Chronic hyperinsulinemia in the fetal rhesus monkey. Effects of physiologic hyperinsulinemia on fetal growth and composition.

One of the hallmarks of the hyperglycemic-hyperinsulinemic infant of the diabetic mother (IDM) is macrosomia and selective organomegaly. Primary hyperinsulinemia, with insulin levels similar to those observed in human IDMs at delivery, was produced in the fetal rhesus monkey during the last third of gestation. The effects of this physiologically relevant hyperinsulinemia, in the absence of hyperglycemia, on fetal growth were studied. Fetal macrosomia, with a 23% increase in total body weight, was observed in physiologically hyperinsulinemic fetuses. A similar 27% increase in weight was produced by fetal insulin levels that were 10 times higher. A logarithmic correlation was observed between fetal birth weight ratio and fetal plasma insulin concentration. In contrast to this increase in weight, skeletal growth, as measured by crown-heel length and head circumference, was not affected by hyperinsulinemia. Only cardiomegaly was found in the low-dose hyperinsulinemic fetuses, whereas cardiomegaly, hepatomegaly, and splenomegaly were produced by hyperinsulinemia in which insulin levels were in the highest range. Compositional analysis of heart and skeletal muscle indicated no differences in the protein, RNA and DNA concentration, or in the protein-to-DNA ratio in hyperinsulinemic fetuses. We interpret these data as indicating that fetal insulin plays the predominant role in controlling the normal, as well as the augmented, fetal weight characteristic of the human infant of the diabetic mother.

Hepatoblastoma. A clinical and pathologic study of 54 cases.

The clinical and pathologic features of 54 children with hepatoblastoma are reviewed. Their average age at diagnosis was 17 months (range: 4 months-4 1/2 years) and there was a predilection for males in a ratio of nearly 2:1. Unusual manifestations included isosexual precocity (two cases), hemihypertrophy and Budd-Chiari syndrome (one case), and synchronous Wilms' tumor (one case). Thirty-two of 49 conventional hepatoblastomas were subclassified as epithelial type (19 predominantly embryonal, 13 predominantly fetal), and 12 had mixed epithelial-mesenchymal histology. Pathologic material in five cases was too limited for reliable subclassification. Hepatoblastomas classified as anaplastic type had more primitive histology with a predominance of small- to medium-sized cells in diffuse sheets. The overall mortality was 76% and the average duration of disease from diagnosis to death was 8 months (range: 1 month-27 months). Complete surgical resection remains the key treatment for achieving long-term survival and was attempted in 33 of the 54 children (61%). There were 13 long-term survivors followed for an average of 9 years. The most common type of hepatoblastoma in these children was epithelial with a predominantly fetal pattern. None of the children with anaplastic tumors survived.

X-linked recessive myotubular myopathy: II. Muscle morphology and human myogenesis.

The classification of centronuclear myotubular myopathies is controversial. Within this group of disorders, congenital X-linked recessive myotubular myopathy (XLMTM), characterized by marked cell hypotrophy and structural resemblance to fetal myotubes, represents a distinct entity. The histologic findings in verified and probable cases of XLMTM are reviewed. In addition, the ultrastructural features of muscle in one case of XLMTM are compared with those of normal fetal muscle at various developmental ages. In XLMTM both muscle and nerve show evidence of immaturity. Proliferation of the sarcotubular organelles in XLMTM, not observed in normal fetal muscle, may be due to impaired innervation.

X-linked recessive myotubular myopathy: I. Clinical and pathologic findings in a family.

Four neonatal deaths in one family were due to X-linked myotubular myopathy. The characteristic alterations in muscle, described in three cases, are marked fiber hypotrophy, size variability, and the presence of internal nuclei or pale areas. The diagnosis can be verified only by obtaining a careful genetic history. Previous occurrence of male neonatal death or stillbirth, or of hypotonia and respiratory insufficiency, is critical in the identification of suspected cases. There is morphologic justification for retaining the name "myotubular myopathy" to distinguish this X-linked disorder from other congenital conditions involving muscle weakness that have similar morphologic features.

Concerning the relative non-toxicity of silacrown ionophores.

Silacrowns, ionophoric materials in which an ethylene bridge of a normal crown ether has been replaced by a R2Si group, facilitate ion transport across liquid membranes. A major aspect of their properties is their nontoxicity when compared to these crown ethers. This is probably due to their ready hydrolysis to the corresponding polyethylene glycols. The glycols also exhibit ion transport properties, even with an efficiency close to the silacrowns but the silacrowns stay intact long enough to partition into the hydrophobic phase of a liquid membrane whereas their hydrolysis products preferentially partition into the aqueous phases. Ready removal from the hydrophobic phase of a membrane will reduce the long term transporting effectiveness of the glycols. Thus, in vivo hydrolysis of the silacrowns will result in the loss of transmembrane carriers. Similar removal will not occur for normal crown ionophores which are both hydrolytically stable and partition into the hydrophobic phase, and remain there for long time periods.

Inotropic influence of macrocyclic polyethers on tracheal smooth muscle.

Incubated guinea pig tracheal smooth muscle exhibited both positive and negative inotropic responses to a variety of crown ether analogs that ranged in size from 12-crown-4 to 30-crown-10 and included molecules whose lipophilicity was modified by the addition of benzo- and cyclohexo-substituents on the basic molecular framework. The inotropic influence of crown ethers may not only be due to their ionophoretic capabilities but may result from their ability to affect alterations in membrane physiology.

Sudden and unexpected death in infancy and childhood: neuropathological findings.

This report describes the neuropathological findings in 58 infants and children dying suddenly and unexpectedly. Utilizing historical, clinical, laboratory and pathological findings, two subgroups were distinguished: in one a cause of death was established (CODE); members of the other (more than 50% of the total sample) were victims of sudden infant death syndrome (SIDS). The importance of historical as well as pathological data in excluding SIDS is stressed. In each subgroup, both focal lesions and diffuse glial reactive hypertrophy were identified in 64% of all children below 9 months of age. These changes were not related to age group or maturation and, except for a history of perinatal asphyxia, lesions were not predictably correlated with clinical data. The brains of children dying of established cause (CODE) are not a suitable control group with which to compare those of SIDS.

Hepatocellular carcinoma. Review of 32 cases in childhood and adolescence.

The clinical and pathologic features of 32 children and adolescents with hepatocellular carcinoma (HCC) are reviewed. Their average age at diagnosis was 9.7 years (range, 5 months to 21 years) and there was a slight predilection for males in a ratio of 1.7 to one. Of eight patients with associated or underlying abnormalities, five had cirrhosis, two had an antecedent (or coexisting) tumor fulfilling pathologic criteria for hepatic adenoma, and one developed HCC ten years after nephrectomy and radiation therapy for a Wilms' tumor. Our data reaffirm the high mortality associated with HCC (91%). Three of five tumors classified as fibrolamellar type were amenable to surgical resection while only 15% of the remaining HCC were operable. The average duration of disease for patients with conventional HCC was 4.2 months, while those with the fibrolamellar variant had a more lingering course (average, 28.5 months). Available data indicate that the fibrolamellar variant should be distinguished from HCC with more conventional histology because of greater resectability and improved overall survival.

Midtrimester diagnosis of severe deforming osteogenesis imperfecta with autosomal dominant inheritance.

Sonographic examination of a fetus whose father had severe deforming osteogenesis imperfecta (OI) was performed. The father had multiple congenital rib and extremity fractures. Subsequent fracture and deformity had suggested an autosomal recessive OI syndrome. However, fetal sonography at 18 weeks gestational age showed foreshortening of long bones in both legs and a reduced thoracic circumference, recapitulating, in part, the father's phenotype. This third reported case of early fetal diagnosis of autosomal dominant OI suggests that the fetal sonographic phenotype reflects that of the affected parent. Implications of this case for the application of fetal sonography in dominant OI syndromes are discussed.

Fingerprint inclusions in normal fetal muscle.

In muscle disease, fingerprint inclusions are variously described as a diagnostic or non-specific alteration. Fingerprint inclusions identified in human fetal muscle suggest these bodies may be transient structures of developmental significance accounting for their infrequent occurrence in myopathies of diverse pathogenesis and clinical expression.

Effect of insulin on the size of skeletal muscle fibers of fetal rhesus monkey.

Increased body weight of insulin-treated fetuses is largely attributed to increased muscle mass. Skeletal muscle from fetal rhesus monkeys was analyzed for differences in the sizes of muscle fibers from monkeys treated in utero with high or low doses of insulin and compared to control (non-insulin-treated) animals. The results indicate no significant difference among the various groups studied and suggest that hyperplasia, not hypertrophy, of skeletal muscle fibers is responsible for the observed increase in muscle mass.

Treatment of myopic astigmatism with photorefractive keratectomy using an erodible mask.

The Summit Technology erodible mask treatment of astigmatism does not alter the keratometric astigmatism significantly, even though the refractive astigmatism appears to improve by about 50%. Myopia is satisfactorily treated with the erodible mask, but there is slightly more undercorrection compared to photorefractive keratectomy (PRK) using an expanding diaphragm. Increasing the minus power in ordering the mask cylinder improves the myopia result, but not the keratometric astigmatism result. The following factors do not influence the keratometric astigmatism result: 1) The type of astigmatism (with-, against-the-rule, or oblique); 2) The initial keratometry readings; and 3) The time from the commencement of epithelial removal to laser treatment.

Hepatic subcapsular hematomas in fetuses and neonatal infants.

In fetuses and neonates hepatic subcapsular hematomas are relatively common lesions and may be life-threatening. Conditions previously associated with these hematomas include trauma, coagulopathies, hypoxia, sepsis, pneumothorax, maternal diseases, and placental lesions. In this study of 755 perinatal autopsies, hepatic subcapsular hematomas were found in 52 (6.9%) cases, including 31 stillborn fetuses and 21 liveborn infants. The average body weight was 690 g. A comparison group consisted of 52 temporally proximal autopsies of fetuses and neonates without hematomas. Body weights, gender, maternal age, and stillbirth or postnatal survival were matched as closely as possible while evaluating the presence or absence of sepsis, pneumothorax, cerebral germinal matrix hemorrhage, trauma, coagulopathy, placental lesions, and maternal diseases. Sepsis was associated with 62% of the cases with hepatic subcapsular hematomas and with 25% of the comparison group (P =.0001). Group B streptococcus infection was the most common cause of sepsis, but many different organisms were isolated. Cerebral germinal matrix hemorrhages were present in 35% of the cases with hematomas and in 14% of the comparison group (P =.0001). No other lesions or conditions were statistically different in the study group versus the comparison group. The delicacy of the hepatic capsule and its connections to the collagen along the sinusoids provide insight for the pathogenesis of hematomas in premature fetuses and neonates. We conclude that sepsis is present in most perinatal cases of hepatic subcapsular hematomas and that such patients also frequently have cerebral germinal matrix hemorrhages. Each of these lesions is a greater hazard among very small premature fetuses or neonates than among older fetuses and neonates.

Photorefractive keratectomy for myopia: 6-month results in 95 eyes.

Ninety-five eyes of 91 patients with myopia from -1.00 to -6.00 D (mean -3.40 D, +/- 1.2) were treated with an ExciMed UV2OOLA 193-nanometer excimer laser (Summit Technology, Inc, Waltham, Mass) (with version 5.5 software) with a 5-millimeter ablation zone. At 6 months, 67 eyes (70%) were within +/- 0.50 D, 84 eyes (88%) were within +/- 1.00 D, and 94 eyes (99%) were within +/- 2.00 D. There was an average overcorrection of +0.25 D which had decreased to +0.18 D by 9 months. Best spectacle corrected visual acuity was 6/6 or better in 88 eyes (94%) and six eyes (6%) had a corrected visual acuity of 6/9. Fifty percent of eyes had slight astigmatism (mean 0.68 D, range 0.25 to 2.00 D) and this reduced to 0.33D (0.02 > p > 0.01) at 6 months.