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Automated detection of macular drusen using geometric background leveling and threshold selection.

BACKGROUND: Age-related macular degeneration (ARMD) is the most prevalent cause of visual loss in patients older than 60 years in the United States. Observation of drusen is the hallmark finding in the clinical evaluation of ARMD. OBJECTIVES: To segment and quantify drusen found in patients with ARMD using image analysis and to compare the efficacy of image analysis segmentation with that of stereoscopic manual grading of drusen. DESIGN: Retrospective study. SETTING: University referral center.Patients Photographs were randomly selected from an available database of patients with known ARMD in the ongoing Columbia University Macular Genetics Study. All patients were white and older than 60 years. INTERVENTIONS: Twenty images from 17 patients were selected as representative of common manifestations of drusen. Image preprocessing included automated color balancing and, where necessary, manual segmentation of confounding lesions such as geographic atrophy (3 images). The operator then chose among 3 automated processing options suggested by predominant drusen type. Automated processing consisted of elimination of background variability by a mathematical model and subsequent histogram-based threshold selection. A retinal specialist using a graphic tablet while viewing stereo pairs constructed digital drusen drawings for each image. MAIN OUTCOME MEASURES: The sensitivity and specificity of drusen segmentation using the automated method with respect to manual stereoscopic drusen drawings were calculated on a rigorous pixel-by-pixel basis. RESULTS: The median sensitivity and specificity of automated segmentation were 70% and 81%, respectively. After preprocessing and option choice, reproducibility of automated drusen segmentation was necessarily 100%. CONCLUSIONS: Automated drusen segmentation can be reliably performed on digital fundus photographs and result in successful quantification of drusen in a more precise manner than is traditionally possible with manual stereoscopic grading of drusen. With only minor preprocessing requirements, this automated detection technique may dramatically improve our ability to monitor drusen in ARMD.

Diagnostic Techniques, Ophthalmological↗

Cataract and survival in an elderly nondiabetic population.

Follow-up ranging between 6 and 8 years of the survival of a cohort of 473 elderly nondiabetic subjects randomly selected from a small English town showed an age- and sex-adjusted association between nuclear cataract at the time of baseline examination and decreased survival (P = .002). Comparing those with and without nuclear cataract, the adjusted relative hazard for death was 1.52 (95% confidence interval, 1.15 to 1.99). This effect remained virtually unchanged when also adjusted for whether the subject reported ever having been a smoker.

Aged↗

The stability of perfluoro-N-octane during vitreoretinal procedures.

OBJECTIVES: To examine the propensity for intraoperative procedures, such as endolaser, to generate polar impurities in perfluorocarbon liquids, either by degradation of the compound or by dissolution of materials contacting the liquid, given the value of these liquids as adjuncts to vitreoretinal procedures and the importance of using pure and inert liquid. METHODS: Perfluoro-N-octane liquid recovered from patients after vitreoretinal procedures was analyzed by gas chromatography, nuclear magnetic resonance, ultraviolet spectroscopy, and a cell proliferation assay. Similar analyses were performed on pure and impure perfluoro-N-octane exposed in vitro to superclinical energy levels of argon and YAG laser, endodiathermy, and endoillumination. RESULTS: No change in chemical structure and only minor (parts per million) increases in dissolved contaminants were observed. The perfluoro-N-octane liquid retained its inertness as indicated by the inability of fibroblasts to attach and proliferate on its surface. CONCLUSION: The structure and biologic inactivity of perfluoro-N-octane are unaffected by vitreoretinal surgical manipulations.

Adolescent↗

Management of cardiovascular disease risk factors in children. A national survey of primary care physicians.

A national survey of family physicians, general practitioners, and pediatricians revealed substantial physician differences in managing cardiovascular disease risk factors in children aged 2 to 18 years. Pediatricians tended to screen younger children but were more conservative in treatment. General practitioners tended to screen less and to initiate intervention in older children, but were more aggressive in therapy. While only 9% of surveyed physicians measured blood cholesterol levels routinely, 72% screened children with family histories of cardiovascular disease. The majority routinely measured blood pressure, but the ages of first measurements differed among physicians. Surprisingly, of those who had treated children with elevated blood pressure or blood cholesterol, 54% said that they had ever used antihypertensive and 12% used lipid-lowering drugs in children, including angiotensin converting enzyme inhibitors and clofibrate. Half the surveyed physicians felt prepared to provide dietary counseling, but only 14% felt successful with it. When asked what they considered were the major cardiovascular risk factors, less than one third of the physicians cited all three major factors: hypertension, hypercholesterolemia, and smoking.

Adolescent↗

Prospective study of posttraumatic stress disorder symptoms and coronary heart disease in the Normative Aging Study.

CONTEXT: Various correlates of posttraumatic stress disorder (PTSD), such as high levels of sympathetic activation and hypothalamic-pituitary-adrenal axis dysregulation, have been linked to arterial damage and coronary heart disease (CHD) risk. While psychological disturbance is frequently found among patients with cardiac disease, whether psychological problems precede or occur as a result of having a potentially fatal disease is not clear. To our knowledge, no prospective studies to date have evaluated whether PTSD is associated with increased risk of CHD. OBJECTIVE: To test the hypothesis that high levels of PTSD symptoms may increase CHD risk, using 2 different measures of PTSD. DESIGN: Prospective cohort study. SETTING: Community-dwelling men from the Greater Boston, Mass, area who served in the military. PARTICIPANTS: Data are from the Veterans Affairs Normative Aging Study. Men who completed either the Mississippi Scale for Combat-Related PTSD in 1990 (n = 1002) or the Keane PTSD scale in 1986 (n = 944) were included in the study. MAIN OUTCOME MEASURE: Incident CHD occurring during follow-up through May 2001. RESULTS: Levels of PTSD symptoms in this cohort were low to moderate. Men with preexisting CHD at baseline were excluded, and PTSD was measured with the Mississippi Scale for Combat-Related PTSD. For each SD increase in symptom level, men had age-adjusted relative risks of 1.26 (95% confidence interval, 1.05-1.51) for nonfatal myocardial infarction and fatal CHD combined and 1.21 (95% confidence interval, 1.05-1.41) for all of the CHD outcomes combined (nonfatal myocardial infarction, fatal CHD, and angina). Findings were replicated using the Keane PTSD scale and somewhat strengthened after controlling for levels of depressive symptoms. CONCLUSIONS: To our knowledge, this is the first study to demonstrate a prospective association between PTSD symptoms and CHD even after controlling for depressive symptoms. These results suggest that a higher level of PTSD symptoms may increase the risk of incident CHD in older men.

Adult↗

Natural history of asymptomatic carotid plaque.

In April 1981, a total of 297 carotid arteries were examined prospectively. All patients were asymptomatic and were referred to the peripheral vascular laboratory at Good Samaritan Medical Center, Phoenix, for real-time B-mode ultrasonography. A measurement of luminal area stenosis was determined to be either greater or less than 75%. In addition, the ultrasound echo pattern was used to classify plaque as either calcified, dense, or soft. If, for any reason, the patient or physician felt that carotid endarterectomy should be performed, the patient was dropped from the study. In addition, the use of antiplatelet medication or anticoagulants constituted disqualification. Three groups of patients were observed for three years or until symptoms became apparent. Patients in all three groups with stenosis greater than 75% at the time of initial study were at greater risk than their peers without significant narrowing; however, even those patients with less than 75% stenosis were at greater risk if the associated plaque was less organized, ie, soft. A definite trend toward higher risk is seen in plaques of lower density. Only 10% of those patients with calcified plaque and a significantly stenotic vessel have developed symptoms. In contrast, only three patients of the original 42 with soft plaque and a tight stenosis are still being observed. This study appears to confirm that soft plaques have a greater tendency toward subintimal hemorrhage, ulceration, or primary embolization than more well-organized plaques.

Arterial Occlusive Diseases↗

Regional brain volume abnormalities and long-term cognitive outcome in preterm infants.

CONTEXT: Preterm infants have a high prevalence of long-term cognitive and behavioral disturbances. However, it is not known whether the stresses associated with premature birth disrupt regionally specific brain maturation or whether abnormalities in brain structure contribute to cognitive deficits. OBJECTIVE: To determine whether regional brain volumes differ between term and preterm children and to examine the association of regional brain volumes in prematurely born children with long-term cognitive outcomes. DESIGN AND SETTING: Case-control study conducted in 1998 and 1999 at 2 US university medical schools. PARTICIPANTS: A consecutive sample of 25 eight-year-old preterm children recruited from a longitudinal follow-up study of preterm infants and 39 term control children who were recruited from the community and who were comparable with the preterm children in age, sex, maternal education, and minority status. MAIN OUTCOME MEASURES: Volumes of cortical subdivisions, ventricular system, cerebellum, basal ganglia, corpus callosum, amygdala, and hippocampus, derived from structural magnetic resonance imaging scans and compared between preterm and term children; correlations of regional brain volumes with cognitive measures (at age 8 years) and perinatal variables among preterm children. RESULTS: Regional cortical volumes were significantly smaller in the preterm children, most prominently in sensorimotor regions (difference: left, 14.6%; right, 14.3% [P<.001 for both]) but also in premotor (left, 11.2%; right, 12.6% [P<.001 for both]), midtemporal (left, 7.4% [P =.01]; right, 10.2% [P<.001]), parieto-occipital (left, 7.9% [P =.01]; right, 7.4% [P =.005]), and subgenual (left, 8.9% [P =.03]; right, 11.7% [P =.01]) cortices. Preterm children's brain volumes were significantly larger (by 105. 7%-271.6%) in the occipital and temporal horns of the ventricles (P<. 001 for all) and smaller in the cerebellum (6.7%; P =.02), basal ganglia (11.4%-13.8%; P</=.005), amygdala (left, 20.2% [P =.001]; right, 30.0% [P<.001]), hippocampus (left, 16.0% [P =.001]; right, 12.0% [P =.007]), and corpus callosum (13.1%-35.2%; P</=.01 for all). Volumes of sensorimotor and midtemporal cortices were associated positively with full-scale, verbal, and performance IQ scores (P<.01 for all). CONCLUSIONS: Our data indicate that preterm birth is associated with regionally specific, long-term reductions in brain volume and that morphological abnormalities are, in turn, associated with poorer cognitive outcome. JAMA. 2000;284:1939-1947.

Brain↗

Accumulated lead exposure and risk of age-related cataract in men.

CONTEXT: Low-level lead exposure may increase the risk for a number of chronic age-related diseases. Several studies have documented the presence of lead in lenses with cataract. The intrusion of lead into the lens may alter lens redox status and cause protein conformational changes that decrease lens transparency. OBJECTIVE: To determine the relationship of cumulative lead exposure with the development of cataract. DESIGN, SETTING, AND PARTICIPANTS: Tibial (cortical) and patellar (trabecular) bone lead levels were measured by K x-ray fluorescence between 1991 and 1999 in a subset of participants in the Normative Aging Study (NAS), a Boston-based longitudinal study of aging in men. Among the first 795 NAS participants to have bone lead levels measured, we reviewed eye examination data (collected routinely every 3-5 years) for the period after the bone lead measurements were taken. We limited the population to men aged 60 years and older who had sufficient eye examination information available (n = 642). Blood lead levels were also measured. MAIN OUTCOME MEASURES: Cataract assessment was done while masked to the lead level results. A participant was considered to have cataract if there was documentation for either eye of cataract surgery or a cataract graded clinically as 3+ or higher on a 4-point scale. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated as estimates of the magnitude and significance of the relationship of lead exposure with cataract, in logistic regression models. RESULTS: The mean age of the study participants was 69 years and cataract was identified in 122 men. The age-adjusted OR (95% CI) for cataract for men in the highest vs lowest quintile of tibia lead level was 2.68 (1.31-5.50). Further adjustment for pack-years of cigarette smoking, diabetes, blood lead levels, and intake of vitamin C, vitamin E, and carotenoids resulted in an OR of 3.19 (95% CI, 1.48-6.90). For patella lead level, there was an increased risk of cataract in the highest vs lowest quintile (OR, 1.88; 95% CI, 0.88-4.02), but the trend was not significant (P = .16). Blood lead levels, more indicative of short-term exposure levels, were not significantly associated with cataract (OR, 0.89; 95% CI, 0.46-1.72; P = .73). CONCLUSIONS: These epidemiological data suggest that accumulated lead exposure, such as that commonly experienced by adults in the United States, may be an important unrecognized risk factor for cataract. This research suggests that reduction of lead exposure could help decrease the global burden of cataract.

Aged↗

Expression of hepatic pyruvate carboxylase mRNA in C57BL/6J Ah(b/b) and congenic Ah((d/d)) mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The activity and level of hepatic pyruvate carboxylase (PC) has been reported to be altered by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment in mice. If alteration in PC level/activity by TCDD influences TCDD toxicity, one would expect to observe an early post-exposure reduction in PC mRNA. To examine the molecular events responsible for the alteration of PC activity in livers of TCDD-treated mice, we designed a synthetic DNA oligonucleotide probe specific for PC mRNA. Northern blot analysis on RNA extracts from hepatic tissue at various times and doses post-TCDD exposure were done. Furthermore, to elucidate the role of the dioxin Ah locus on alterations of PC activity by TCDD, we utilized C57BL/6J (Ahb/b, Ah high TCDD affinity) mice and a congenic (Ahd/d, AH low TCDD affinity) mouse strain. At 8 days post TCDD treatment, a dose-dependent reduction of hepatic PC mRNA levels was observed in Ahb/b mice. The response, reduction in PC mRNA levels, in the Ahb/b strain was about 10-fold greater than that of comparably exposed congenic Ahd/d mice. These results indicate that previously reported reductions in PC activity/level by TCDD treatment of mice is a consequence of a reduction in PC mRNA levels and that the effect requires a competent Ah receptor.

Animals↗

Obesity and breast disease. The role of the female sex hormones.

An Australian study of 513 women evaluated associations between obesity and both benign and malignant breast disease, and in particular investigated the role of female sex hormones. Women who gained more than 10 kg from early womanhood had a two-fold increase in risk of developing breast cancer, whereas lean women had a greater risk of being treated for benign breast disease. Obese women with breast cancer were more likely to have Stage II tumors but there was no significant association between obesity and tumor size or estrogen and progesterone receptor status. Obesity was strongly associated with the proportions of nonprotein-bound and albumin-bound estradiol, and inversely associated with sex hormone binding globulin (SHBG) levels and the proportion of SHBG-bound estradiol. In addition, age at menarche was inversely associated, and age at menopause directly associated with recalled weight at those time periods. These data demonstrate weight gain as a risk factor for breast cancer, and suggest a possible mechanism supporting its development.

Adolescent↗

Morphological analysis of the postnatally developing marsupial lung: The quokka wallaby.

We investigated the events that take place during the postnatal morphogenesis of the lung of the quokka wallaby, Setonix brachyurus, using the light microscope and both the scanning and transmission electron microscopes. The lung of term, newborn babies (joeys) at 3-days of postnatal life was at late canalicular stage and comprised large airways and tubules separated by thick mesenchymal interstitium. The tubules were lined by a low cuboidal epithelium but had few portions with true gas exchange barrier where capillaries came into close contact with squamous type of epithelium. By the fifth day postpartum, the lung entered the early saccular stage characterised by large air sacs, thinner septa, a better developed double capillary system and conversion of the cuboidal epithelium into a squamous one of type I cells interrupted by groups of cuboidal type II cells with lamellar bodies. Transitory respiratory bronchioles were recognisable toward the end of this stage. Formation of secondary septa started by Day 15, dividing the saccules into several generations of smaller air spaces. There were alternating and concurrent periods of tissue proliferation and air space expansion, followed by septal thinning. Alveolization started from about 125 days postpartum when the first burst of small sized air spaces bounded by septa with a single capillary layer were encountered. By Day 180 the process of alveolization was completed with only occasional septa showing a double capillary system and by Day 210 postnatally, the lung resembled that of an adult. For the first time in a mammal, the canalicular stage was encountered postnatally during lung development.

Age Factors↗

Copper/zinc superoxide dismutase is phosphorylated and modulated specifically by granulocyte-colony stimulating factor in myeloid cells.

Using two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (2-D SDS-PAGE) of 32P-labeled cytosolic and membrane extracts, we identified a 21.5 kDa phosphoprotein with an isoelectric point of 6.0 in NFS-60 cells that was phosphorylated maximally at 15 min by treatment with granulocyte-colony stimulating factor (G-CSF) but not with interlevkin-3 (IL-3) or colony-stimulating factor-1 (macrophage-colony stimulating factor (CSF-1 (M-CSF)). The phosphorylation of this protein, designated 21.5/6.0, was unaffected by a series of antiproliferative agents [32]. These findings suggested that the 21.5/6.0 phosphoprotein may be involved in specific G-CSF-mediated biological responses such as activation and/or differentiation. We sought to characterize this 21.5/6.0 by a novel combination of 2-D SDS-PAGE and hydroxyapatite (HTP)-chromatography. Amino acid sequence determination of 21.5/6.0 revealed it to share a high level of homology with copper/zinc superoxide dismutase (Cu/Zn-SOD), indicating that a Cu/Zn-SOD is phosphorylated following treatment with G-CSF. This is the first report of the phosphorylation and possible involvement of Cu/Zn-SOD protein in granulocyte activation/differentiation events. In addition, Cu/Zn-SOD levels and activity were diminished by G-CSF but not IL-3 treatment. This new protocol combining 2-D SDS-PAGE and HTP-chromatography allows the characterization of low abundance phosphoproteins involved in the cellular responses to G-CSF and presumably to other cytokines/growth factors.

Animals↗

Variable adhesion of different red blood cell products to activated vascular endothelium under flow conditions.

Red blood cells (RBCs) that have been stored prior to transfusion show increased adherence to vascular endothelium in vitro, which suggests a potential for stored blood transfusion to impede blood flow in some patients. Transfusion is often required in patients with sepsis or inflammation; however, whether activation of endothelium affects stored RBC-endothelial cell (EC) interactions is unknown. We investigated whether storage time and leukocyte content of RBC products influences the adhesion of RBCs to activated ECs. RBCs from nonleukocyte-reduced (S-RBCs), buffy-coat-poor (BCP-RBCs), and leukocyte-filtered (LF-RBCs) products and cultured EC layers were pretreated with endotoxin, tumor necrosis factor-alpha (TNF-alpha), or medium alone prior to perfusion of the RBCs across the EC layer in a continuous flow microchamber. After a single day of RBC storage, the number of adherent RBCs was increased in the endotoxin and TNF-alpha pretreated groups compared to the unactivated-control group. These differences were statistically significant for S-RBCs and LF-RBC products (P < 0.05). In contrast, there was no significant difference in RBC adherence to activated and unactivated endothelium at other time-points of RBC product storage. The strength of adhesion of stored RBCs from S-RBC products to activated ECs was not altered following treatment; however, endotoxin significantly increased the adhesive strength of LF-RBCs to endothelium. These results demonstrate that while fresh RBCs show increased adhesion to activated endothelium, storage of RBCs did not promote increased adhesion to activated endothelium. However, inflammatory conditions promote stronger adhesion of stored RBCs to ECs, which may contribute to impaired tissue perfusion in some transfusion recipients.

Blood Component Removal↗

Occupational determinants of bone and blood lead levels in middle aged and elderly men from the general community: the Normative Aging Study.

BACKGROUND: Few studies of the general population have investigated risk factors for elevated levels of lead in bone in relation to occupation. METHODS: Six hundred and fifty six community-exposed men had their bone and blood lead levels measured (by K-X-ray fluorescence). Based on their occupational histories, participants were categorized into those who worked in white-collar (WC) occupations (59%) or blue-collar (BC) occupations (41%). No subjects had worked in a primary lead industry (e.g., smelting). RESULTS: In multivariate regression models that adjusted for age, race, education, smoking, alcohol ingestion and retirement status, BC subjects had tibia and patella lead concentrations that were 5.5 (95% CI: 3.2-7.8) and 6.5 (95% CI: 3.1-9.8) microg/g higher than WC subjects, respectively. Interaction terms pairing race with occupational status indicated that in non-white BC subjects, tibia and patella lead levels were higher still by 11.3 (95% CI: -2 to 24.5) and 20.5 (95% CI: 1.2-39.8) microg/g, respectively. Blood lead levels were low for these mostly retired men (mean [SD]: 6.1 [3.9] microg/g) and in multivariate regression models, occupational status was not a significant predictor of blood lead levels; however, an interaction between race and occupational status was also suggested, with non-white BC subjects having blood lead levels that were predicted to be higher by 4.5 (95% CI: 0.3-8.7) microg/dl. CONCLUSIONS: Bone lead levels are higher in the men who worked in BC occupations even if they have not worked in primary lead-exposed occupations. This effect is markedly stronger in non-white BC workers and suggests an interaction between occupational exposures and race/ethnicity with respect to cumulative exposure to lead. A similar interaction was suggested by models of blood lead levels.

Adult↗

Kousseff syndrome: a causally heterogeneous disorder.

The existence of Kousseff syndrome as a distinct entity has been thrown into doubt by a recent study conducted on the family originally reported by Kousseff. In all cases where chromosome 22q11.2 FISH testing has been undertaken, including the original sibship, a chromosome 22q11.2-microdeletion has been identified. We report two cases of sacral myelomeningocele associated with a conotruncal cardiac anomaly or "Kousseff syndrome." The first case, a 4-year-old girl, had a sacral myelomeningocele, tetralogy of Fallot, microcephaly, hydrocephalus, hypoplasia of the corpus callosum and mild-moderate developmental delay. Chromosome 22q11.2 FISH was normal and the facial phenotype was not that of velocardiofacial syndrome. Sequencing of the entire coding region of CITED2 did not reveal a mutation. The second case, a male infant, was found to have a 22q11.2-microdeletion. These cases confirm Kousseff syndrome to be a causally heterogeneous disorder.

Abnormalities, Multiple↗