Carlos R. Abramowsky

T-Cell Lymphomas Containing Epstein–Barr Viral DNA in Patients with Chronic Epstein–Barr Virus Infections

Fatal T-cell lymphomas developed in three patients with a chronic illness manifested by fever, pneumonia, dysgammaglobulinemia, hematologic abnormalities, and extraordinarily high titers of antibody to the Epstein-Barr virus (EBV) capsid antigen (greater than 10,000) and early antigen (greater than 640) but low titers to the EBV nuclear antigen (less than or equal to 40). To understand the pathogenesis of these tumors better, we determined the immunophenotype of the tumor cells and analyzed tumor-cell DNA for EBV genomes and for lymphoid-cell gene rearrangements. More than 80 percent of the cells in tumors had an activated helper T-cell phenotype (T4, T11, la positive). The EBV genome was found by in situ hybridization in tumor tissue from each patient. Southern blot assay of DNA digests from one patient showed the same pattern as that of the EBV-infected marmoset line, B95-8. DNA digests from two patients showed a monoclonal proliferation of T cells determined on the basis of uniform T-cell-receptor gene rearrangements and a single band for the joined termini of the EBV genome. We conclude that EBV may infect T cells and contribute to lymphomas in selected patients with severe EBV infections.

Clinical and pathologic aspects of recurrent placental villitis

In a retrospective survey, recurrent villitis was identified in ten of 59 patients in whom placental villitis had been diagnosed. The ten patients had a total of 41 pregnancies, with a reproductive loss of 60 per cent. In addition to enhanced fetal losses in all trimesters of gestation and postnatally, the incidences of fetal growth retardation and premature delivery were increased. There was no evidence of recent TORCH (toxoplasma, rubella, cytomegalovirus, herpes) infection, but all patients tested had rubella immunity. In six patients genital cultures were positive for gonorrhea and assorted microorganisms. Uterine abnormalities, including two septate uteri, one incompetent cervix, one submucosal leiomyoma, and one retroflexion, were common, and vaginal bleeding had occurred in five patients. Other factors included obesity (five patients) and clinical and laboratory evidence of autoimmunity (four of the five patients tested). In a control group of 20 patients with nonrecurrent villitis, the perinatal loss rate (37 per cent) was lower, and the incidences of positive cultures, uterine structural anomalies, obesity, and autoimmunity were also lower. Placental histologic findings included decidual plasma cell and intervillous fibrin and histiocytic infiltration, in addition to villous inflammation. These lesions, although consistent for a given patient, defined two clinically relevant groups of patients. The results of this study suggest that recurrent villitis is more frequent than previously reported, that it is associated with high perinatal mortality, and that immunologic and structural abnormalities in the host may play a role in its pathogenesis.

The effects of placental malaria on mother-to-child HIV transmission in Rakai, Uganda.

We examined the association of placental malaria and mother-to-child transmission (MTCT) of HIV in a prospective community-randomized trial in Rakai District, Uganda. In the 746 HIV-positive mother-infant pairs, the MTCT rate was 20.4%. Placental malaria was more common in HIV-positive than HIV-negative women. After multivariate adjustment for HIV viral load, the risk of MTCT associated with placental malaria was 2.89 and with HIV viral load the risk was 2.85. Interventions to prevent malaria during pregnancy could potentially reduce MTCT.

Clonal relationship between precursor T-lymphoblastic leukaemia/lymphoma and Langerhans-cell histiocytosis

1but the biological basis for this link is unknown. We report two cases of Langerhans-cell histiocytosis arising in the context of precursor T-lymphoblastic leukaemia/lymphoma. The Langerhans-cell histiocytosis cells and the precursor T-lymphoblastic leukaemia/lymphoma cells had identical rearrangements of the gene for T-cell receptor � , confirming a clonal relation between the two neoplastic diseases. In April, 1996, a 5-year-old boy presented with a mediastinal mass and a white-cell count of 2·9� 10 9 /L. Bone-marrow aspiration showed precursor T-cell acute lymphoblastic leukaemia; cerebrospinal fluid was negative. He had a complete response to the BerlinFrankfurt-Munster middle-risk schedule. However, from August, 1998, to October, 1998, he developed multiple penile lesions and a biopsy sample showed Langerhans-cell histiocytosis. Between 1998 and 2002 he received several chemotherapeutic regimens and radiotherapy (total dose 44·8 Gy), without a sustained complete response. Regimens included: etoposide and prednisolone; combinations of topical chlormethine, indometacin, betamethasone-depot, vinblastine, thalidomide, etanercept, and intralesional methylprednisolone; mercaptopurine, vinblastine, and 500 mg/m 2 metho

Fetus-in-fetu with malignant recurrence

Fetus-in-fetu is an unusual condition in which a vertebrate fetus is enclosed within the abdomen of another fetus. These occurrences are usually benign. This report describes an instance of malignant recurrence after resection of a fetus-in-fetu.

Placental findings in singleton stillbirths

OBJECTIVE: To compare placental lesions for stillbirth cases and live birth controls in a population-based study. METHODS: Pathologic examinations were performed on placentas from singleton pregnancies using a standard protocol. Data were analyzed overall and within gestational age groups at delivery. RESULTS: Placentas from 518 stillbirths and 1,200 live births were studied. Single umbilical artery was present in 7.7% of stillbirths and 1.7% of live births, velamentous cord insertion was present in 5% of stillbirths and 1.1% of live births, diffuse terminal villous immaturity was present in 10.3% of stillbirths and 2.3% of live births, inflammation (eg, acute chorioamnionitis of placental membranes) was present in 30.4% of stillbirths and 12% of live births, vascular degenerative changes in chorionic plate were present in 55.7% of stillbirths and 0.5% of live births, retroplacental hematoma was present in 23.8% of stillbirths and 4.2% of live births, intraparenchymal thrombi was present in 19.7% of stillbirths and 13.3% of live births, parenchymal infarction was present in 10.9% of stillbirths and 4.4% of live births, fibrin deposition was present in 9.2% of stillbirths and 1.5% of live births, fetal vascular thrombi was present in 23% of stillbirths and 7% of live births, avascular villi was present in 7.6% of stillbirths and 2.0% of live births, and hydrops was present in 6.4% of stillbirths and 1.0% of live births. Among stillbirths, inflammation and retroplacental hematoma were more common in placentas from early deliveries, whereas thrombotic lesions were more common in later gestation. Inflammatory lesions were especially common in early live births. CONCLUSIONS: Placental lesions were highly associated with stillbirth compared with live births. All lesions associated with stillbirth were found in live births but often with variations by gestational age at delivery. Knowledge of lesion prevalence within gestational age groups in both stillbirths and live birth controls contributes to an understanding of the association between placental abnormality and stillbirth. LEVEL OF EVIDENCE: II

Placental membrane inflammation and risks of maternal-to-child transmission of HIV-1 in Uganda.

UNLABELLED Prospective follow-up of 172 HIV-infected pregnant women and their infants was conducted at Mulago Hospital, Kampala, Uganda during 1990 to 1992. Information was collected on maternal immune status (CD4 counts or clinical AIDS), and concurrent infections with sexually transmitted diseases. Infants were observed on a follow-up basis to determine HIV infection, using polymerase chain reaction (PCR) under 15 months of age and enzyme immunoassay/Western blot for those older than 15 months. Placental membrane inflammation (chorioamnionitis and funisitis), and placental villous inflammation (villitis, intervillitis, and deciduitis) were diagnosed by histopathology. Mother-to-child HIV transmission rates were assessed, and adjusted odds ratios (OR) and 95% confidence intervals (95% CI) of transmission were estimated using women with no placental pathology or evidence of immune suppression as a reference group. RESULTS The overall mother-to-child HIV transmission rate was 23.3%. Women with no placental membrane inflammation or immune suppression had a transmission rate of 11.3%; compared with 25.5% in women with placental inflammation and no immunosuppression (adjusted OR, 2.87; 95% CI, 1.04-7.90), and 37.0% in immunosuppressed women (OR, 3.07; 95% CI, 1.42-6.67). We estimate that 34% of HIV transmission could be prevented by treatment of placental membrane inflammation in nonimmunocompromised women. Transmission rates were 40.9% with genital ulcer disease (OR, 3.57; 95% CI, 1.28-9.66). Placental villous inflammation and artificial rupture of membranes did not increase transmission rates and cesarean section was associated with a nonsignificant reduction of risk (OR, 0.70; 95% CI 0.24-2.06). CONCLUSION Placental membrane inflammation increases the rate of mother-to-child HIV transmission.

Expression of Inhibitor-of-Apoptosis Protein (IAP) Livin by Neuroblastoma Cells: Correlation with Prognostic Factors and Outcome

Livin is a recently identified member of the Inhibitor-of-Apoptosis protein (IAP) family of antiapoptosis proteins, and expression has been reported in melanoma and some types of carcinoma. We evaluated livin expression in paraffin-embedded tumor tissue from 68 patients with neuroblastoma (NB) and 7 NB cell lines by immunoperoxidase using an anti-livin monoclonal antibody. Eighteen (26.5%) of the 68 NB tumor tissues showed high livin expression, 36 (53%) showed low-intermediate expression, and 14 (20.5%) were negative. Similarly, 4 NB cell lines showed high livin expression, and 3 showed intermediate expression. In primary NB tissue, livin was observed mainly in tumor neuropil, an extension of tumor cell cytoplasm, and the cytoplasm itself. By reverse transcriptase–polymerase chain reaction, livin expression was confirmed in all 7 NB lines and in frozen tissue from 1 of 3 primary tumors examined to date, in agreement with immunohistochemical data; both livin α and β isoforms were detected. In the NB cases, we further analyzed the correlation between livin expression and clinical and biological features with established prognostic significance (i.e., age at diagnosis, stage, histology, and MYCN oncogene status), and patients’ outcome. Livin expression alone did not appear to have an effect on survival; however, patients with high livin expression and amplified MYCN had significantly decreased survival compared with patients lacking both markers or with either of these markers alone. These results suggest that (a) livin is expressed in primary and cultured neuroblastoma cells and (b) high livin expression may identify a subset of neuroblastoma patients with a particularly poor prognosis among those with MYCN amplified tumors.

The nephropathy of cystic fibrosis: A human model of chronic nephrotoxicity

Patients with cystic fibrosis are chronically exposed to several potentially nephrotoxic factors. These include bacterial infections with their associated immune complexes and the antibiotics (aminoglycosides) used in their treatment. In addition, diabetes mellitus, liver disease, and cor pulmonale, commonly seen in these patients, may produce renal injury. To assess the extent of this injury, we performed morphologic and immunopathologic studies of the kidneys of 34 patients at autopsy. The group included 23 female and 11 male patients; their ages ranged from 4 months to 35 years and their disease was diagnosed one month to 22 years prior to death. The histological changes included glomerulomegaly, a mesangiopathic lesion, and tubulointerstitial disease frequently associated with acute and chronic tubular injury. The last was characterized by abundant tubular lysosomal proliferation and tubular atrophy suggestive of chronic amino-glycoside injury. Diagnostic diabetic lesions were not seen. Immunofluorescence studies predominantly revealed deposits of IgM or C3, or both, in glomeruli and arterioles in 18 patients. Although an anti-Pseudomonas antiserum did not show bacterial antigens in the tissues, elution studies in two specimens demonstrated antibacterial antibodies. These observations, coupled with the finding of ultrastructural glomerular deposits, suggest immune complex-mediated injury. No correlation was found between the severity or type of renal histologic lesion and patient age or duration of cystic fibrosis. Despite the occurrence of renal failure in six patients, renal involvement is currently of limited clinical concern in cystic fibrosis. Nevertheless, continued exposure to bacterial immune complexes and aminoglycosides, among other factors, can result in potentially serious renal disease.

Vertical Transmission of Babesia microti, United States

Babesiosis is usually acquired from a tick bite or through a blood transfusion. We report a case of babesiosis in an infant for whom vertical transmission was suggested by evidence of Babesia spp. antibodies in the heel-stick blood sample and confirmed by detection of Babesia spp. DNA in placenta tissue.