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PubMed2001

Selective and nonselective inverse agonists for constitutively active type-1 parathyroid hormone receptors: evidence for altered receptor conformations.

The spontaneous signaling activity of some G protein-coupled receptors and the capacity of certain ligands (inverse agonists) to inhibit such constitutive activity are poorly understood phenomena. We investigated these processes for several analogs of PTH-related peptide (PTHrP) and the constitutively active human PTH/PTHrP receptors (hP1Rcs) hP1Rc-H223R and hP1Rc-T410P. The N-terminally truncated antagonist PTHrP(5-36) functioned as a weak partial/neutral agonist with both mutant receptors but was converted to an inverse agonist for both receptors by the combined substitution of Leu(11) and D-Trp(12). The N-terminally intact analog [Bpa(2)]PTHrP(1-36)-a partial agonist with the wild-type hP1Rc-was a selective inverse agonist, in that it depressed basal cAMP signaling by hP1Rc-H223R but enhanced signaling by hP1Rc-T410P. The ability of [Bpa(2)]PTHrP(1-36) to discriminate between the two receptor mutants suggested that H223R and T410P confer constitutive receptor activity by inducing distinct conformational changes. This hypothesis was confirmed by the observations that: 1) the double mutant receptor hP1Rc-H223R/T410P exhibited basal cAMP levels that were 2-fold higher than those of either single mutant; and 2) hP1Rc-H223R and hP1Rc-T410P internalized (125)I-PTHrP(5-36) to markedly different extents. The overall results thus reveal that two different types of inverse agonists are possible for PTHrP ligands (nonselective and selective) and that constitutively active PTH-1 receptors can access different conformational states.

Animals↗
PubMed1991

Growth hormone-binding protein activity is inversely related to 24-hour growth hormone release in normal boys.

To investigate the physiological relationship between serum GH-binding proteins and 24-h GH release, we compared the 24-h GH pulse attributes in serum samples obtained at 20-min intervals to the serum GH-binding protein activity (GH-BP) from 38 normal boys between 7 5/12 and 18 4/12 yr of age. GH-BP was determined in a serum sample from each study (containing less than 1.0 micrograms/L GH) using a standardized GH-BP assay. GH-BP results are expressed as the percentage of [125I]human GH bound to the high affinity GH-BP complex (peak II) per 160 microL serum. There were significant inverse relationships between the high affinity (receptor-related) GH-BP and several characteristics of 24-h GH release. Specifically, GH-BP was significantly (P less than 0.005 for all), but negatively, correlated with mean 24-h GH concentration (r = -0.62), sum of the GH pulse amplitudes (r = -0.57), sum of the GH pulse areas (r = -0.55), interpulse mean GH concentration (r = -0.53), and number of GH pulses per 24 h (r = -0.53). In addition, GH-BP correlated positively with the mean time interval between pulses (r = 0.59). There was also a significant positive correlation (r = 0.75; P less than 0.001) between GH-BP and the subject's age-adjusted body mass index SD score (BMI-SDS). Each characteristic of 24-h GH release correlating inversely with GH-BP also correlated inversely with BMI-SDS (P less than 0.01 for all comparisons). GH-BP did not, however, correlate with plasma insulin-like growth factor-I levels, serum testosterone concentrations, or height SDS. Binding to the low affinity GH-BP (peak I) did not correlate significantly with any of the examined GH pulse attributes, BMI-SDS, or the degree of binding to the high affinity GH-BP (peak II). We conclude that an inverse relationship exists between the high affinity serum GH-BP and 24-h GH release in boys under normal physiological conditions. We speculate that abnormalities in this relationship probably also exist and may underlie some disorders of growth.

Adolescent↗
PubMed2005

Antagonist- and inverse agonist-driven interactions of the vitamin D receptor and the constitutive androstane receptor with corepressor protein.

Ligand-dependent signal transduction by nuclear receptors (NRs) includes dynamic exchanges of coactivator (CoA) and corepressor (CoR) proteins. Here we focused on the structural determinants of the antagonist- and inverse agonist-enhanced interaction of the endocrine NR vitamin D receptor (VDR) and the adopted orphan NR constitutive androstane receptor (CAR) from two species with the CoR NR corepressor. We found that the pure VDR antagonist ZK168281 and the human CAR inverse agonist clotrimazole are both effective inhibitors of the CoA interaction of their respective receptors, whereas ZK168281 resembled more the mouse CAR inverse agonist androstanol in its ability to recruit CoR proteins. Molecular dynamics simulations resulted in comparable models for the CoR receptor interaction domain peptide bound to VDR/antagonist or CAR/inverse agonist complexes. A salt bridge between the CoR and a conserved lysine in helix 4 of the NR is central to this interaction, but also helix 12 was stabilized by direct contacts with residues of the CoR. Fixation of helix 12 in the antagonistic/inverse agonistic conformation prevents an energetically unfavorable free floatation of the C terminus. The comparable molecular mechanisms that explain the similar functional profile of antagonist and inverse agonists are likely to be extended from VDR and CAR to other members of the NR superfamily and may lead to the design of even more effective ligands.

Amino Acid Sequence↗
PubMed1980

"Inverse substrates" for trypsin-like enzymes.

"Inverse substrates" for bovine thrombin and human plasmin were demonstrated. "Inverse substrates" for the enzymes are characterized as specific substrates in which the arrangement of site-specific group is reversed compared to that of normal substrate, e.g., a cationic center is included in their leaving group instead of being in their acyl moiety (K.Tanizawa, Y.Kasaba, Y.Kanaoka, J. Am. Chem. Soc. 99. 4485-4488). Kinetic characteristics of thrombin, plasmin and trypsin toward "inverse substrates" were compared. Based on these observations, differences in active centers of the trypsin homologs were discussed. Behavior of p- and m-hydroxyphenylguanidine derivatives as new "inverse substrates" for trypsin was also reported.

Animals↗
PubMed1989

A nonlinear least squares program, MULTI(FILT), based on fast inverse Laplace transform for microcomputers.

A nonlinear curve fitting program MULTI(FILT) into which the fast inverse Laplace transform (FILT) is incorporated was developed on a microcomputer. FILT is an algorithm for the numerical inversion of Laplace-transformed equations (image equations) to generate the corresponding real time courses. The pharmacokinetic models can be defined in the form of Laplace-transformed equations as a subroutine in MULTI(FILT). MULTI(FILT) achieves the numerical inversion of the defined image equations according to FILT and the subsequent curve-fitting of the inverse-transformed time courses to the experimental data points to estimate the pharmacokinetic parameters by the nonlinear least-squares method. MULTI(FILT) has a function to impose constraints on the pharmacokinetic parameters. In order to verify the reliability of MULTI(FILT), the pharmacokinetic parameters estimated by MULTI(FILT) were compared with those by MULTI using 100 time courses which were artificially generated according to the Monte Carlo method, based on data for theophylline and bishydroxycoumarin. The estimated pharmacokinetic parameters by MULTI(FILT) agreed with those by MULTI. Thus, it is suggested that FILT, developed in the field of electronic technology, is also useful in the pharmacokinetic field.

Mathematics↗
PubMed2004

Diagnostic use of T2-weighted inversion-recovery magnetic resonance imaging in acute coronary syndromes compared with 99mTc-Pyrophosphate, 123I-BMIPP and 201TlCl single photon emission computed tomography.

BACKGROUND: The incidence of missed diagnoses of acute cardiac ischemia in the emergency department could be reduced by a new imaging modality. In the present study, the clinical significance of (99m)Tc-pyrophosphate (PYP), (123)I-beta-methyl-p-iodephenyl-pentadecanoic acid (BMIPP), (201)TlCl scintigraphy (imaging) and T2-weighted inversion-recovery magnetic resonance imaging (MRI) for the detection of culprit lesion in patients with acute coronary syndromes (ACS) was compared. METHODS AND RESULTS: The study group comprised 18 patients with ACS: 12 patients with acute myocardial infarction (AMI) (11 males; mean age, 63+/-11 years) and 6 patients with unstable angina (UA) (3 males, mean age, 67+/-5 years). Of the 12 patients with AMI, 10 underwent (201)TlCl and PYP single photon emission computed tomography (SPECT) studies as a dual-energy acquisition ((201)TlCl/PYP) and 8 underwent (201)TlCl SPECT within 1 week of the BMIPP study. All 18 patients underwent BMIPP SPECT and MRI. The MRI pulse sequence was black blood turbo short-inversion-time inversion recovery (STIR) (breath-hold T2-weighted studies). The T2-weighted inversion-recovery MRI showed higher sensitivity and negative predictive value than PYP and (201)TlCl, and higher specificity and positive predictive value than BMIPP and (201)TlCl. The area under the receiver-operating characteristic curve for PYP, BMIPP, (201)TlCl and MRI was 0.787, 0.725, 0.731 and 0.878, respectively. The difference between the areas of MRI and BMIPP was significant (p<0.05). CONCLUSION: Accurate detection of culprit lesion is improved by using MRI rather than BMIPP, particularly for patients with ACS.

Acute Disease↗
PubMed1983

Two electrocardiographic patterns with or without transient T-wave inversion during recovery periods of variant anginal attacks.

Continuous electrocardiographic recordings during anginal attacks in patients with variant angina were reviewed. Twenty-seven attacks in 15 patients were associated with transient T-wave inversion during recovery periods of angina (type A), while in another 69 attacks in 28 patients there was no T-wave inversion (type B). In none of the patients was there an ischemic T-wave inversion during angina-free periods. Both the maximum elevation (0.79 +/- 0.57 mV) and duration (5.3 +/- 1.2 min) of ST-segment deviation of type A attacks were significantly higher and longer than those of type B (0.44 +/- 0.27 mV, 2.8 +/- 1.4 min). Ten patients who had both type A and type B attacks one time or the other were selected for further evaluation. In these 10, the duration of ST-segment elevation was significantly longer during type A attacks (5.2 +/- 1.2 min, n = 18) than during type B attacks (2.7 +/- 1.2 min, n = 20) but there was no significant difference in the maximum ST-segment elevation. Giant U-wave inversion appeared in 15% of the type A attacks, but never in type B. Therefore, the T-wave abnormality related to ischemic episodes in patients with variant angina seems to be associated with more severe ischemia of longer duration than milder episodes of transient ischemia.

Adult↗
PubMed1989

Spatial distribution of exercise-induced ST-segment depression and U-wave inversion in identifying the ischemic site in patients with coronary artery disease.

Eighty-seven unipolar electrocardiograms were simultaneously recorded before and after symptom-limited treadmill exercise in 75 patients with coronary artery narrowing (greater than equal to 70%) and without previous myocardial infarction. Body surface distributions of ST segment depression were divided into 3 types; upper, lower, and diffuse types. Body surface distributions of U-wave inversion were divided into 2 types; upper, and lower types. These distribution patterns were compared with the location of ischemia determined by T1-201 exercise myocardial perfusion imaging. For ST-segment depression, a considerable number of patients had diffuse-type ST depression, whether the site of ischemia was anterior (22/32, 69%), inferior (18/27, 67%) or both (5/5, 100%). However, upper-type ST depression was associated with anterior ischemia, and lower-type ST depression, with inferior ischemia. The sensitivity and specificity of the spatial distribution of ST depression in identifying the myocardial ischemic site were 27% and 95% for anterior ischemia. The sensitivity and specificity of the spatial distribution of St depression in identifying the myocardial ischemic site were 27% and 95% for anterior ischemia respectively, and 28% and 88% for inferior ischemia, respectively. The incidence of U-wave inversion was moderate (29/75, 39%), but the distribution pattern was specific for the site of ischemia; upper-type U inversion associated with anterior ischemia, and lower type with inferior ischemia. The sensitivity and specificity were 59% and 100% for anterior ischemia respectively, and 22% and 100% for inferior ischemia respectively. By a combination of ST-depression and U-inversion, the sensitivity and specificity were 78% and 95% for anterior ischemia, and 44% and 88% for inferior ischemia. Body surface electrocardiographic mapping provided important information in the non-invasive diagnosis of the site of myocardial ischemia.

Adult↗
PubMed2006

Inverse agonist activity of sarpogrelate, a selective 5-HT2A-receptor antagonist, at the constitutively active human 5-HT2A receptor.

Mutations producing constitutively active G-protein coupled receptors have been found in the pathophysiology of several diseases, implying that inverse agonists at the constitutively active receptors may have preferred therapeutic applications. Because of the involvement of 5-HT(2A) receptors in mediating many cardiovascular diseases, constitutively active mutants of the 5-HT(2A) receptor may be responsible for the disease states. Thus, the purpose of the present study was to investigate the inverse agonist activity of sarpogrelate, a selective 5-HT(2A)-receptor antagonist, and its active metabolite, M-1; and we compared their activities with those of other 5-HT(2A)-receptor antagonists such as ritanserin, ketanserin, and cyproheptadine. Using a constitutively active mutant (C322K) of the human 5-HT(2A) receptor, we demonstrated that like other 5-HT(2A)-receptor antagonists, sarpogrelate acts as a potent inverse agonist by significantly reducing basal inositol phosphate levels. However, there were no significant differences between sarpogrelate and other 5-HT(2A)-receptor antagonists for their inverse agonist activity. Compared with the wild type receptor, mutant receptor displayed significantly higher affinity for 5-HT and lower affinity for sarpogrelate. These results indicate that stabilization of the inactive conformation of the 5-HT(2A) receptor may be a key component of the mechanism of action of sarpogrelate.

Binding, Competitive↗
PubMed2001

Hepatic vein transit time of an ultrasound contrast agent: simplified procedure using pulse inversion imaging.

The aim of this study was to ascertain whether a new ultrasound technique, namely pulse inversion imaging, could assess the arrival of a contrast agent in the hepatic veins, and to describe possible advantages of this procedure in determining transit time over a previously described method based upon spectral Doppler quantification. 15 subjects were scanned using pulse inversion imaging. A bolus injection of 2.5 g Levovist (Schering AG, Berlin, Germany) 300 mg x ml(-1) was given into an antecubital vein. Median transit times of 16 s (range 14-20 s) were found in patients with liver cirrhosis (n=4), 22 s (range 16-27 s) in patients with focal liver lesions (n=8) and 31 s (range 30-32 s) in control subjects (n=3). The maximum interobserver variation was 2 s and the maximum intraobserver variation was 3 s (n=10). Transit time was assessed by both pulse inversion imaging and spectral Doppler quantification in six patients. Comparison of the two methods showed transit times within 2 s apart in five patients and within 5 s apart in one patient. In conclusion, it is possible to assess transit time using pulse inversion imaging. This method is simpler than a previously described method requiring computer analysis. Moreover, several liver veins can be assessed simultaneously. Different transit times were observed in different liver veins in two patients with liver tumours. A short transit time (<27 s) appears to be found only in patients with liver disease. After transit time assessment, it is possible to use the injected contrast agent for late phase imaging of the liver parenchyma.

Adult↗
PubMed2006

Inversion of irradiance and remote sensing reflectance in shallow water between 400 and 800 nm for calculations of water and bottom properties.

What we believe to be a new inversion procedure for multi- and hyperspectral data in shallow water, represented by the subsurface irradiance and remote sensing reflectance spectra, was developed based on analytical equations by using the method of nonlinear curve fitting. The iteration starts using an automatic determination of the initial values of the fit parameters: concentration of phytoplankton and suspended matter, absorption of gelbstoff, bottom depth, and the fractions of up to six bottom types. Initial values of the bottom depth and suspended matter concentration are estimated analytically. Phytoplankton concentration and gelbstoff absorption are initially calculated by the method of nested intervals. A sensitivity analysis was made to estimate the accuracy of the entire inversion procedure including model error, error propagation, and influence of instrument characteristics such as noise, and radiometric and spectral resolution. The entire inversion technique is included in a public-domain software (WASI) to provide a fast and user-friendly tool of forward and inverse modeling.

Journal Article↗
PubMed2006

Influence of fiber optic probe geometry on the applicability of inverse models of tissue reflectance spectroscopy: computational models and experimental measurements.

Accurate recovery of tissue optical properties from in vivo spectral measurements is crucial for improving the clinical utility of optical spectroscopic techniques. The performance of inversion algorithms can be optimized for the specific fiber optic probe illumination-collection geometry. A diffusion-theory-based inversion method has been developed for the extraction of tissue optical properties from the shape of normalized tissue diffusion reflectance spectra, specifically tuned for a fiber probe that comprises seven hexagonally close-packed fibers. The central fiber of the probe goes to the spectrometer as the detecting fiber, and the surrounding six outer fibers are connected to the white-light source as illumination fibers. The accuracy of the diffusion-based inversion algorithm has been systematically assessed against Monte Carlo (MC) simulation as a function of probe geometry and tissue optical property combinations. By use of this algorithm, the spectral absorption and scattering coefficients of normal and cancerous tissue are efficiently retrieved. Although there are significant differences between the diffusion approximation and the MC simulation at short source-detector (SD) separations, we show that with our algorithm the tissue optical properties are well retrieved within the SD separation of 0.5-3 mm that is compatible with endoscopic specifications. The presented inversion method is computationally efficient for eventual real-time in vivo tissue diagnostics application.

Computer Simulation↗
PubMed2003

Probe gain with population inversion in a four-level atomic system with vacuum-induced coherence.

For a four-level atomic system with a doublet of closely spaced levels, we find that, owing to the coherence that results from the vacuum of the radiation field, population trapping at excited levels and probe gain with population inversion can be achieved with weak incoherent pumping. This gain is different from both the conventional lasing gain and gain without inversion in that there exists population inversion on probe transitions but the inversion is achieved by the vacuum-induced coherence.

Journal Article↗
PubMed1992

Androgens in relation to prenatal development and postnatal inversion of the gubernacula in rats.

Exposure of male rats to the anti-androgen flutamide during fetal life, from day 10 after conception to the day of birth, allowed quantitatively unaltered development of the gubernacula. Apparently, androgens play no important role or no role at all in their growth. Castration of newborn male rats did not interfere with the inversion during further postnatal life of the gubernacula to create the muscular parts of the scrotum (cremaster muscles). Prenatal exposure to flutamide, followed by castration immediately after birth, also allowed gubernacular inversion and cremaster muscle growth. Neonatal administration of testosterone, after castration at birth, did not enhance gubernacular inversion or promote cremaster muscle growth in infancy or during adulthood. Apparently, postnatal gubernacular inversion and cremaster muscle growth are independent not only of androgens, but also of all testis hormones. Neonatal administration of the potent androgen 5 alpha-dihydrotestosterone propionate suppressed gonadotrophin secretion and, in intact males, inhibited testicular growth. Administration from the day of birth to day 33 delayed testicular descent and enhanced growth of the genital apparatus, but did not affect the size of the cremaster muscles. These experiments indicate that androgens are not involved in the processes that create the cavities into which testes descend to acquire their full reproductive potential.

Androgens↗
PubMed2000

The role of the use of different host plants in the maintenance of the inversion polymorphism in the cactophilic Drosophila buzzatii.

Inversion polymorphisms often have been associated with fitness variation. Cactophilic Drosophila buzzatii has been used widely for the study of the maintenance of chromosomal variation. The purpose of this paper is to address the relative importance of variable selection regimes associated with the use of three different host cacti and antagonistic pleiotropy in the maintenance of chromosomal variation. Using homokaryotypic stocks derived from several lines homozygous for four second-chromosome arrangements, we show that inversions significantly affect first-instar larva to adult viability (VT), developmental time (DT) and adult thorax length (TL). We also show that the effects of inversions on DT and VT are dependent on the cactus rearing media. The effects of polymorphic gene arrangements on life-history traits suggest the existence of trade-offs between early and late fitness components. The dosage of arrangement 2st, the ancestral gene order, was negatively correlated with DT and TL, whereas flies carrying the derived arrangements 2j and 2jq7 had longer DTs and larger TLs. Arrangements 2st and 2jq7 increased viability, at least in one of the cactus media tested. Our results suggest that environmental heterogeneity, as represented by the use of different cactus hosts and the trade-off between DT and TL, may be involved in the maintenance of the polymorphism. In addition, our data suggest that the chromosomal phylogeny may be decoupled from the evolution of the genes affecting life-history traits linked to the inversion system.

Animals↗
PubMed2005

"Over-the-wire" inversion saphenectomy: a simple, minimally invasive vein harvesting technique for arterial bypass.

PURPOSE: To examine the feasibility and clinical outcome of a novel, minimally invasive technique for harvesting the great saphenous vein (GSV) for use in peripheral arterial bypass surgery. METHODS: Between May 2001 through March 2003, 27 patients (15 men; mean age 71+/-10 years) underwent extremity bypass procedures for limb salvage (88%) or disabling claudication (12%) using the inversion technique to harvest the GSV. The veins were turned "inside out" using a unique catheter and guidewire system. With the endothelial surface exposed, valve leaflets were excised, and adherent thrombus was washed away. Veins were inverted again to turn the endothelial surface back inside the lumen for use as a bypass conduit. RESULTS: Inversion vein harvesting and arterial bypass were completed in 24 (89%) of 27 patients; 2 patients were treated with synthetic grafts because of small GSVs. Another patient was found after vein harvesting to have inadequate arterial outflow despite a good quality conduit. The average vein length was 45+/-10 cm; a mean 4+/-1 incisions were made, including those for arterial exposure. Incisions made to divide vein tributaries averaged 2 cm in length. Duration of vein harvesting was 25 minutes (range 5-80). Wound complications were minor (2 hematomas, 2 cases of erythema, 2 seromas). Of 6 grafts that occluded after 30 days, 5 involved small-diameter vein grafts (< 3.5 mm). At a mean 12 months, primary and assisted primary graft patency rates were 88% (14/16) and 94% (15/ 16), respectively, for grafts with minimum diameters > or = 4 mm versus 38% (3/8) primary patency for veins < 4 mm (n = 8, p < 0.001). The limb salvage rate was 92% (22/24). CONCLUSIONS: Over-the-wire inversion saphenectomy is a simple and reliable minimally invasive technique for arterial bypass. Incisions are small and cosmetically superior to those of the traditional long incision method. One-year follow-up suggests that grafts harvested by inversion technique have excellent durability when the minimum vein diameter is > or = 4 mm, as determined by preoperative vein mapping.

Aged↗
PubMedDate not supplied

Inverse analyses of transport of chlorinated hydrocarbons subject to sequential transformation reactions.

Chemical and biological transformations can significantly affect contaminant transport in the subsurface. To better understand such transformation reactions, an equilibrium-nonequilibrium sorption transport model, HYDRUS-1D, was modified by including inverse solutions for multiple breakthrough curves resulting from the transport of solutes undergoing sequential transformations. The inverse solutions were applied to miscible-displacement experiments involving dissolved concentrations of trichloroethylene (TCE) undergoing reduction and/or transformations in the presence of zero-valent metal porous media (i.e., iron or copper-coated iron filings) to produce ethylene. The inverse model solutions provided a reasonable description of the transport and transformation processes. Simultaneous fitting of multiple breakthrough curves of TCE and ethylene placed additional constraints on the inverse solution and improved the reliability of parameter estimates. Confidence intervals of optimized parameters were reduced significantly in comparison with those obtained by fitting TCE breakthrough curves independently. Further evidence for accurate parameter estimates was given when the parameter values agreed with previously reported values from independent batch and degradation experiments. Optimized values of the normalized degradation rates for the equilibrium (1.4 x 10(-4) to 7.2 x 10(-5) L h(-1)m(-2)) and nonequilibrium (1.2 x 10(-4) to 5.5 x 10(-5)L h(-1)m(-2)) models compared well with values (0.03 to 6.5 x 10(-5) L h(-1) m(-2)) obtained from previous studies. The estimated TCE-iron sorption coefficients (0.52 to 2.85 L kg(-1)) were also consistent with a previously reported value (1.47 L kg(-1)).

Biotransformation↗
PubMed1989

The diagnosis of pulmonary nodules: comparison between standard and inverse digitized images and conventional chest radiographs.

We compared plain chest radiographs, standard (bones white) digitized images, and inverse-intensity (bones black) images to determine their ability to identify pathologically confirmed malignant pulmonary nodules. The images were digitized by using a photo-optical laser scanner and were displayed on a 1024 x 1024 x 8 bit system capable of operator-controlled magnification (2x or 4x) and nonlinear (logarithmic/exponential) contrast transformation in both standard and inverse-intensity modes. Receiver-operator curve analysis was used to study the detection performance of six observers who viewed 40 images obtained in 15 normal subjects and 25 abnormal subjects. There was no statistically significant difference in the area under the ROC curve between the standard digital images and the plain chest radiographs. However, ROC areas were significantly greater (p less than or equal to .05) for inverse-intensity digital images when compared with either standard-intensity digital images or plain chest radiographs. These results suggest that inverse-intensity images may have some advantages in the detection of pulmonary nodules.

Humans↗