Jill Lipsett

Anomalous Coronary Arteries: A Multicenter Pediatric Autopsy Study

Anomalous coronary arteries (ACAs) are a potential cause of myocardial ischemia resulting in arrhythmias, angina, infarction, and sudden death. We analyzed 7857 pediatric autopsy cases from four tertiary centers to gain an overall picture of the range and significance of ACAs within this pediatric autopsy population. The incidence of ACAs was 0.5%, with ectopic origin from the aorta (43%) being most frequent, followed by ACA arising from the pulmonary trunk (40%). The mean age at death was 2.2 years (4 h-14 years). ACAs were associated with other anomalies in 57% of cases, 43% of these being cardiac defects. Growth retardation was noted in 50% of the cases. Examination of the heart showed cardiomegaly in 92% of cases, which was marked (> 95 percentile) in 63%, but histologically apparent ischemic damage was seen in only 50% of cases. ACAs arising from the pulmonary trunk were associated with earlier death (1.4 years), more frequent cardiomegaly (100%), and more frequent myocardial scarring (92%) than other types of anomalies. Although the terminal presentation was sudden death in 45% of cases, ACAs associated with other cardiac defects presented mainly with problems related to the latter anomalies. The results highlight the need to examine coronary arteries carefully during the pediatric autopsy. Not only are the positions of the coronary artery ostia important, but also the variations in the angles of arterial take-off, initial courses through the aortic adventitia, subsequent courses, and presence of ostial ridges or membranes that may result in significant compromise of blood flow.

Effect of antenatal tracheal occlusion on lung development in the sheep model of congenital diaphragmatic hernia: a morphometric analysis of pulmonary structure and maturity.

The incidence of congenital diaphragmatic hernia (CDH) is 1:1,207–5,000, and the condition is associated with high mortality and morbidity, attributed principally to associated pulmonary hypoplasia. Repairing the diaphragmatic defect by antenatal surgery has high mortality, mainly due to premature labor. Antenatal tracheal occlusion, which is achievable by less invasive methods, stimulates lung growth (weight and DNA). However, its effectiveness in reversing structural and maturational abnormalities and its optimal timing requires further investigation. We hypothesized that (1) antenatal tracheal occlusion performed in the lamb model of congenital diaphragmatic hernia will stimulate lung growth and structural development and restore lung structure and maturity toward normal levels by term gestation; (2) effects will be detectable by morphometric measurements of the following parameters: lung volume, ratio of parenchyma to nonparenchyma, volume density of connective tissue within nonparenchyma, ratio of gas exchange tissue to airspace in parenchyma, gas exchange surface area, capillary loading, alveolar/airspace density and alveolar perimeter; (3) effects will be seen in all lobes of the lung; and (4) a greater effect will be observed when tracheal occlusion is performed early rather than late in gestation.

Morphometric analysis of preterm fetal pulmonary development in the sheep model of congenital diaphragmatic hernia.

ABSTRACT Congenital diaphragmatic hernia (CDH) in humans carries high mortality/morbidity attributed to associated pulmonary hypoplasia. An understanding of the effects of CDH on fetal lung growth is important for development of successful treatments. This study aimed to quantitate structural differences between normal and CDH-affected preterm lamb lungs. We hypothesized that (a) pulmonary hypoplasia is present in preterm CDH-affected lungs; (b) the relative degree of pulmonary hypoplasia increases with gestation; and (c) the left upper lobe (LUL) is affected most. Fetal lambs were allocated to two groups. One group underwent surgery (72–74 days gestation) inducing CDH. Both groups (n = 7, n = 7) were delivered by cesarean section at 129 days (term: 145–149). Lungs were obtained at autopsy, were inflation-fixed, processed for histology, and morphometry was performed. Preterm lungs of CDH-affected lambs in comparison to those of normal lambs demonstrated a reduction in the following: lung weight (37.7 g vs. 116.3 g); lung weight:body weight (0.012 vs. 0.040); fixed lung volume (33.6 ml vs. 96.9 ml); gas-exchange surface area (4.56 m2 vs. 13.70 m2); parenchyma:nonparenchyma (59:41 vs. 72:28); and parenchymal airspace:tissue (16:84 vs. 35:65). Non-parenchyma connective tissue was increased (58%), airspaces were more numerous (1077/mm2) and smaller (perimeter 76.6 μm), gas-exchange surface density (2394 cm−1) was greater and capillary loading (0.04 ml/m2) was reduced compared to preterm normal lung (49%; 778/mm2; 108.7 μm; 2003 cm−1, 0.11 ml/m2, respectively). The LUL was affected most. These data quantitate pulmonary hypoplasia in preterm CDH-affected lambs. Comparisons with published data indicate increasing relative hypoplasia as gestation proceeds. Fetal interventions will affect lung development, depending on timing, with intervention still likely to be worthwhile during late gestation.

Morphometric analysis of pulmonary development in the sheep following creation of fetal diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) in humans is relatively common and associated with high mortality attributed mainly to pulmonary hypoplasia. Previous animal models have induced CDH late in gestation, in contrast to the human situation, and only limited morphometric analyses have been reported. We undertook early surgical creation of CDH in fetal lambs, days 72-74 of gestation (n = 8), with unoperated lambs (n = 8) as controls. At 143 days (term = 145-149) a cesarean section was performed and the lungs were obtained, inflation fixed, divided into lobes, and processed for morphometry. In the CDH group the total lung volumes (51.3 mL compared to 223.8 mL) and gas exchange surface areas (5.85 m2 versus 26.43 m2) were less than one quarter of control values. Capillary loading was reduced from 0.3 mL/m2 in controls to 0.12 mL/m2 in CDH and parenchymal volume reduced from 77% in controls to 57% in CDH. Within parenchyma, gas exchange tissue volume was increased in CDH (66%) compared with controls (50%). CDH lungs had primitive air sacs/alveoli that were smaller (perimeter 83 microns) and more numerous (1321 per mm2) than in controls (perimeter 132 microns, 504 per mm2). The left lung and left upper lobe were affected most. Induction of CDH in the lamb at this early age results in quantifiable, reproducible pulmonary hypoplasia from which comparisons can be made with the human condition.

Pathologic features of farm and tractor-related fatalities in children.

A study of 15 childhood fatalities due to farm or tractor-related accidents demonstrated extensive injuries typified by crushing, evisceration, and amputation of limbs. Although these injuries are characteristic of industrial accidents in adults, such accidents do not commonly occur in children. However, the unique circumstance of the farm, which incorporates home and industrial environments, results in particularly severe patterns of injuries in accidental childhood deaths. A knowledge of the range of machines that are used and the environment of the farm facilitates assessment of the types of injuries that may be found at autopsy in cases of pediatric farm accident. Language: en

Paraproteinemic Crystalloidal Keratopathy: An Ultrastructural Study of Two Cases, Including Immunoelectron Microscopy

The ultrastructural appearances of corneal crystalloidal deposits are described in two patients with an IgG-kappa paraproteinemia of uncertain pathogenesis. The crystalloids in one patient were overwhelmingly intracellular and were found mainly in stromal keratocytes, but also in basal corneal epithelial cells and the limbal vascular endothelium. Four types of crystalloid or immunoprotein-containing granules were recognizable in this case: 1) fibrillary crystalloids with a curvilinear filamentous substructure; 2) angulated geometric crystalloids that often had a linear filamentous substructure and transverse or oblique periodicity; 3) cordlike crystalloids; and 4) lysosomelike granules with amorphous contents. Immunoelectron microscopy demonstrated that all of these structures labeled for kappa-light chains, and rectangular type 2 crystalloids showed approximately a twofold greater concentration of the colloidal gold probe than the type 1 fibrillary crystalloids. The evidence suggested development of the crystalloids within lysosomes, with a progression from the granules containing amorphous material, through fibrillary crystalloids, to the geometric structures. The circumferential distribution of the corneal deposits, as well as the presence of vascular endothelial crystalloids and reduplication of external laminae around limbal blood vessels, suggests that the crystalloids originated predominantly or entirely from the blood, with transport of immunoprotein across damaged limbal microvasculature. The abnormal vasculature may also have contributed to corneal edema, which in turn may have exacerbated corneal opacification. The crystalloidal deposits in the other case were exclusively extracellular; they were located beneath and between corneal basal epithelial cells, and predominantly as a mantle around individual keratocytes. The crystalloids in this case consisted overwhelmingly of thick-walled tubules about 40 nm in diameter that labeled for both kappa-light chains and gamma chains with the colloidal gold immunoprobe. In addition, lucent vesicles within keratocytes were found only in sections labeled for kappa-light chains and were positive. The factors that might contribute to the formation of corneal crystalloidal deposits in immunoproliferative disorders are discussed, and include: 1) an inherent propensity for crystallization of some immunoglobulins or kappa-light chains, perhaps because of abnormal molecular structure; and 2) local factors in the cornea that might promote deposition and crystallization of immunoprotein, such as temperature, pH, the water content, and extracellular matrix components.

Farm and tractor-related fatalities in children in South Australia

To analyse the circumstances surrounding farm and tractor‐related childhood fatalities in South Australia, to identify potentially dangerous situations and to delineate prevention strategies.

Fire deaths in children in South Australia from 1989 to 1998

Abstract: A study was undertaken of childhood deaths caused by fires in South Australia over a 10‐year period from 1989 to 1998. A total of 23 deaths of children occurred with an age range of 2 months to 16 years (mean 5 years 10 months; M:F = 13:10). Fourteen deaths were associated with house fires, four with fires in cars and four were miscellaneous or unspecified. While house fire deaths remained the major cause of childhood fire deaths (65%), deaths in car fires accounted for a significant proportion of cases (17%). Although the numbers are small, cars represented a specific danger because of their confined space with highly flammable interiors, lockable doors, and built in non‐childproof lighters. Cars should not be regarded as suitable places to leave young children, or for children to play in unsupervised.

Effect of immediate versus slow intrauterine reduction of congenital diaphragmatic hernia on lung development in the sheep: A morphometric analysis of term pulmonary structure and maturity

The incidence of congenital diaphragmatic hernia (CDH) is 1:1,200–5,000, and the condition is associated with high mortality and morbidity attributed principally to associated pulmonary hypoplasia. One treatment approach has been for intrauterine intervention to induce lung growth to a sufficient level to allow survival at birth. Repair of the hernia in utero has been attempted, using a method of immediate reduction and repair of the hernia (patch) compared to a slow reduction method using a silastic “silo” sewn over the diaphragm defect to contain the hernial contents. In animal studies, this second method has been associated with lower fetal morbidity and mortality. This study, utilizing the sheep model of CDH, focuses on analysis of lung structural development and maturation, comparing the efficacy of the immediate vs. slow methods of hernial repair in preventing/reversing pulmonary hypoplasia. We hypothesized that: a) Both the immediate (patch) and slow (silo) methods of hernia repair performed in the lamb model of CDH will stimulate lung growth and structural development and restore lung structure and maturity towards normal levels by term gestation; b) Effects will be detectable by morphometric measurement of the following parameters: lung volume; parenchyma to nonparenchyma tissue ratio; volume density of connective tissue in nonparenchyma; gas exchange tissue to airspace ratio; gas exchange surface area; capillary loading; alveolar/airspace density; and alveolar perimeter; c) Effects will be seen in all lobes of the lung; and d) There will be no significant difference in lung size or structural parameters between the two groups.

Analysis of the conducting airway system in the lung: a new method combining morphometry with mathematical modeling for airway classification.

Although the lung is structurally complex, it is suitable for morphometric analysis of the structural determinants of lung function in health and disease. Analysis of the organized branching airways has been problematic because of the need to identify and classify airways before structural characteristics of different‐order branches can be determined. Airway casts have been used to identify relationships between branches, measure some structural features, and develop mathematical models that describe simply the relationships between generations. However, cast preparation destroys surrounding tissue, including the airway wall, thus precluding analysis of these structural elements. We describe a new approach using tissue sections which combines the classification of airways into Strahler order (SO) with tissue structural analysis. Lung‐tissue sections are prepared, and outer (OD) and inner (ID) diameters are determined over a wide range of airways. The line equation relating log OD vs. SO is determined using measured values for SO1 (terminal bronchioles) and SO8 (first branch bronchi). Mean ODs can then be calculated for each of the other SO groups, and measurements can be classified. Calculations can be made for the mean number of branches and airway lengths (given the log linear relationship of these factors with SO and morphometrically determined volume densities for airway lumen), and for individual airway resistance and total resistances for each SO. For an example, mean data are presented for airways in the adult sheep (n = 13). The methodology presented allows identification of subtle alterations in airway structures which may be affecting selected orders of airways, with specific implications for changes in lung function. Anat Rec 266:51–57, 2002.