Faculty Bibliography

Byler disease (ByD) is an autosomal recessive disorder in which cholestasis of onset in infancy leads to hepatic fibrosis and death. Children who have a clinically similar disorder, but are not members of the Amish kindred in which ByD was described, are said to have Byler syndrome (ByS). Controversy exists as to whether ByD and ByS (subtypes of progressive familial intrahepatic cholestasis [PFIC]) represent one clinicopathological entity. The gene for ByD has been mapped to a 19-cM region of 18q21-q22. PFIC caused by a lesion in this region, including ByD, can be designated PFIC-1. Examination of haplotypes in siblings with ByS in two unrelated non-Amish families showed that the gene(s) responsible for their disorder(s) did not lie in the PFIC-1 candidate region. On light microscopy and transmission electron microscopy (TEM), liver tissue differed between Amish children with PFIC-1, who had coarsely granular bile and at presentation had bland intracanalicular cholestasis, and the children with ByS in the two non-Amish families, who had amorphous or finely filamentous bile and at presentation had neonatal hepatitis. Bile acid composition of bile also differed: In the Amish children with PFIC-1 and in one ByS family, the proportional concentration of chenodeoxycholic acid (CDCA) in bile was low compared with normal bile; in the other ByS family, it was only slightly reduced. Genetic analysis and light microscopy and TEM of liver may help distinguish PFIC-1 from other forms of ByS.

Multiple foci of heterotopic liver in the jejunum were sequentially discovered in an infant boy at the ages of 1 day, 2 months, and 4 months. This is the second reported case of jejunal heterotopic liver, a rare entity in any site. Progressive histological changes indicative of biliary duct obstruction were observed in the hepatic heterotopias, which demonstrated no connections to the main body of the liver or biliary tree.

We report a case of an infantile myofibromatosis with hemangiopericytoma-like features arising in the tongue of a 5-month-old female infant. Many authors now classify neoplasms as infantile myofibromatosis that were previously called infantile hemangiopericytoma. The ultrastructural features of our tumor illustrate its biphasic nature and provide a possible explanation for its histogenesis. Infantile myofibromatosis, including those diagnosed as infantile hemangiopericytomas, rarely arise in any intraoral location. Despite the generally good prognosis associated with these neoplasms, complete surgical excision is recommended to avoid recurrences.

Recent work has implicated nitric oxide (NO) in several aspects of male genital physiology including erectile function and androgen secretion, as well as in vitro effects on sperm motility and capacitation. The objectives of this study were to characterize the distribution of endothelial nitric oxide synthase (eNOS) in "normal" human testis, epididymis, and vas deferens and in testis pathology. Nitric oxide synthase protein was localized immunohistochemically using an eNOS monoclonal antibody. Endothelial NOS protein co-localized to areas that showed positive NADPH diaphorase activity. Within the testis, eNOS protein was localized to the cytoplasm of Leydig cells and Sertoli cells at all stages of spermatogenesis. Within the epididymis and vas deferens, eNOS was localized to the epithelium. Endothelial NOS was also localized to endothelial cells in all tissues; it was not detectable in normal germ cells. Endothelial NOS and diaphorase activity were, however, detected in degenerating or apoptotic intraepithelial germ cells. In addition, prematurely shed spermatocytes and spermatids had intense eNOS expression. Previous studies have suggested a role for NOS in the contractile, hemodynamic, and hormonal aspects of testicular function as well as in epididymal secretion. The studies reported herein suggest a role for eNOS in spermatogenesis and germ cell degeneration.

The cellular expression of pituitary gonadotropin receptors in gonadal tissues is poorly defined because of the lack of suitable reagents. In this study, we developed in situ hybridization and reverse transcription polymerase chain reaction techniques for the evaluation of follicle-stimulating hormone receptor (FSHR) expression in the ovary and fallopian tube. Using a single-strand RNA probe, we demonstrated that FSHR mRNA expression is strongest in Graafian follicles. Within these developing follicles, granulosa cells showed the greatest expression, although both theca interna and theca externa were also positive, interna greater than externa. Granulosa cells in both primary and primordial follicles were positive, with primordial follicles showing only weak focal positivity. Ovarian surface epithelium and fallopian tube epithelium, not previously recognized to express FSHR, were both strongly positive. The FSHR expression in the ovary and fallopian tube was confirmed by reverse transcription polymerase chain reaction. Our results indicated that the FSHR is expressed in a cell-specific fashion at different stages of follicular development and is also expressed in ovarian surface and fallopian tube epithelia. The presence of FSHR in ovarian surface epithelium and of gonadotropin-binding sites in ovarian neoplasms provide additional evidence supporting the derivation of epithelial ovarian tumors from the surface epithelium and should promote heightened interest in the gonadotropin theory of ovarian tumorigenesis. More importantly, this study shows the feasibility of evaluating FSHR expression by both in situ hybridization and reverse transcription polymerase chain reaction. Application of these techniques to tumor specimens will help to elucidate the role of gonadotropins and their receptors in the carcinogenesis of gynecological tumors.

Acute pancreatitis, reported in 17% of pediatric patients with acquired immune deficiency syndrome (AIDS), is said to have a poor prognosis. We describe the pancreatic changes observed at autopsy from 71 children with human immunodeficiency virus (HIV) infection and document their nature, extent, and clinical relevance. The median age at autopsy of the children was 17 months (range, 2 months to 19 years); 38 were boys and 33 were girls. Parental intravenous drug use was the most frequent risk factor for AIDS, followed by blood transfusions. Respiratory failure and sepsis constituted the predominant causes of death. Nonspecific changes, such as edema, inflammation, fibrosis, inspissated material in acini and ducts, and enlarged Langerhans' islet predominated. Acute and chronic pancreatitis were mild except in one instance of a fatal acute probably dideoxyinosine-associated pancreatitis. Pancreatic involvement by opportunistic infections, such as cytomegalovirus (CMV), Mycobacterium avium intracellulare (MAI), and Candida, was focal and rare despite the high prevalence of these infections at autopsy. Focal lymphoplasmacytic infiltration and vascular calcifications were also observed. We conclude that pancreatic changes were frequently noted at autopsy in children with AIDS. They were usually mild, reflected systemic disease states, and were usually not life threatening. The incidence of opportunistic infections of the pancreas was low.

OBJECTIVES: To describe the pulmonary pathology and clinical outcome in children with acute hypoxemic respiratory failure after bone marrow transplantation. DESIGN: Review of medical records and pathologic material of patients diagnosed with acute hypoxemic respiratory failure after bone marrow transplantation. SETTING: Pediatric intensive care unit (ICU) of a teaching hospital. PATIENTS AND METHODS: Retrospective review of a consecutive cohort of children, with a history of bone marrow transplantation admitted to the pediatric ICU during a 7-yr study period, and who met a published definition of acute hypoxemic respiratory failure. For each admission, the pediatric ICU course and outcome were reviewed. Pathologic material that was obtained from the patients was reexamined and assigned to one of the following categories: acute or organizing diffuse alveolar damage, pulmonary hemorrhage, nonspecific interstitial pneumonitis, or infectious pneumonia. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-three patients satisfied criteria for inclusion in the study group. Indications for bone marrow transplantation were: solid tumor (30%), leukemia (44%), congenital immunodeficiency (19%), and aplastic anemia (7%). Patients were admitted to the pediatric ICU a median of 1 month (range 0 to 126) after bone marrow transplantation. Thirty-eight (88%) patients died in the pediatric ICU. Tissue histologic material was available from 21 (49%) patients. Six (29%) of 21 patients had acute diffuse alveolar damage; one (5%) had organizing diffuse alveolar damage; three (14%) had nonspecific interstitial pneumonitis; and two (10%) had pulmonary hemorrhage. Infectious pneumonia occurred in nine (43%) cases (five fungal; four viral). CONCLUSIONS: The acute mortality rate (88%) for children with acute hypoxemic respiratory failure after bone marrow transplantation is similar to that reported for adults with this combination of conditions. Diffuse alveolar damage, the histologic hallmark of adult respiratory distress syndrome, was present in a minority (33%) of patients. Infectious pneumonia was the most frequent cause of acute hypoxemic respiratory failure in patients who had pathologic tissue available, emphasizing the need for aggressive diagnostic studies and early institution of antifungal and antiviral therapy.

Familial arrhythmogenic right ventricular dysplasia is a rare cardiomyopathy that is usually diagnosed on postmortem examination or on presentation with progressive congestive heart failure. We present a patient in whom an automatic implantable cardioverter-defibrillator was inserted prophylactically. A review of the condition and possible therapies is included.

We prospectively studied 62 consecutive infertile men who underwent 100 intraoperative wet prep cytological examinations of testis biopsy material obtained simultaneously with permanently fixed specimens. Wet preps were performed by placing a small sample of fresh testicular tissue on a slide, adding a drop of Ringer's lactate, and compressing the specimen under a glass coverslip. Among these 100 wet preps, complete sperm with tails were identified in 62 specimens, of which 44 contained nonmotile sperm and 18 contained motile sperm. Reproductive tract obstruction was documented in 65 testes (65%) on subsequent reconstructive surgery and/or inferred from histological evaluation, including mean mature spermatid counts on the permanent sections fixed in Bouin's solution. Obstruction was absent in the remaining testes (35%). All 18 testes with motile sperm found on wet prep were obstructed. These testes were also found to have complete spermatogenesis, a category selected to include normal spermatogenesis and slight hypospermatogenesis, determined by examination of the permanently fixed sections. The finding of motile vs. nonmotile sperm on a wet prep has positive predictive values of 100% vs. 81% for the presence of reproductive tract obstruction and 94% vs. 86% for complete spermatogenesis, respectively. The presence of motile sperm in human testis biopsy specimens is a novel finding. When any complete sperm with tail is found in a testis biopsy wet prep, obstruction is likely. When motile sperm are present, obstruction is almost certain, and immediate exploration and reconstructive surgery can be justified.(ABSTRACT TRUNCATED AT 250 WORDS)