Biomedical subjects
Publications and source records attributed to M A Greco.
A 13-year-old boy with Down syndrome (DS) had a brainstem glioma confirmed at autopsy, 10 years after receiving prophylactic cranial irradiation for acute myeloblastic leukemia. There is no clear association of brain tumors with DS; despite a reported link between leukemia and glioma, a causal association with radiation therapy is more likely.
A method providing more sensitive detection of transglutaminase substrates was developed to localize transglutaminase activity in tissue and to identify in vivo substrates in epidermal extracts. The enhanced sensitivity of this method was achieved via the generation of a monoclonal antibody (designated E7) made to dansylcadaverine. Transglutaminase substrates were visualized by western blot after a 1-min incubation with dansylcadaverine in contrast to the 2 h required when [14C]putrescine incorporation was measured by autoradiography of SDS-polyacrylamide gels. In addition, putative substrates not apparent using conventional methods were readily detected by western analysis. An ELISA assay to measure transglutaminase activity showed similar sensitivity to the traditional radiometric assay (Lorand et al., 1972). The correlation between the ELISA procedure and the radiometric assay was high (r2 = 0.924). Strips of neonatal human and mouse skin incubated in dansylcadaverine-supplemented culture medium were used to localize enzyme activity and to detect substrates in vivo. Transglutaminase activity was demonstrated at the cellular periphery in the upper spinous and granular cell layers of the epidermis. Substrates detected in epidermal extracts were similar to those detected using the in vitro assay. This technique allows for highly sensitive and nonradiometric analysis of both enzymatic activity and the substrates involved. The extension of this methodology to an in vivo system is the first demonstration of a system in which the dynamics of cornified envelope assembly may be further studied.
Patients with retinoblastoma have an increased risk of developing second primary tumors. Only a few examples of sinonasal small cell neoplasms developing after radiation therapy for retinoblastoma have been reported. We report one such case that developed 18 years after treatment for retinoblastoma. Histologic examination revealed a small, blue, round cell tumor without rosettes or cytoplasmic glycogen. Immunohistochemically, the tumor cells were positive for neuron-specific enolase, synaptophysin, and S-100 protein, but negative for epithelial and mesenchymal markers, suggesting that this was a primitive neuroectodermal tumor. Cytogenetic studies of this tumor failed to reveal the chromosome 13 abnormality typical of retinoblastoma and the t(11:22) translocation typical of the group of peripheral neuroepitheliomas.
A case of primary lymphoma of the ovary with extensive stromal luteinization is presented. Immunohistochemical markers that work satisfactorily in fixed tissues allowed a diagnosis of B cell lymphoma to be made on formalin-fixed tissue sections. Immunohistochemical analysis of frozen tissue and genotypic analysis confirmed the diagnosis of B cell lymphoma. By electron microscopy two populations of cells, including large atypical lymphoid cells and luteinized stromal cells, were identified. Presentation with amenorrhea and resumption of menstrual periods after removal of the tumor suggested the possibility of functional activity in the luteinized stromal cells. Stromal luteinization has not been previously described in primary ovarian lymphoma.
A 13-month-old immunocompetent girl had fever, rash, and multisystem disease, and she eventually died of cardiac failure. Autopsy revealed intracellular viral inclusions of the herpesvirus group, with results of in situ hybridization positive for human herpesvirus-6. This is apparently the first case of fatal disseminated herpesvirus-6 infection.
We report nine examples of a distinct cutaneous plaque-like proliferation of fibroblasts and myofibroblasts. Eight of nine lesions were located in or around the shoulder, including axilla and upper arm. There was a predominance of women to men of 8:1. The lesions measured from 1 to 2 cm in greatest diameter. All patients were young adults (mean age 29.8 yr). All lesions involved the reticular dermis in a plaque-like fashion and extended to the upper part of the subcutaneous septa in seven cases. The lesions consisted of a proliferation of very uniform slender spindle-shaped cells arranged as well-defined elongated and intersecting fascicles with a predominantly parallel arrangement to the skin surface. There was no evidence of cytologic atypia and mitotic figures were infrequent. The spindle-shaped cells were separated by thin collagen fibers. Elastic fibers were preserved and some of them appeared thicker than normal. All adnexal structures were spared. Immunohistochemistry revealed that the cells stained positively for vimentin and muscle actin, but lacked smooth-muscle specific actin, desmin, and S-100 protein. Some dermal dendrocytes stained positively for Factor XIIIa, but the spindle-shaped cells were negative. Electron microscopy studies revealed a mixture of fibroblasts, myofibroblasts, and undifferentiated mesenchymal cells. All lesions were treated by conservative excision; follow-up information revealed no evidence of recurrence. We name this distinct lesion dermatomyofibroma. To the best of our knowledge, this entity has not been previously described in the literature.
Villous stromal cells (VSC) play an important role in fetomaternal placental immune function. We studied the phenotype of VSC in infection by cytomegalovirus (CMV) and syphilis as well as nonspecific villitis and compared the findings with gestational age-matched controls. Monoclonal antibodies directed against total leukocytes, T cells, B cells, macrophages, dendritic cells, granulocytes and HLA-DR as well as polyclonal antibodies against S-100, alpha-1 antichymotrypsin, and lysozyme were used. In controls, the immunocytochemical response for each marker was either negative or weakly positive. In contrast, the VSC in CMV-infected and nonspecific villitis showed intense reactivity to various macrophage markers. In syphilis, reactivity with macrophage markers such as lysozyme and MAC387 were weaker, and reactivity to HLA-DR and S-100 was much stronger. Endothelial cells strongly expressed the monocyte/granulocyte marker CD15 in the diseased states, especially in syphilis, relative to controls. We conclude that the phenotype of VSC is altered in disease states and that the changes are dependent to some degree on the specific subset of chronic villitis.
HIV infection is responsible for a major proportion of the immunodeficiency disease seen in the pediatric population. The radiologic findings are varied and generally non-specific. The development of secondary neoplasms may present new diagnostic and therapeutic challenges as therapy for superimposed infections becomes more successful.
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In a retrospective study we assessed the hepatic changes in children with the acquired immunodeficiency syndrome by reviewing 12 biopsy specimens and 48 autopsy specimens from 54 children. Hepatopathology differed in biopsy and autopsy material. In biopsy specimens, chronic active hepatitis with predominantly T8 lymphocytes by tissue immunochemistry was common (five of 12 specimens). Fatty degeneration and hepatocellular necrosis were either absent, mild, or patchy. On the other hand, at autopsy, chronic active hepatitis was not observed. The most prominent changes were extensive fatty degeneration, nonspecific portal mononuclear infiltration, portal fibrosis, and confluent (ischemic) necrosis. Opportunistic infections such as Mycobacterium avium-intracellulare (MAI) were noted only at autopsy. In addition, three unusual morphologic characteristics were noted: nodular lymphoplasmacytic portal infiltrate, a pseudosarcomatous variant of Mycobacterium avium-intracellulare infection, and multinucleated giant cells (foreign both type and giant cell transformation of hepatocytes).
The pathology of term placentas from seropositive human immunodeficiency virus (HIV)-infected and seronegative women was investigated by routine histologic, immunocytochemical, and in situ hybridization techniques. Placentas were evaluated for evidence of villitis, chorioamnionitis, and funisitis. Membranes, trophoblast, and decidua were also examined by immunohistochemistry using monoclonal HIV p24 antibody. Twenty placentas were evaluated by combined immunochemical and in situ hybridization techniques, using a 35S-labeled RNA probe complementary to the 3' long terminal repeat and envelope region of HIV-1. HIV-seropositive placentas did not show significant villitis; however, the incidence of chorioamnionitis increased (P less than .01). HIV antigens and nucleic acids were identified in the trophoblast of 10% of the placentas that also showed chorionitis. Term HIV-positive placentas may show histologic changes that may or may not be directly related to the virus. Analysis of tissues from earlier gestational placentas may prove more informative in clarifying the mechanism of maternal-fetal HIV transmission.
A retrospective review of charts of 156 human immunodeficiency virus-infected children cared for during a 7.5-year period revealed 11 episodes of disseminateed candidiasis (DC) occurring in 11 patients (7%). All 11 patients developed the fungal infection in the context of advanced human immunodeficiency virus infection. All but one were hospital-acquired, occurring at a mean of 2.3 months after admission. Ten patients had been febrile for more than 14 days before diagnosis. Previous oral thrush and central venous catheters (73 and 82% of patients) represented major predisposing factors for development of DC. Neutropenia (2 of 11 patients) did not represent a major risk factor for DC. Candida albicans was isolated in 9 patients, Rhodotorula minuta in 1 patient and 1 fungal isolate could not be identified. Sources of isolation were blood (8 of 11 patients), central venous catheters (3 of 11) and urine (2 of 11). Lungs (6 of 11 patients), esophagus (5 of 11) and brain, heart and kidneys (3 patients each) were the organs most often involved in DC. Antemortem diagnosis was achieved in only 7 (64%) patients; none of the 4 patients with DC diagnosed postmortem had been treated before death. Seven patients were treated with amphotericin B; 6 of them died but only 3 were treated for more than 7 days of therapy. The overall mortality was 90% (10 of 11 patients). In all 20% of the 50 human immunodeficiency virus-infected children who died at our hospital during the study period had an episode of DC in close proximity to their death. DC was considered the direct cause of death in 4 of 10 children.
A patient with human immunodeficiency virus infection presented with a soft-tissue mass which histologically and clinically mimicked an angiosarcoma. Ultrastructural study, however, revealed bacteria identical to those seen in cutaneous bacillary angiomatosis, but the patient had no skin lesions. To our knowledge, this represents the first report of soft tissue involvement by bacillary angiomatosis without the presence of skin lesions.
A Wilms' tumor from a 12-month-old boy showed epithelial and mainly rhabdomyoblastic differentiation. In addition, the kidney contained foci of nephroblastomatosis, a lesion predisposing to the development of nephric tumors. Flow cytometry indicated that the tumor DNA content was in the diploid range with an increased S-phase. Chromosome studies of the cultured tumor cells showed a dominant pattern of 49,XY, +8,9qh+, +12, +12,18q+, without obvious deletion of 11p. A few cells showed additional losses, deletions, or structural rearrangements superimposed on the basic pattern, but no normal metaphases were observed. The DNA from the tumor was probed for several loci on 11p because variations of 11p (deletion or translocation) have been reported in roughly one third of Wilms' tumors, and the critical gene in Wilms' has been localized to 11p13. In this case, 11p genes maintained heterozygosity or showed no detectable alteration in gene dosage when compared with peripheral-blood DNA. Therefore, despite histologic indication of an underlying constitutional defect, no genomic lesion of 11p was identified.
We describe a case of fibrous histiocytoma of the trachea diagnosed in a 17-year-old female who presented with symptoms of 'asthma'. Management included rigid bronchoscopy with biopsy and debulking of this obstructing tumor, later excised with partial tracheal resection. Although tracheal tumors are quite rare in children, the majority (6/9) of reported cases of fibrous histiocytoma of the trachea have been described in the pediatric age group. The possibility of a tracheal neoplasm as a cause of wheezing, stridor or hemoptysis in children should be recognized. Control of the airway without tracheotomy may facilitate surgical cure via tracheal resection in such cases.
A wild-type strain of the yeast Saccharomyces cerevisiae grown at a medium [Cu] of less than or equal to 50 nM contained less Cu,Zn superoxide dismutase (SOD) mRNA (60%), protein (50%), and activity (50%) in comparison with control cultures grown in normal synthetic dextrose medium ([Cu] approximately 150 nM). A compensating increase in the activity of MnSOD was observed, as well as a smaller increase in MnSOD mRNA. These medium [Cu]-dependent differences were observed in cultures under N2 as well. Addition of Cu2+ (100 microM) to Cu-depleted cultures resulted in a rapid (30 min) increase in Cu,ZnSOD mRNA (2.5-fold), protein (3.5-fold), and activity (4-fold). Ethidium bromide (200 micrograms/ml of culture) inhibited by 50% the increase in Cu,ZnSOD mRNA, while cycloheximide (100 micrograms/ml of culture) inhibited completely the increase in protein and activity. Addition of Cu2+ to greater than or equal to 100 microM caused no further increase in these parameters but did result in a loss of total cellular RNA and translatable RNA, a decline in the population of specific mRNAs, a decrease in total soluble protein and the activity of specific enzymes, and an inhibition of incorporation of [3H]uracil and [3H]leucine into trichloroacetic acid-insoluble material. Cu,ZnSOD mRNA, protein, and activity appeared relatively more resistant to these effects of Cu toxicity than did the other cellular constituents examined. When evaluated in cultures under N2, the cellular response to [Cu] of greater than or equal to 100 microM was limited to the inhibition of radiolabel incorporation into trichloroacetic acid-insoluble material. All other effects were absent in the absence of O2. The data indicated that medium (cellular) Cu alters the steady-state level of Cu, ZnSOD. This regulation may be at the level of transcription. In addition, Cu,ZnSOD exhibits the characteristics of Cu-stress protein in that it and its mRNA are enhanced relative to other cellular species under conditions of Cu excess. This observation and the O2-dependence of some of the manifestations of Cu excess suggest that one mechanism of Cu toxicity involves the superoxide radical anion O2-.
Chronic villitis with villous lymphoplasmacytic, histiocytic infiltrate and stromal necrosis may have various etiologies. Infection with cytomegalovirus (CMV) is a frequent cause of such villitis, but the nuclear and cytoplasmic inclusions diagnostic of CMV are often not apparent. In this study placentas with chronic villitis were analyzed for CMV DNA by means of in situ hybridization. Of the eight cases of chronic villitis studied, three demonstrated inclusions diagnostic of CMV infection. On in situ hybridization, three additional cases had detectable CMV DNA. CMV was detected in endothelial, histiocytic, and fibroblastic cells and occasionally in the trophoblast. In cases with characteristic CMV inclusions, CMV DNA was often present in cells that lacked inclusions. CMV DNA was not detected in unremarkable placental tissue obtained from normal deliveries. It is concluded that CMV is commonly found in lymphoplasmacytic and histiocytic villitis and that in situ analysis for CMV is a rapid, easy, and sensitive way to detect the virus in placentas.
Cytomegalovirus in children with human immunodeficiency virus (HIV) infection can result in widespread involvement of enteric ganglion cells. Intestinal ganglioneuronitis, as noted in the two infants cited, expands the spectrum of neurologic lesions in children with acquired immunodeficiency syndrome (AIDS).