion (control, 19.0 ml/min; treated, 67.4 ml/min; p < 0.01). Unbound clearance values significantly increased for R-ibuprofen (control, 19.5 L/min; treated, 38.7 L/min) but not for 13C-S-ibuprofen (11.8 versus 10.6 L/min, respectively). The fractional inversion of ibuprofen calculated from the urinary metabolite data was increased after clofibrate pretreatment (clofibrate group, 66.4%; control, 53.5%; p < 0.01). However, this was not evident when fractional inversion was calculated from the plasma concentration-time data for the unmetabolized drug. CONCLUSIONS: Clofibrate altered the stereoselective disposition of ibuprofen in healthy volunteers by increased formation of R-ibuprofenoyl-coenzyme A rather than by an effect on oxidative metabolism of ibuprofen. This interaction has potential therapeutic implications.

Adult↗
PubMed1988

Musculo-skeletal magnetic resonance imaging using inversion recovery pulse sequences at 0.08 T.

The potential of magnetic resonance imaging (MRI) for the assessment of musculo-skeletal tumours has until recently been underestimated. Most reports in the literature describe the MRI appearances of musculo-skeletal tumours using spin-echo pulse sequences with high field, superconductive magnets. This paper describes the use of inversion recovery pulse sequences using a low field resistive magnet for the study of musculo-skeletal disorders. Thirty patients who had either radiological evidence of a bone tumour or a soft tissue mass were studied by low field MRI and inversion recovery, and calculated T1 images compared with the tissue histology of the mass. It has been found that inversion recovery images display the size and extent of both bone and soft tissue tumours and that the use of coronal and axial images enable clear display of the relationship of bone and soft tissue tumours to the major blood vessels, muscle and cortical bone.

Adolescent↗