Arthur G. Weinberg

The neonatal blood count in health and disease.I. Reference values for neutrophilic cells

Reference ranges for absolute total neutrophils/mm3, absolute immature neutrophils/mm3, and the fraction of immature to total neutrophils (I:T proportion) during the first 28 days of life are developed from 585 peripheral blood counts obtained from 304 normal neonates and 320 counts obtained from 130 neonates with perinatal complications demonstrated to have no statistically significant effect on neutrophil dynamics. Perinatal factors other than bacterial disease which significantly alter neutrophil dynamics include maternal hypertension, maternal fever prior to delivery, hemolytic disease, and periventricular hemorrhage. The predictive value of these reference ranges in identifying bacterial disease in the first week of age varies with the neutrophil factor evaluated and the clinical setting. Neutropenia in the presence of respiratory distress in the first 72 hours had an 84% likelihood of signifying bacterial disease, whereas neutropenia in the presence of asphyxia had a 68% likelihood of signifying bacterial disease. An abnormal I:T proportion had an accuracy of 82% and 61%, respectively, in the same clinical settings. Elevations of either immature or total neutrophils were less specific. Interpretation of abnormal neutrophil factors must include consideration of both infectious and noninfectious perinatal events.

Prenatal Dexamethasone Programs Hypertension and Renal Injury in the Rat

Abstract—Dexamethasone is frequently administered to the developing fetus to accelerate pulmonary development. The purpose of the present study was to determine if prenatal dexamethasone programmed a progressive increase in blood pressure and renal injury in rats. Pregnant rats were given either vehicle or 2 daily intraperitoneal injections of dexamethasone (0.2 mg/kg body weight) on gestational days 11 and 12, 13 and 14, 15 and 16, 17 and 18, or 19 and 20. Offspring of rats administered dexamethasone on days 15 and 16 gestation had a 20% reduction in glomerular number compared with control at 6 to 9 months of age (22 527±509 versus 28 050±561, P <0.05), which was comparable to the percent reduction in glomeruli measured at 3 weeks of age. Six- to 9-month old rats receiving prenatal dexamethasone on days 17 and 18 of gestation had a 17% reduction in glomeruli (23 380±587) compared with control rats (P <0.05). Male rats that received prenatal dexamethasone on days 15 and 16, 17 and 18, and 13 and 14 of gestation had elevated blood pressures at 6 months of age; the latter group did not have a reduction in glomerular number. Adult rats given dexamethasone on days 15 and 16 of gestation had more glomeruli with glomerulosclerosis than control rats. This study shows that prenatal dexamethasone in rats results in a reduction in glomerular number, glomerulosclerosis, and hypertension when administered at specific points during gestation. Hypertension was observed in animals that had a reduction in glomeruli as well as in a group that did not have a reduction in glomerular number, suggesting that a reduction in glomerular number is not the sole cause for the development of hypertension.

The occurrence of hepatoma in the chronic form of hereditary tyrosinemia.

A 5 1/2-year-old child with hepatocarcinoma complicating hereditary tyrosinemia is presented. A review of the literature and an attempted follow-up of previously reported patients with the chronic form of hereditary tyrosinemia have disclosed 16 cases of hepatocarcinoma occurring in 43 patients surviving beyond 2 years of age (37%). This incidence is considerably higher than that generally given for the occurrence of hepatoma in adults with macronodular cirrhosis. Females and males are equally at risk. Additional factors beyond the development of cirrhosis are likely operative in the induction of hepatocarcinoma in patients with this metabolic disorder; those surviving beyond infancy are at considerable risk for the development of fatal hepatic neoplasms.

Precursor B-cell lymphoblastic lymphoma: A study of nine cases lacking blood and bone marrow involvement and review of the literature

We describe 9 cases of precursor B-cell lymphoblastic lymphoma (LYL) without evidence of marrow or blood involvement. Four patients had superficial nodal disease, 2 cutaneous involvement, and 1 each ovarian, retroperitoneal, or tonsillar primary tumor. Six patients had limited disease; 3 patients were stage III. Immunophenotyping revealed a terminal deoxynucleotidyl transferase (TdT)-positive, immature B-cell population with variable expression of CD10, CD20, and CD45. All patients are in complete clinical remission (median follow-up, 14 months). A literature review yielded 105 patients with a diagnosis of precursor B-cell LYL based on less than 25% marrow involvement. Of these, 64% were younger than 18 years. Skin, lymph nodes, and bone were the most common sites of disease. Mediastinal involvement was uncommon. TdT, CD19, CD79a, CD10, and HLA-DR were the most frequently expressed antigens, while CD45 and CD20 were expressed in only two thirds of the cases. Cytogenetic analysis showed additional 21q material as a recurring karyotypic abnormality. At a median follow-up of 26 months, 74% of patients were alive; the median survival was 19 months for patients dying of disease. Comparison with precursor B-cell acute lymphoblastic leukemia showed several overlapping features, although distinct differences were identified.

The differential leukocyte count in the assessment and outcome of early-onset neonatal group B streptococcal disease

The usefulness of the differential white blood cell count in distinguishing early-onset group B streptococcal disease from other causes of neonatal respiratory distress was studied in 45 infants with culture-proved infection. The initial diagnosis was hyaline membrane disease in 19 infants, wet lung syndrome 13, and other causes of respiratory distress in 13. Thirty-nine (87%) had abnormal absolute neutrophil counts, 25 with neutropenia and 14 with neutrophilia. The absolute immature neutrophil count was elevated in 19 infants (42%). Forty-one infants (91%) had an abnormal immature neutrophil to total neutrophil ratio. All infected infants were identified when both the absolute total neutrophil count and ratio were used. The differential white cell count appears to be a useful tool for screening infants presenting with respiratory distress in the first 48 hours of life and for separating early-onset group B streptococcal disease from other causes of neonatal respiratory distress.

Weekly Cyclodextrin Administration Normalizes Cholesterol Metabolism in Nearly Every Organ of the Niemann-Pick Type C1 Mouse and Markedly Prolongs Life

Niemann-Pick type C1 (NPC1) disease arises from a mutation inactivating NPC1 protein that normally moves unesterified cholesterol from the late endosomal/lysosomal complex of cells to the cytosolic compartment for processing. As a result, cholesterol accumulates in every tissue of the body causing liver, lung, and CNS disease. Treatment of the murine model of this disease, the npc1−/− mouse, s.c. with β-cyclodextrin (4000 mg/kg) one time each week normalized cellular cholesterol metabolism in the liver and most other organs. At the same time, the hepatic dysfunction seen in the untreated npc1−/− mouse was prevented. The severity of cerebellar neurodegeneration also was ameliorated, although not entirely prevented, and the median lifespan of the animals was doubled. However, in contrast to these other organs, lung showed progressive macrophage infiltration with development of lipoid pneumonitis. These studies demonstrated that weekly cyclodextrin administration overcomes the lysosomal transport defect associated with the NPC1 mutation, nearly normalizes hepatic and whole animal cholesterol pools, and prevents the development of liver disease. Furthermore, this treatment slows cerebellar neurodegeneration but has little or no effect on the development of progressive pulmonary disease.

Allergic aspergillosis: A newly recognized form of sinusitis in the pediatric population

In 1983, Katzenstein, et al. first described a form of noninvasive sinusitis in adults, which was histologically identical to allergic bronchopulmonary aspergillosis, with mucin‐containing eosinophils, Charcot‐Leyden crystals, and fungal elements resembling Aspergillus species. The authors have treated six pediatric patients ages 8 to 16 who had findings typical of allergic Aspergillus sinusitis. All patients presented with nasal polyposis and progressive facial deformity. All patients had computed tomography findings of diffuse expansile sinus disease and four patients had evidence of bony erosion, raising the suspicion of malignancy. At surgery, all were found to have multiple sinuses densely packed with greenish‐black inspissated mucin. Therapy consisted of wide surgical drainage with careful follow‐up and nasal steroids.

Spitz nevi and atypical Spitz nevi/tumors: a histologic and immunohistochemical analysis

A subset of Spitz nevi poses substantial diagnostic difficulty, even among experts, due to its resemblance to malignant melanoma. These lesions are termed atypical Spitz nevi/tumors and there is currently a lack of objective criteria for predicting their biologic behavior. We compared the expression of Ki-67, p21, and fatty acid synthase by immunohistochemistry in 10 atypical Spitz nevi, 28 typical Spitz nevi, 19 compound melanocytic nevi and 18 invasive malignant melanomas. There was a progressive increase in fatty acid synthase cytoplasmic expression with statistically significant differences observed between Spitz nevi and atypical Spitz nevi (P=0.003) and between atypical Spitz nevi and malignant melanoma (P<0.050). Ki-67 nuclear staining was lower in both typical and atypical forms of Spitz lesions than in malignant melanoma (P<0.001). The degree of P21 nuclear expression in atypical Spitz nevi was not significantly different than in Spitz nevi, but was significantly greater than expression in conventional nevi and approached significance after multiple comparisons corrections for malignant melanoma. Thus, a high level of P21 expression makes a tumor more likely to be a typical or atypical Spitz nevus than a malignant melanoma, especially when coupled with a low Ki-67 index and weak expression of fatty acid synthase. These immunohistochemical observations support the concept that atypical Spitz nevi are distinct lesions of borderline biologic behavior residing between Spitz nevi and malignant melanoma. The study also compared a large array of histologic features of 16 cases of typical Spitz nevi in children with 12 typical Spitz nevi in adults. The adult lesions were significantly more likely to be intradermal and to display dermal fibroplasia, but were histologically similar to their pediatric counterparts in all other respects.

Renal angiomyolipomas and HMB-45 reactivity.

Background. Renal angiomyolipomas (RAML) are mesenchymal hamartomas composed of varying amounts of blood vessels, smooth muscle, adipose tissue, and supporting connective tissue. Although most of these tumors are easy to recognize, some show unusual histologic features and may pose a diagnostic dilemma. Recent reports indicate that RAML are immunoreactive for HMB‐45 antibody, which is directed against a premelanomasome‐associated glycoprotein and is thought to be specific for melanocytic differentiation.

Nongerminomatous malignant germ cell tumors in children: a review of 89 cases from the pediatric oncology group, 1971-1984

Clinical and morphologic features of 89 cases of childhood yolk sac tumor (YS) and embryonal carcinoma (EC) (29 associated with teratomas) submitted to the Rare Tumor Registry of the Southwest Oncology Group (1971–1979) or the Pediatric Oncology Group (1980–1984) between 1971 and 1984 were reviewed and submitted to statistical analysis. This review showed an improved survival for each 5‐year period regardless of tumor site, no statistically significant difference between “pure” tumors and those mixed with other teratomatous components, no statistically significant difference between YS and EC in children, a better than reported prognosis for sacrococcygeal tumors occurring after the neonatal period, a particularly poor prognosis for neonatal “benign” sacrococcygeal teratomas respected without coccygectomy when they recur as YS, excellent survival for all testicular tumors regardless of age or the presence of EC, and the occurrence of mediastinal tumors in females.