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In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease.

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder associated with akinesia, tremor and rigidity. While the characteristic Lewy body pathology targets pigmented and other brainstem nuclei at post-mortem, activated microglia are found in both subcortical and cortical areas. [11C](R)-PK11195 is a positron emission tomography (PET) marker of peripheral benzodiazepine sites (PBBS), which are selectively expressed by activated microglia. We examined 18 PD patients clinically and with [11C](R)-PK11195 and [18F]-dopa PET. Compared to 11 normal controls, the PD patients showed significantly increased mean levels of [11C](R)-PK11195 binding in the pons, basal ganglia and frontal and temporal cortical regions. Eight PD patients were examined longitudinally, and their [11C](R)-PK11195 signal remained stable over 2 years. Levels of microglial activation did not correlate with clinical severity or putamen [18F]-dopa uptake. Our in vivo findings confirm that widespread microglial activation is associated with the pathological process in PD. The absence of significant longitudinal changes suggests that microglia are activated early in the disease process, and levels then remain relatively static, possibly driving the disease via cytokine release.

Aged↗

The Alzheimer's disease neuroimaging initiative.

With increasing life expectancy in developed countries, the incidence of Alzheimer's disease (AD) and its socioeconomic impact are growing. Increasing knowledge of the mechanisms of AD facilitates the development of treatment strategies aimed at slowing down or preventing neuronal death. AD treatment trials using clinical outcome measures require long observation times and large patient samples. There is increasing evidence that neuroimaging and cerebrospinal fluid and blood biomarkers may provide information that may reduce sample sizes and observation periods. The Alzheimer's Disease Neuroimaging Initiative will help identify clinical, neuroimaging, and biomarker outcome measures that provide the highest power for measurement of longitudinal changes and for prediction of transitions.

Aged↗

The inner dynamics of positive human-animal interactions: Investigating the roles of oxytocin, opioids, dopamine, serotonin and the proteome.

Research on the neuroendocrine basis of positive interactions has predominantly focused on oxytocin (OT), although dopamine (DA) and opioids also play crucial roles. Furthermore, these neurotransmitters are known to interact with each other but have seldom been studied concurrently. In this study, we quantified longitudinal changes in these neurotransmitters using a within-subject, 2 × 2 factorial design by varying human familiarity (familiar versus unfamiliar) and contact type (positive contacts versus ignoring) for 10 min human-pig interaction sessions. We obtained cerebrospinal fluid samples from 10 pigs through a spinal catheter 65 and 5 min before the test and at 10, 30, 60, 120 and 240 min after the start of the test. Samples at various timepoints were analysed for OT, DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), β-endorphin opioids concentrations, and using proteomics to explore novel protein candidates. Additionally, the duration and frequency of physical contacts initiated by the pig toward the human were coded from videos. The test condition (human familiarity × contact type) had a significant effect on the concentration of β-endorphin (F1118.59 = 4.45; P = 0.04) and 5-HIAA (F1,73.47 = 5.02; P = 0.03), and tended to affect the concentration of OT (F1, 119.8 = 3.19; P = 0.08) and DOPAC (F1,70.57 = 3.31; P = 0.07), but pairwise comparisons were not significant or showed complex changes. Specifically, OT was highest when the unfamiliar humans ignored the pig compared to when they delivered positive contacts (t70.6 = 3.31; P = 0.008), and β-endorphin tended to be higher after interacting with the familiar human compared to the unfamiliar humans (60 min post-test; t37.9 = 3.3; P = 0.055). There were only minor differences in the pigs' behaviour, suggesting that pigs seemed to perceive all test conditions as positive. Nevertheless, β-endorphin and OT appear to relate to different aspects of the interactions, possibly familiarity vs. novelty respectively.

Animals↗

Survival in idiopathic pulmonary fibrosis-cytotoxic agents compared to corticosteroids.

STUDY OBJECTIVE: To compare the survival of patients with IPF treated retrospectively with corticosteroids alone, to survival of patients treated with immunosuppressive and corticosteroids combined. DESIGN: Non-randomized retrospective cohort study. SETTING: Three tertiary centers in Brazil. PATIENTS: Eighty-two IPF patients were included. The diagnosis was confirmed by open lung biopsy in 48. Patients received either corticosteroids alone (group I) or cytotoxic agents in addition to corticosteroids (group II). MEASUREMENTS AND RESULTS: The primary end-point was mortality. Secondary outcome included longitudinal changes in FVC. Mean age was 66+/-8 years. FVC was 71+/-17% of predicted. There were 48 deaths during the study period (59%), 44 secondary to respiratory causes. From preliminary univariate analysis, for the group as a whole, worse survival was found to be associated with FVC% <70% of predicted (P=0.004), evidence of disease progression by follow-up FVC measurements (P=0.01), and pharmacologic treatment (P=0.014). Median survival was 25 months for the group I, and 45 months for the group II (Log-Rank=6.45, P=0.01). After adjusting for FVC > or =70% and<70% of predicted, there was evidence to indicate that survival was associated with recommended pharmacologic treatment only in patients with FVC> or =70% (Log Rank=6.84, P=0.009). CONCLUSIONS: The combination of immunosuppressive agents and prednisone results in better survival when compared to prednisone alone in patients with IPF. The benefit seems to occur only in patients with less severe disease, as reflected by FVC> or =70%.

Aged↗

Increase in gray matter and decrease in white matter volumes in the cortex during treatment with atypical neuroleptics in schizophrenia.

The effects of atypical antipsychotic treatment on the brain volume deficits associated with schizophrenia are poorly understood. We assessed the brain volumes of eleven healthy controls and 29 patients with schizophrenia, using magnetic resonance imaging at baseline and at follow-up after two years of treatment with atypical neuroleptics. Two groups of patients were analyzed: treatment-naïve patients (n = 17) and chronic treatment-resistant patients (n = 12). Treatment-naïve patients received risperidone during the follow-up period, whereas chronic patients received clozapine. Gray matter (GM) and white matter (WM) volumes in the frontal, parietal, occipital, and temporal lobes were measured. Contrary to the controls, both groups of patients presented GM increases and WM decreases in the parietal and occipital lobes (p < .005). Frontal GM also increased in the chronic group with clozapine. There was a significant (p < .001) inverse relationship between the baseline volumes (GM deficit/WM excess) and the longitudinal change. These GM and WM changes were not related to changes in weight. Thus, treatment with risperidone and clozapine in schizophrenia may have an effect on gray and white matter volume and needs further exploration.

Adult↗

Predictors of improvement in social support: Five-year effects of a structured intervention for caregivers of spouses with Alzheimer's disease.

Those who provide care at home for a spouse with Alzheimer's disease (AD) endure considerable challenges, including social isolation and increasing caregiving responsibilities. We examine the extent to which an intervention that helps spouse-caregivers mobilize their social support network, helps them better adapt to the caregiving role. We used detailed social support information collected from 200 spouse-caregivers participating in a randomized, controlled trial of enhanced social support services in the USA. Using random effects regression models, we found that individuals in the intervention group reported higher levels of satisfaction with their social support network over the first 5 years of the intervention than those in the support group. Higher levels of emotional support, more visits, and having more network members to whom they felt close were all individually predictive of longitudinal changes in social support network satisfaction. We conclude with a discussion of the importance of having psychological respite when caregivers spend their days in the home and are isolated.

Aged↗

Fruit and vegetable intake: Few adolescent girls meet national guidelines.

OBJECTIVE: To examine longitudinal changes in daily fruit and vegetable consumption among black and white adolescent girls and calculate the percent of girls who met the Healthy People 2010 recommendations. METHODS: Girls (1186 black and 1126 white) who participated in the National Heart, Lung, and Blood Institute Growth Health Study (NGHS) were included if they had completed a 3-day food diary for at least one of six annual assessments visits, beginning at ages 11 or 12. Mixed models estimated the association of visit and race with (a) average daily consumption of fruits and vegetables and (b) the probability of meeting intake recommendations on one or more out of 3 days. RESULTS: For girls of both races, fruit and vegetable consumption increased with age; white girls showed a greater increase in fruit and nutrient-rich vegetable intake than black girls. Across visits, girls consumed considerably fewer than the recommended daily servings of fruits (1.0-1.5), vegetables (1.7-2.5), or nutrient-rich vegetables (0.25). Most girls (95%) failed to meet Healthy People 2010 recommendations. CONCLUSIONS: Public health efforts are needed to meet Healthy People 2010 objectives.

Adolescent↗

Maternal serum thromboxane B2 concentrations do not predict improved outcomes in high-risk pregnancies in a low-dose aspirin trial. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medical Units.

OBJECTIVE: The aim of the study was too determine whether, in a low-dose aspirin trial in high-risk pregnancies, a decrease in maternal serum thromboxane B2 level predicted improved pregnancy outcomes. STUDY DESIGN: This multicenter, randomized, double-blind trial included 2539 women, 1010 of whom had sufficient serum samples at enrollment and at 24 to 28 weeks' gestation, 34 to 38 weeks' gestation, or both to assess longitudinal changes in thromboxane B2 level and their effects on pregnancy outcomes. Women were randomly assigned between 13 and 26 weeks' gestation to receive daily aspirin (60 mg) or placebo. RESULTS: Overall and in all subgroups women assigned to receive aspirin had markedly lower maternal thromboxane B2 concentration values than did those assigned to receive a placebo (P =.0001). Changes in thromboxane levels were not, however, correlated with adverse pregnancy outcomes. Women with >/=50% reduction in maternal serum thromboxane B2 concentrations from baseline had occurrences of preeclampsia (P =.922), preterm birth (P =.375), small for gestational age neonates (P =.938), and grade III or IV intraventricular hemorrhage (P = 1.000) similar to those of women who had <50% reduction. Similar results were found for women with thromboxane B2 level decreases of <15 versus >15 ng/mL and women with thromboxane B2 level decreases to <10 versus >/=10, <5 versus >/=5, and <1 versus >/=1 ng/mL. Maternal thromboxane B2 concentrations at enrollment were also not predictive of adverse outcomes. CONCLUSION: Neither maternal serum thromboxane B2 concentrations at enrollment nor their subsequent reduction were predictive of adverse pregnancy outcomes in a low-dose aspirin trial.

Aspirin↗

Longitudinal observations on mutations conferring ganciclovir resistance in patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis: The Cytomegalovirus and Viral Resistance Study Group Report Number 8.

PURPOSE: Cytomegalovirus retinitis is the most common intraocular infection in patients with acquired immunodeficiency syndrome (AIDS). With prolonged suppressive anticytomegalovirus maintenance therapy, resistance occurs in over 25% of patients. We evaluated longitudinal changes in the cytomegalovirus genotype in patients with cytomegalovirus retinitis who developed ganciclovir resistance that was demonstrated in either the blood or urine. METHODS: Patients with AIDS and previously untreated cytomegalovirus retinitis were followed prospectively for the occurrence of resistance while on treatment. Blood and urine specimens were obtained periodically for cytomegalovirus culture according to a predetermined schedule. Positive isolates were tested for phenotypic susceptibility and for mutations in the UL97 and UL54 genes. RESULTS: A mutation conferring resistance to ganciclovir in either the UL97 or UL54 gene was detected in 18 patients. In general, patients with a genotypically resistant virus developed increasing phenotypic resistance over time. There was a suggestion that unless therapy was changed, UL97 mutations tended to persist. In seven of eight patients, the mutations identified in isolates from the blood and urine were identical. In selected patients, there was a suggestion that a mixed population of cytomegalovirus might be present. Progression of the retinitis in an involved eye (15 of 18), contralateral eye retinitis (10 of 11), and extraocular cytomegalovirus disease (5 of 18) occurred commonly among patients with resistant virus. CONCLUSION: Resistance-conferring mutations in the cytomegalovirus genome emerge and may persist when the selective pressure for resistance is maintained. Some patients appear to harbor complex subpopulations of virus with different mutations and different levels of phenotypic resistance. Changes in therapy may result in a shift in virus population and changes in the cytomegalovirus genotype identified.

AIDS-Related Opportunistic Infections↗

Long-term follow-up of ocular findings in children with Stickler's syndrome.

PURPOSE: To document the longitudinal changes in eye status of children diagnosed with Stickler's syndrome in the first decade of life. METHOD: All patients with cleft palate were referred for eye examination. Of these, patients with systemic findings of Stickler's syndrome were included in this report. RESULTS: Thirty-four eyes in 17 patients met inclusion criteria, with median best-corrected recognition acuity of 20/30. The mean cycloplegic refraction at presentation was -5.00 diopters, and the mean refraction at last visit was -5.50 diopters. CONCLUSIONS: Refractive errors, cataracts, and vitreoretinal abnormalities can be detected early in life in patients with Stickler's syndrome, and refractive error changed little during the follow-up period.

Cataract↗

Hippocampus in Alzheimer's disease: a 3-year follow-up MRI study.

BACKGROUND: Due to the progressive nature of Alzheimer's disease (AD), it has been proposed that serial imaging studies tracking the course of progression might improve the diagnostic accuracy of AD. METHODS: Longitudinal changes in hippocampal volumes were evaluated using magnetic resonance imaging (MRI) over a period of 3 years in 27 AD patients and 8 control subjects. RESULTS: A statistically nonsignificant trend towards accelerated volume loss in the AD group compared to control subjects was observed. During the study period, the average shrinkage of the hippocampal volume ranged from -2.2% to -5.8% in control subjects, and from -2.3% to -15.6% in AD patients. CONCLUSIONS: The observed changes at an individual level were small, and within the accuracy range of the measurements. Therefore, serial MRI of the hippocampus did not offer any advantage over a single MRI to support the diagnosis of AD in this study sample.

Aged↗

RESIO revisited: visual function assessment and cataract surgery in British Columbia.

BACKGROUND: Cataract surgery in a population with mild levels of functional impairment was studied in the Regional Evaluation of Surgical Indications and Outcomes (RESIO) project. The RESIO investigators assessed the overall visual function assessment (VFA) score before and after surgery. In this study we reanalysed available RESIO data to better understand the findings for individual VFA items in this patient population. METHODS: We calculated effect sizes for longitudinal changes in each VFA item and for changes in overall VFA scores using the Mann-Whitney statistic. We considered effect sizes less than 0.3 as small, between 0.3 and 0.8 as moderate, and more than 0.8 as large. We compared differences in the individual VFA item scores before and after cataract surgery using a paired t test and Wilcoxon's signed-rank test. RESULTS: Of the 32 surgeons originally involved in the RESIO project, 18 (60%) agreed to have the data for their patients reanalysed. We found pre- and postoperative VFA data for 709 cataract operations (mean age of patients 73.4 years [standard deviation 9.4 years]; 60.7% women). Of the 47 people with a perfect preoperative VFA score, 28 (59.6%) had a perfect score postoperatively, 13 (27.6%) had a score of 90 or better, 5 (10.6%) had a score of 87 to 90, and 1 (2.1%) had a score of 67. Among the 200 people with a preoperative VFA score of 90 to 99, postoperatively the VFA score improved for 146 (73.0%), remained the same for 43 (21.5%) and worsened for 11 (5.5%). The mean scores for all individual VFA items improved postoperatively. The largest improvements were noted for "driving during the day" (effect size 1.1), "self-care activities" (0.8), "driving during the night" (0.5), "doing fine handiwork" (0.5), "reading newspaper or book" (0.4) and "participating in religious activities" (0.4). INTERPRETATION: The original conclusion from the RESIO project seems correct: based on VFA, the current threshold for cataract surgery in British Columbia is very low. Individual VFA items, particularly reading and night driving, are most strongly and consistently influenced by cataract surgery, regardless of overall VFA score. In the absence of visual acuity data, it is not possible to relate VFA to cataract surgical decision-making in British Columbia.

Activities of Daily Living↗

Precision of in vivo colorimetric assessments of teeth.

PURPOSE: The repeatability of an intraoral positioning device for a tristimulus photoelectric colorimeter was assessed with the left maxillary central incisors of seven subjects. MATERIAL AND METHODS: Intraclass correlation coefficients and repeatability color differences were determined from repeated color measurements made by the same examiner on 3 separate days. Interexaminer repeatability was tested by comparing CIELAB measurements of the same tooth made by two different examiner combinations, both using the positioning device. RESULTS: High intraclass correlation coefficients were demonstrated for intraexaminer and interexaminer repeatability. Repeatability color differences were 0.34 delta E units for intraexaminer assessments, whereas interexaminer repeatability color differences were 0.13 and 0.61 delta E units for the two examiner pairs. CONCLUSIONS: It was concluded that a colorimeter, equipped with a custom positioning jig, had acceptable precision for intraoral measurement of longitudinal changes in tooth color.

Analysis of Variance↗

High-turnover osteopenia in preterm infants: determination of urinary pyridinium cross-links of collagen.

Osteopenia is a frequent condition in preterm infants, but its pathogenesis is uncertain. In the present study, we measured longitudinal changes in the excretion of pyridinium cross-links of collagen (specific markers of bone resorption) and evaluated the relationship between collagen cross-links and other indexes of bone and renal function in preterm infants. In these infants, urinary collagen cross-links were markedly increased on day 7 and day 30 of life and at estimated full-term gestation. The values were several times higher than those of older children and almost comparable to those of healthy full-term infants. Cross-link excretion did not correlate with beta2-microglobulin (B2M) or N-acetyl-beta-D-glucosaminidase (NAG) activity (markers of renal function), indicating that cross-link excretion is not influenced directly by infantile renal function. High serum osteocalcin and low bone mineral density (BMD) in the lumbar spine were also observed at estimated full-term gestation. There was no significant correlation between collagen cross-link excretion and either serum osteocalcin or spine BMD. We conclude that a state of high bone turnover underlies the development of osteopenia in preterm infants.

Aging↗

Effect of insecticide-treated bed nets on the dynamics of multiple Plasmodium falciparum infections.

The rates of acquisition and loss of individual genotypes belonging to the FC27 family of the Plasmodium falciparum merozoite surface protein 2 (msp2) gene were studied in 120 children aged 5 months to 2.5 years, in a randomized controlled trial of insecticide-treated bed nets (ITNs) in Kiberege village, Tanzania. Analysis of longitudinal changes in positivity for individual alleles in samples collected at intervals of one month indicated that the average duration of infections, allowing for undetected parasite genotypes, was 73 d in those aged < 18 months and 160 d in children aged > or = 18 months, consistent with a shift from acute to chronic infection with age. Overall, 51% of genotypes infecting the host were estimated to be detected by polymerase chain reaction-restriction fragment length polymorphism analysis in any one sample of 0.5 microL of packed peripheral blood cells. In children less than 18 months old this sensitivity was 61% (SE = 6%) compared with 41% (SE = 6%) in older children. Conversely, the rate of appearance of new parasite genotypes was higher in children < 18 months of age than in older children, but this partly reflected the difference in sensitivity. The overall incidence of new infections was estimated to be reduced by 17% in ITN users. There was no statistically significant difference between users and non-users in observed infection multiplicity, sensitivity, recovery rate, or estimated infection rates for individual alleles. This suggests that, in areas of high P. falciparum endemicity, ITNs have little effect on the establishment of chronic malaria infection.

Alleles↗

Potamon: a dynamic model for predicting phytoplankton composition and biomass in lowland rivers.

POTAMON is a unidimensional, non-stationary model, designed for simulating potamoplankton from source to mouth. The forcing variables are discharge, river morphology, water temperature, available light and nutrient inputs. Given the description of several algal categories, POTAMON allows to simulate algal "successions" at a particular site, as well as longitudinal changes of potamoplankton composition and biomass. The algal categories differ by their physiology, their loss rates, and their sensitivity to grazing by zooplankton. Two zooplankton categories were considered, Brachionus-like and Keratella-like, which differ by their clearance rate, their incipient limiting level, their selectivity towards phytoplankton, and their growth yield. The model simulates satisfactorily the onset and the magnitude of the phytoplankton spring bloom in the Belgian part of R. Meuse, the biomass decrease in early summer, and the autumn bloom. It also renders the major variations of algal assemblages along the river. The model allows to confirm that the main driving variables of potamoplankton dynamics in a eutrophic river are physical factors: discharge and related variables (e.g. retention time), light and temperature. In addition, the simulations confirm that the zooplankton-phytoplankton interaction may result in phytoplankton biomass fluctuations and compositional changes. POTAMON can be useful to explore plankton dynamics in a large river, and it may become a tool to test various management measures.

Animals↗

Strategy for identifying biomarkers of aging in long-lived species.

If effective anti-aging interventions are to be identified for human application, then the development of reliable and valid biomarkers of aging are essential for this progress. Despite the apparent demand for such gerotechnology, biomarker research has become a controversial pursuit. Much of the controversy has emerged from a lack of consensus on terminology and standards for evaluating the reliability and validity of candidate biomarkers. The initiation of longitudinal studies of aging in long-lived non-human primates has provided an opportunity for establishing the reliability and validity of biomarkers of aging potentially suitable for human studies. From the primate study initiated in 1987 at the National Institute on Aging (NIA), the following criteria for defining a biomarker of aging have been offered: (1) significant cross-sectional correlation with age; (2) significant longitudinal change in the same direction as the cross-sectional correlation; (3) significant stability of individual differences over time. These criteria relate to both reliability and validity. However, the process of validating a candidate biomarker requires a greater standard of proof. Ideally, the rate of change in a biomarker of aging should be predictive of lifespan. In short-lived species, such as rodents, populations differing in lifespan can be identified, such as different strains of rodents or groups on different diets, such as those subjected to calorie restriction (CR), which live markedly longer. However, in the NIA primate study, the objective is to demonstrate that CR retards the rate of aging and increases lifespan. In the absence of lifespan data associated with CR in primates, validation of biomarkers of aging must rely on other strategies of proof. With this challenge, we have offered the following strategy: If a candidate biomarker is a valid measure of the rate of aging, then the rate of age-related change in the biomarker should be proportional to differences in lifespan among related species. Thus, for example, the rate of change in a candidate biomarker of aging in chimpanzees should be twice that of humans (60 vs 120 years maximum lifespan); in rhesus monkeys three times that of humans (40 vs 120 years maximum lifespan). The realization of this strategy will be aided by developing a primate aging database, a project that was recently launched in cooperation with the NIA, the National Center for Research Resources, and the University of Wisconsin Regional Primate Research Center.

Aging↗

Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology.

OBJECTIVES: This study was designed to evaluate whether calcium deposition in the coronary arteries is related to atherosclerotic plaque burden and narrowing of the arterial lumen. BACKGROUND: Many studies have recently documented the feasibility of electron beam computed tomography to detect and quantify coronary artery calcification in patients. Although these studies suggest a general relation between calcification and severity of coronary artery disease, the value of coronary calcium in defining atherosclerotic plaque and coronary lumen narrowing is unclear. Previous pathologic comparisons have failed to detail such a relation in identical histologic sections. This finding may be due to atherosclerotic remodeling. METHODS: A total of 37 nondecalcified coronary arteries were processed, sectioned at 3-mm intervals (723 sections) and evaluated by computer planimetry and densitometry. RESULTS: A significant relation between calcium area and plaque area was found on a per-heart basis (n = 13, r = 0.87, p < 0.0001), per-artery basis (left anterior descending coronary artery [LAD]: n = 13, r = 0.89, p < 0.0001; left circumflex coronary artery [LCx]: n = 11, r = 0.7, p < 0.001; right coronary artery [RCA]: n = 13, r = 0.89, p < 0.0001) and per-segment basis (n = 723, r = 0.52, p < 0.0001). In contrast, a poor relation existed between residual histologic lumen area and calcium area for individual hearts (r = 0.48, p = NS), individual coronary arteries (LAD: r = 0.59, p = NS; LCx: r = 0.10, p = NS; RCA: r = 0.59, p = NS) and coronary segments (r = 0.07, p = NS). Longitudinal changes in external elastic lamina areas were highly correlated with changes in plaque area values (r = 0.60, p < 0.0001), whereas lumen area did not correlate with plaque size change (r = 0.01, p = NS). CONCLUSIONS: Coronary calcium quantification is an excellent method of assessing atherosclerotic plaque presence at individual artery sites. Moreover, the amount of calcium correlates with the overall magnitude of atherosclerotic plaque burden. This study suggests that the remodeling phenomenon is the likely explanation for the lack of a good predictive value between lumen narrowing and quantification of mural calcification.

Adult↗