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M Laruelle

Publications and source records attributed to M Laruelle.

At least 73 records · Page 4Linked to original sources

Euphorigenic doses of cocaine reduce [123I]beta-CIT SPECT measures of dopamine transporter availability in human cocaine addicts.

The in vivo potency of euphorigenic doses of intravenous cocaine for displacing [123I]beta-CIT ([123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane) binding to striatal dopamine transporters (DAT) was assessed in human cocaine addicts using single photon emission computed tomography (SPECT). Cocaine-dependent subjects (n = 6) were injected with [123I]beta-CIT and imaged 24 h later under equilibrium conditions. Sequential cocaine infusions (0.28 +/- 0.03 and 0.56 +/- 0.07 mg/kg) produced significant (P < 0.0005) reductions in the specific to non-specific equilibrium partition coefficient, V3" (6 +/- 6 and 17 +/- 3%), a measure proportional to DAT binding potential. Regression analysis of the logit transformed data enabled reliable determination of the Hill coefficient (0.51) and 50% displacement (ED50) dose of cocaine (2.8 mg/kg). These preliminary data suggest that cocaine produces behavioral effects in humans at measurable levels of DAT occupancy.

Carrier Proteins↗

Characterization of the dopamine transporter in nonhuman primate brain: homogenate binding, whole body imaging, and ex vivo autoradiography using [125I] and [123I]IPCIT.

IPCIT [2 beta-carboisopropoxy-3 beta-(4-iodophenyl)tropane; also designated RTI-121] is the isopropyl ester of beta-CIT [2 beta-carbomethoxy-3 beta-(4-iodophenyl) tropane]. Although beta-CIT binds to dopamine (DA), serotonin (5-HT) and norepinephrine (NE) transporters, IPCIT has been reported to be selective for the DA transporter. IPCIT was labeled with 125I and its receptor binding to membranes prepared from baboon striatum was compared with that of [125I] beta-CIT. These studies confirmed the relative selectivity of IPCIT for the DA transporter in comparison to 5-HT and NE transporters. The nonspecific binding of [125I]IPCIT was almost four times greater than that of [125I] beta-CIT. The biodistribution of IPCIT was examined in two baboons with whole body imaging for 24-30 h after administration of 3 mCi of 123I-labeled tracer. The brain uptake peaked within the first hour at 9.2% of the injected dose and the majority of activity in the body cleared through the hepatobiliary system. The distribution of activity within the brain was examined with ex vivo autoradiography in one monkey injected with [123I]IPCIT. Activity was concentrated in the caudate and putamen and had values of 5 and 7 microCi/cm3 per microCi/g, respectively. The distribution in brain regions receiving moderately dense serotonergic innervation (e.g. superior colliculus and thalamus) had levels of activity equivalent to that in cerebellum. This study confirmed the in vitro and in vivo selectivity of IPCIT for the DA transporter but also showed that [125I]IPCIT had higher in vitro nonspecific binding than [125I] beta-CIT.

Animals↗

Age-related decline in striatal dopamine transporter binding with iodine-123-beta-CITSPECT.

UNLABELLED: The effect of age on human striatal dopamine (DA) transporters was investigated with SPECT using the ligand [123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT). METHODS: Iodine-123-beta-CIT binding in the striatum was examined in 28 healthy human subjects (14 men, 14 women) who ranged in age from 18 to 83 yr. Following injection with [123I]beta-CIT (mean +/- s.d. = 9.9 +/- 1.2 mCi), subjects were scanned with the brain-dedicated CERASPECT camera. A reconstructed transaxial slice 13.3-mm thick at the level of maximal striatal activity was used to determine tracer uptake in striatal and occipital regions of interest. The stability of regional uptake on Day 2 (approximately 18-24 hr postinjection) permitted estimation of the specific-to-nondisplaceable equilibrium partition coefficient: V3", calculated as (striatal--occipital)/occipital uptake at equilibrium. RESULTS: Values of V3" ranged from 3.6 to 11.4 for this sample (6.7 +/- 1.9). V3" showed a significant inverse correlation with age (r = -0.73, n = 28, p < 0.0001). Linear regression analysis revealed that V3" declined by 51% over the age range studied or approximately 8% per decade. CONCLUSION: These findings confirm postmortem reports of dopamine transporter loss with aging. In vivo methodologies may permit the age-related degeneration of dopamine nerve terminals to be studied in relation to the cognitive and motor deficits that occur in normal aging.

Adolescent↗

SPECT imaging of striatal dopamine release after amphetamine challenge.

UNLABELLED: This study assesses the feasibility of using SPECT to image intrasynaptic dopamine release in human striatum following dextroamphetamine sulfate (d-amphetamine) challenge testing. METHODS: A bolus plus constant infusion administration schedule of the D2 receptor radiotracer [123I]iodobenzamide ([123I]IBZM) was used to obtain a stable baseline for reliable quantitation of the d-amphetamine effect. Eight healthy subjects first underwent a controlled experiment to demonstrate that stable levels of striatal and occipital activities could be maintained from 150 to 420 min during programmed infusion of the tracer. Next, seven subjects underwent the experiment with d-amphetamine. The experimental conditions were identical except that 0.3 mg/kg amphetamine was injected intravenously at 240 min. The behavioral effects of d-amphetamine were measured by self-rating on the following analog scales: euphoria, alertness, restlessness and anxiety. RESULTS: The d-amphetamine injection induced a 15% +/- 4% (mean +/- s.d.) decrease in D2 receptor availability, measured as the specific-to-nonspecific equilibrium partition coefficient (V3"). The d-amphetamine injection induced marked increase in euphoria, alertness and restlessness scores. The intensity of these behavioral responses correlated with the decrease in D2 availability measured with SPECT. In contrast, the anxiety response was milder and not correlated with the decrease in D2 availability. CONCLUSION: These studies demonstrate the feasibility of using [123I]IBZM programmed infusion and SPECT imaging to measure endogenous dopamine release after d-amphetamine challenge and to study brain neurochemical correlates of emotions.

Adolescent↗

Reproducibility of SPECT measurement of benzodiazepine receptors in human brain with iodine-123-iomazenil.

UNLABELLED: Iodine-123-iomazenil is a SPECT radiotracer used to image and quantify benzodiazepine receptors. The reproducibility of the measurement of benzodiazepine receptors in human brain with [123I]iomazenil and SPECT was investigated with a test/retest paradigm. METHODS: Six subjects underwent two experiments during a 1-wk interval. Iodine-123-iomazenil was injected as a single bolus (12 mCi). The time-activity curves of the tracer in the arterial plasma were measured and corrected for metabolites. Regional time-activity curves of five brain regions were measured with the CERASPECT camera for 145 min postinjection with serial 2-min acquisitions. Data were analyzed using three kinetic models that included a two-compartment model, an unconstrained three-compartment model and a three-compartment model with a constraint on the nondisplaceable compartment. RESULTS: The results from the various analyses and fitting strategies were compared. The variability (average absolute difference between test and retest, expressed as a percentage of the mean of both measurements) was 10% to 17%, depending on the outcome measure and the fitting procedure. The most reproducible outcome measure was the regional tracer distribution volume relative to the total arterial concentration (VT'). VT' showed an average regional variability of 10% +/- 2%, with an intraclass correlation coefficient of 0.81. CONCLUSION: SPECT measurement of regional [123I]iomazenil VT' is reproducible and reliable. The use of regional ratios results in a significant loss of information.

Adult↗

Simplified multidose preparation of iodine-123-beta-CIT: a marker for dopamine transporters.

UNLABELLED: Iodine-123-beta-CIT is a SPECT radioligand for dopamine and 5-HT transporters with potential use in Parkinson's disease, schizophrenia and cocaine addiction studies. At present, preparation of no-carrier-added (NCA) [123I] beta-CIT is achieved by iododestannylation of a trialkylstannyl precursor with sodium [123I]iodide in the presence of oxidizing agent, followed by preparative HPLC. The purpose of this study was to develop a faster and simpler method for the routine preparation of this radiopharmaceutical. METHODS: Purification of the labeled compound was accomplished by solid phase extraction (SPE) with a C-18 Sep-Pak Light cartridge, which removed unreacted iodide, reaction reagents, polar side products and tributylstannyl precursor. The tributylstannyl precursor was preferred as starting material over the trimethylstannyl precursor due to its higher lipophilicity, allowing better separation of the labeled product and precursor. A TLC method was developed to assess the radiochemical purity of the final product. RESULTS: The method produced [123I] beta-CIT in high radiochemical yields (75% +/- 4%), with high radiochemical purity (> or = 98%) and specific activity (> 67000 Ci/mmole), in 1.5 hr. The final formulation was sterile and pyrogen free. CONCLUSION: The results obtained by solid phase extraction are consistent with those obtained by the HPLC method; with the advantage that the SPE method does not require solvent extraction, evaporation under reduced pressure or HPLC purification.

Binding Sites↗

In vivo quantification of dopamine D2 receptor parameters in nonhuman primates with [123I]iodobenzofuran and single photon emission computerized tomography.

[123I]Iodobenzofuran ([123I]IBF) is a new single photon emission computed tomography (SPECT) tracer for visualization of the dopamine D2 receptors. A tracer constant infusion paradigm was developed to measure the binding potential, density (Bmax) and affinity (KD) of the dopamine D2 receptor in baboons. Three baboons underwent both a single bolus and a constant infusion study. For the single bolus experiment, the striatal binding potential (134 +/- 24 ml g-1, mean +/- S.D.) was derived by kinetic analysis. For the constant infusion experiments, the striatal binding potential (127 +/- 16 ml g-1) was derived by equilibrium analysis. The two sets of experiments thus provided consistent data. Low specific activity constant infusion experiments were performed to measure KD (0.08 nM) and Bmax (12.7 nM). In vitro experiments carried out at 37 degrees C with [125I]IBF on rat striatal homogenate membranes provided results in agreement with the SPECT data. These studies suggested the feasibility of quantitation of dopamine D2 receptor parameters with [123I]IBF SPECT imaging.

Animals↗

Comparison of three high affinity SPECT radiotracers for the dopamine D2 receptor.

The regional brain distribution and pharmacological specificity of three high affinity tracers for the dopamine (DA) D2 receptor: [123I]IBF, [123I]epidepride, and [123I]2'-ISP were assessed by SPECT imaging of non-human primates. The ratios of striatal-to-occipital activities at the time of peak striatal uptake were 2.2, 6.3 and 1.7, respectively. From the peak striatal activities, washout rates were 33, 4 and 16%/h for [123I]IBF, [123I]epidepride and [123I]2'-ISP, respectively. The reversibility of the striatal uptake of all three agents was demonstrated by the rapid displacement induced by the dopamine D2 selective antipsychotic agent raclopride, which increased washout rates to 96, 58 and 43%/h. The administration of d-amphetamine, which induces release of dopamine, had no noticeable effect on [123I]epidepride but increased the washout rate of [123I]IBF. These results suggest that, among these three agents, [123I]epidepride is the superior tracer for in vivo displacement studies because of its slow washout and high target-to-background ratios. However, for tracer kinetic modeling, [123I]IBF may be the superior agent because of its early time of peak uptake and its higher target-to-background ratios than [123I]2'-ISP.

Animals↗

Pharmacokinetics of the three radioiodinated dopamine D2 receptor ligands [123I]IBF, [123I]epidepride and [123I]2'-ISP in nonhuman primates.

The pharmacokinetics of three radioiodinated high affinity dopamine D2 receptor binding ligands-two benzamide neuroleptics (IBF and epidepride) and the butyrophenone neuroleptic analog 2'-iodospiperone (2'-ISP)-were measured in nonhuman primates. [123I]IBF and [123I]epidepride were prepared by iododestannylation of the corresponding tributylstannyl derivative, whereas [123I]2'-ISP was labeled by (NH4)2SO4 mediated iodide for bromide exchange starting from 2'-bromospiperone. Labeled products were purified by HPLC and were obtained in > 93% radiochemical purity and > 7000 Ci/mmol sp. act. After i.v. injection in baboons, serial arterial plasma samples were extracted with ethyl acetate (IBF and epidepride) or denatured with methanol (2'-ISP) and analyzed by HPLC. For IBF, plasma levels of parent compound dropped to 50% of the plasma activity within 20 min post injection and the major radiometabolite was lipophilic. For epidepride, it took 30-40 min for parent content to reach 50% and the major radiometabolite was polar. For 2'-ISP, parent composition dropped to 60% after about 15 min. Arterial input curves for IBF and epidepride fit three-exponential models with terminal half-life of 54-76 and 50-59 min, respectively. Whole body images were acquired using the conjugate counting method. The distribution of all three agents was qualitatively similar, with major excretion through the hepatobiliary route. Peak whole brain uptake, observed within 20 min for all three tracers, was estimated as 7% injected dose for [123I]IBF, 8% for [123I]epidepride and 5% for [123I]2'-ISP.

Animals↗

Graphical, kinetic, and equilibrium analyses of in vivo [123I] beta-CIT binding to dopamine transporters in healthy human subjects.

The in vivo kinetics of the dopamine (DA) transporter probe 123I-labeled 2 beta-carboxymethoxy-3 beta-(4-iodophenyl) tropane ([123I] beta-CIT) in striatum was investigated with single-photon emission computerized tomography (SPECT) in five healthy human subjects. The aim of this study was to derive an adequate measure of the DA transporter density that would not be affected by regional cerebral blood flow or peripheral clearance of the tracer. SPECT data were acquired on the day of injection (day 1) from 0 to 7 h and on the following day (day 2) from 19 to 25 h. Arterial sampling on day 1 was used to measure the input function. Graphical, kinetic, and equilibrium analyses were evaluated. Graphical analysis of day 1 data, with the assumption of negligible dissociation of the tracer-receptor complex (k4 = 0), was found to be blood flow-dependent. A three-compartment kinetic analysis of day 1 data were performed using a three (k4 = 0)- and a four (k4 > 0)-parameter model. The three-parameter model estimated the konBmax product at 0.886 +/- 0.087 min-1. The four-parameter model gave a binding potential (BP) of 476 ml g-1, a value consistent with in vitro measurements. The stability of the regional uptake on day 2 allowed direct measurement of the specific to nonspecific equilibrium partition coefficient (V3" = k3/k4 = 6.66 +/- 1.54). Results of day 1 kinetic analysis and day 2 equilibrium analysis were well correlated among subjects. Simulations indicated that the error associated with the day 2 equilibrium analysis was acceptable for plasma tracer terminal half-lives > 10 h. We propose the equilibrium analysis on day 2 as the method of choice for clinical studies since it does not require multiple scans or the measurement of the arterial plasma tracer concentrations.

Adult↗

SPECT quantification of [123I]iomazenil binding to benzodiazepine receptors in nonhuman primates: I. Kinetic modeling of single bolus experiments.

The aim of this work was to study the feasibility and reproducibility of in vivo measurement of benzodiazepine receptors with single photon emission computerized tomography (SPECT) in the baboon brain. Arterial and brain regional activities were measured for 420 min in three baboons after single bolus injection of the benzodiazepine antagonist [123I]iomazenil. Data were fit to a three-compartment model to derive the regional binding potential (BP), which corresponds to the product of the receptor density, (Bmax) and affinity (1/KD). Regional BP values (from 114 in striatum to 241 in occipital) were in good agreement with values predicted from in vitro studies. Constraining the regional volume of distribution of the nondisplaceable compartment to the value measured during tracer constant infusion experiments in baboons (Laruelle et al., 1993) improved the identifiability of the rate constants. Each experiment was repeated to investigate the reproducibility of the measurement. The regional average reproducibility was 10 +/- 5%, expressed as coefficient of variation (CV). Results of equilibrium analysis at peak uptake were in good agreement with results of kinetic analysis. Empirical counts ratio methods were found to be poorly sensitive to benzodiazepine receptor density. These studies suggest the feasibility of quantitative measurement of benzodiazepine receptors by kinetic analysis of SPECT data and the inadequacy of empirical methods of analysis, such as counts ratios, to evaluate differences in receptor density.

Animals↗

SPECT quantification of [123I]iomazenil binding to benzodiazepine receptors in nonhuman primates: II. Equilibrium analysis of constant infusion experiments and correlation with in vitro parameters.

In vivo benzodiazepine receptor equilibrium dissociation constant, KD, and maximum number of binding sites, Bmax, were measured by single photon emission computerized tomography (SPECT) in three baboons. Animals were injected with a bolus followed by a constant i.v. infusion of the high affinity benzodiazepine ligand [123I]iomazenil. Plasma steady-state concentration and receptor-ligand equilibrium were reached within 2 and 3 h, respectively, and were sustained for the duration (4-9 h) of the experiments (n = 15). At the end of the experiments, a receptor saturating dose of flumazenil (0.2 mg/kg) was injected to measure nondisplaceable activity. Experiments were carried out at various levels of specific activity, and Scatchard analysis was performed for derivation of the KD (0.59 +/- 0.09 nM) and Bmax (from 126 nM in the occipital region to 68 nM in the striatum). Two animals were killed and [125I]iomazenil Bmax and KD were measured at 22 and 37 degrees C on occipital homogenate membranes. In vitro values of Bmax (114 +/- 33 nM) and 37 degrees C KD (0.66 +/- 0.16 nM) were in good agreement with in vivo values measured by SPECT. This study demonstrates that SPECT can be used to quantify central neuroreceptors density and affinity.

Animals↗

Methyl 3 beta-(4-[125I]iodophenyl)tropane-2 beta-carboxylate in vitro binding to dopamine and serotonin transporters under "physiological" conditions.

Methyl 3 beta-(4-[125I]iodophenyl)tropane-2 beta-carboxylate ([123I]beta-CIT) is a single photon emission computed tomographic radiotracer for in vivo labeling of dopamine (DA) and serotonin (5-HT) transporters. Single photon emission computed tomographic experiments in nonhuman primates showed that [123I]beta-CIT in vivo binding to DA transporters had a much slower washout than binding to 5-HT transporters. This observation was not predicted from previously published in vitro studies. These studies, performed at 22 degrees C in nonphysiological buffer, reported similar affinity of [125I]beta-CIT for DA and 5-HT transporters. We now report [125I]beta-CIT binding parameters to fresh rat membranes at 22 degrees C and 37 degrees C, in a buffer mimicking the composition of cerebrospinal fluid. At both temperatures, binding to DA transporters was best fit by a two-site model, whereas binding to 5-HT transporters was compatible with one population of sites. At 22 degrees C, [125I]beta-CIT showed similar affinity to high-affinity DA (0.39 nM) and 5-HT transporter sites (0.47 nM). Increasing the incubation temperature from 22 degrees C to 37 degrees C reduced binding to DA transporters by 60%, whereas binding to 5-HT transporters was only marginally affected. In vitro kinetic experiments failed to detect significant differences in on or off rates that could explain the observed in vivo kinetics. These experiments thus failed to explain [125I]beta-CIT in vivo uptake kinetics, suggesting the existence of specific factors affecting the in vivo situation.

Animals↗

Compartmental modeling of iodine-123-iodobenzofuran binding to dopamine D2 receptors in healthy subjects.

UNLABELLED: Iodine-123-labeled iodobenzofuran ([123I]IBF) is a potent dopamine D2 antagonist that provides good visualization of D2 receptors in primates. METHODS: The feasibility of measuring dopamine D2 binding potential with [123I]IBF in humans was evaluated in eight healthy subjects. Following [123I]IBF injection (6 mCi), scans were acquired every 10 min for 160 min with the brain-dedicated CERASPECT camera. Arterial activities were obtained at various intervals and corrected for the presence of metabolites by extraction followed by reverse-phase high-performance liquid chromatography. RESULTS: Reconstructed images exhibited adequate basal ganglia-to-occipital ratios (from 1.96 +/- 0.34 at 30 min to 3.54 +/- 0.71 at 150 min, mean +/- s.d.). Time-activity curves demonstrated reversibility, with peak basal ganglia uptake at 50 +/- 25 min. Regional time-activity curves were analyzed with kinetic three-compartment modeling and graphic analysis. In all subjects, D2 binding potential values, as derived by both methods, were in excellent agreement (mean +/- s.d. D2 binding potential = 129 +/- 51). An empiric count ratio method that does not require measurement of arterial tracer concentrations was evaluated and found to be in reasonable agreement with the model-derived binding potential. CONCLUSION: Iodine-131-IBF is a suitable ligand for quantitative studies of D2 receptor density with SPECT in humans.

Adult↗

SPECT measurement of benzodiazepine receptors in human brain with iodine-123-iomazenil: kinetic and equilibrium paradigms.

UNLABELLED: Iodine-123-iomazenil binding to benzodiazepine receptors in human brain was measured with SPECT using kinetic and equilibrium methods. METHODS: In the kinetic experiments (n = 6), regional time-activity curves after a single bolus injection of the tracer were fit to a three-compartment model to provide estimates of the rate constants K1 to k4. The binding potential (equal to the product of the receptor density and affinity) was derived from the rate constants. In the equilibrium method (n = 8), the tracer bolus injection was followed by a constant tracer infusion to induce a sustained equilibrium state. The regional equilibrium volume of distribution was calculated as the ratio of the regional brain concentration-to-the free parent tracer steady-state plasma concentration. In three experiments, a receptor-saturating dose of flumazenil was injected for direct measurement of the nondisplaceable compartment distribution volume. RESULTS: The kinetic and equilibrium method results were in good agreement in all regions investigated. Iodine-125-iomazenil binding potential measured in vitro in 12 postmortem samples was found to be consistent with SPECT in vivo measurements. CONCLUSION: These studies demonstrated the feasibility of quantification of receptor binding with SPECT.

Adult↗

Active and inactive enantiomers of 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane: comparison using homogenate binding and single photon emission computed tomographic imaging.

2 beta-Carbomethoxy-3 beta-(4-iodophenyl)tropane (beta-CIT; also designated RTI-55) is an analog of cocaine that has been developed as a single photon emission computed tomography radiotracer that labels dopamine and serotonin transporters. We have prepared the 125I- and 123I-labeled ([1R] "active" and [1S] "inactive") enantiomers of beta-CIT. Total homogenate binding of the 125I-labeled inactive isomer to baboon caudate and cortex was approximately equal to nonspecific binding of the active isomer in cortex and much lower than total binding of the active isomer in caudate. However, inactive isomer homogenate binding in caudate was somewhat higher than in cortex, and during single photon emission computed tomography scanning in vivo striatal (1S)-[123I]beta-CIT uptake was also slightly greater than in cortex. Following intravenous administration of the 123I-labeled enantiomers, the plasma clearances of the active and inactive enantiomers were not significantly different. Single photon emission computed tomography imaging demonstrated that a bolus dose of nonradioactive (1R)-beta-CIT rapidly displaced the uptake of (1R)-[123I]beta-CIT. In contrast, the brain uptake of (1S)-[123I]beta-CIT was not displaced by nonradioactive (1R)-beta-CIT using either a bolus ("kinetic") or bolus plus constant infusion ("equilibrium") paradigm for administration of the radiotracer. In scans with bolus administration of radiotracer, peak striatal uptake of the active isomer was approximately twice that of the inactive isomer. In comparison to the 123I-labeled active tracer, the inactive tracer showed earlier times to peak activity and faster washouts of activity in all brain regions. These studies demonstrate beta-CIT stereoselectivity using both homogenate binding and in vivo imaging and suggest that the inactive enantiomer may be a useful measure of the kinetics of both blood-brain barrier transport and nonspecific binding.

Animals↗

Single photon emission computed tomographic imaging demonstrates loss of striatal dopamine transporters in Parkinson disease.

[123I][(1R)-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane] ([123I]beta-CIT) labels dopamine transporters and is, therefore, a marker of neurons that degenerate in Parkinson disease. Single photon emission computed tomography imaging with [123I]beta-CIT showed that radioactivity in striatal regions in healthy subjects increased during a 2-day imaging study, whereas that in Parkinsonian patients peaked earlier at reduced levels relative to healthy subjects. Kinetic analyses of radioactivity in plasma and brain suggest that this decrease was due to an approximately 65% loss of target sites in patients compared with healthy subjects; greater losses occurred in putamen than in caudate. All patients showed lateralized differences in striatal uptake, with greater losses in the striatum contralateral to the side of the body with initial symptoms. These preliminary results suggest that [123I]beta-CIT is a marker for the loss of striatal dopamine terminals in patients with Parkinson disease. Single photon emission computed tomographic imaging with [123I]beta-CIT may be useful for early diagnosis of the disorder, for monitoring the progression of the disease, and for distinguishing the idiopathic disorder from other Parkinsonian syndromes with more widespread pathology.

Adult↗