Uncertain clinical significance of duodenal mucosal abnormalities in HIV-infected individuals. Results of a case-control study.

Previous research has described abnormalities of duodenal mucosal morphology in human immunodeficiency virus (HIV)-infected individuals. We wanted to determine the frequency of disturbed villus architecture and investigate its relationship to HIV-related chronic diarrhea. We conducted a case-control study of 120 HIV-infected men, 63 with and 57 without chronic diarrhea. Stools were cultured for bacteria and examined for ova and parasites; esophagogastroduodenoscopy and flexible sigmoidoscopy with mucosal biopsies were performed. Biopsy tissue was examined using light and electron microscopy to detect enteric pathogens and to evaluate mucosal morphology. The mean CD4+ cell count was 143/min3, and enteric pathogens were detected in 56 of 120 men (47%). In approximately half the study sample (57%), duodenal villus architecture was normal; complete villus flattening was not observed. We detected no association between chronic diarrhea and altered villus architecture. Although further study is needed to clarify the pathogenesis of altered duodenal mucosal morphology, our results suggest that the clinical significance of the abnormalities may be small.

Observations on the pathological spectrum and clinical course of microsporidiosis in men infected with the human immunodeficiency virus: follow-up study.

The purposes of this research were to determine whether microsporidian infection is accompanied by structural alterations of the duodenal mucosa and to characterize the clinical and morphological evolution of intestinal microsporidiosis. In a previous systematic electron microscopic evaluation of mucosal biopsy specimens from patients with human immunodeficiency virus infection, we detected Enterocytozoon bieneusi in the duodenal tissue of 31 men. This report concerns a follow-up study of these 31 men, who underwent repeated clinical and laboratory evaluations, including repeated duodenal biopsies. Eighteen men had chronic diarrhea at enrollment and 13 had no diarrhea. The CD4+ cell counts (per mm3) ranged from 10 to 660 and were normal for three men. E. bieneusi infection was accompanied by a wide spectrum of histopathology of duodenal tissue; over a mean follow-up of 15 months, no consistent change in duodenal mucosal morphology was observed, and diarrhea did not invariably develop. These observations indicate that diarrhea and severe villus injury do not invariably accompany infection. Further studies are needed to determine the relationship between E. bieneusi infection and clinical illness.

The role of Microsporidia in the pathogenesis of HIV-related chronic diarrhea.

OBJECTIVE: To determine whether infection with Microsporidia leads to diarrhea in patients with human immunodeficiency virus (HIV) infection. DESIGN: Case-control study. SETTING: Primary care outpatient HIV clinic at a Veterans Affairs medical center. PATIENTS: One hundred six HIV-infected men, 55 with and 51 without chronic diarrhea. MEASUREMENTS: Each patient underwent upper endoscopy and flexible sigmoidoscopy to obtain duodenal, rectal, and sigmoid colonic biopsy specimens. At the time of endoscopy, a fresh stool was obtained for culture, ova and parasite assessment, and Cryptosporidium examination. Biopsy tissue was examined using electron microscopy to detect Microsporidia. RESULTS: The microsporidian parasite Enterocytozoon bieneusi was detected in the duodenal biopsy specimens of 31 of 106 men (29%); 24 of 106 men (23%) had other enteric pathogens. No significant difference was observed in the occurrence of microsporidiosis in patients with (18 of 55 [33%]) and without (13 of 51 [25%]) chronic diarrhea (odds ratio, 1.42; 95% CI, 0.61 to 3.31). A similar nonsignificant difference was observed after controlling for CD4 count and other enteric pathogens (odds ratio, 1.66; 95% CI, 0.68 to 4.06). Among patients with microsporidiosis, no difference was observed in the intensity of infection (defined by the presence of few, moderate, or abundant organisms) among cases and controls (P > 0.2). CONCLUSIONS: This is the first report to document the presence of E. bieneusi in HIV-positive patients without gastrointestinal symptoms. No significant difference was observed in the occurrence of E. bieneusi infection in HIV-infected patients with or without chronic diarrhea. Thus, the association between microsporidiosis and diarrhea, if one exists, may not be as strong as is currently believed.

Enterovesical fistula due to non-Hodgkin lymphoma in AIDS.

Enterovesical fistula associated with lymphoma is exceedingly rare. We report three patients with the acquired immunodeficiency syndrome who presented with fecaluria and pneumaturia. Non-Hodgkin lymphomas involving the intestine and the urinary bladder creating an enterovesical fistula were found at surgery in two patients and at autopsy in the third. Extranodal lymphomas are becoming more common in AIDS patients, so that the possibility of lymphoma should be considered in the differential diagnosis of enterovesical fistulas in these patients.

Multiple pathogens may induce growth factor cascade resulting in KS.

While lipopolysaccharide endotoxin is the most prominent inducer of the kinecascade (TNF alpha, IL-1, 4, 6, 8) that leads to shock and multiple organ failure, bacterial exotoxins and products of certain gram positive bacteria can induce the same end results. We theorize that more than one pathogen can induce the sequence of protooncogene activation and growth factor release that results in the formation of KS. If KS has its own unique viral etiology, this virus has not as yet been isolated or identified but we continue to search for it. However, it is entirely possible that these lesions do not have a single well-defined etiologic agent but are the result of multiple agents cooperating in a set sequence. An endogenous, or apathogenic exogenous, retrovirus may replace HIV for initiator growth factor induction in CD4 cells in the classical (Mediterranean) or iatrogenic disease; and other pathogens co-exist or sequentially replace each other in the African endemic disease; whereas an array of viral pathogens (prominent among them CMV) take over growth factor induction in endothelial cells proliferating in response to the initiator growth factor (oncostatin M) released from HIV-infected CD4 lymphocytes in AIDS-KS.

Viral expressions in Reed-Sternberg cells.

In the murine system natural hybridoma formation was observed first in 1968-9. In the #620 to 818 system a mouse leukemia virus-(MLV-) producer diploid lymphoma cell fused with an immune plasma cell. The tetraploid fusion product cells grew in suspension cultures and as ascites tumors in mice and continued the production of MLV particles and MLV-neutralizing antibodies. Analogy between the #620 to 818 system and the origin of RS cells is proposed. Indirect evidence suggests retroviral infection of the mononuclear HD cell which presumably is an interdigitating reticulum (IR) cell. Reactive B and T cells interact in an abnormal manner and fuse with the retrovirally infected IR cell. The fusion product cells display hyperdiploidy and a disarray of markers as IR markers are lost due to dedifferentiation (and regained upon differentiation induction) and B and/or T cell markers are gained. Conventional theories for the origin of RS cells fail to explain the great heterogeneity of their markers. Derivation of RS cells from IR cells and B and/or T lymphocytes as natural hybridomas offers plausible explanation for all the features of RS cells.

Peripheral mucoepidermoid tumour of the lung.

Mucoepidermoid tumours of the bronchial tree are uncommon neoplasms, which are believed to arise from terminal ducts of the proximal tracheobronchial tree. The first case of a peripheral mucoepidermoid tumour of the lung is reported.

Primary angiosarcoma of the cuboidal bone: a case report.

Primary angiosarcoma of bone is a rare neoplasm. The unique cytomorphologic and ultrastructural aspects of a primary angiosarcoma of the cuboid bone diagnosed by fine-needle aspiration are presented. Smears and cell block preparations revealed single and clustered large, pleomorphic, and spindle-shaped cells with a markedly hemorrhagic background. Electron microscopy revealed characteristic features of endothelial cells including rare Weibel-Palade bodies. The clinical, cytologic, histologic, and ultrastructural aspects of the case are discussed.

The effect of HIV infection on phagocytosis and killing of Staphylococcus aureus by human pulmonary alveolar macrophages.

Pulmonary alveolar macrophages (PAM) play a central role in host defense against pulmonary infection. The authors studied the number, viability, and ultrastructure of PAM recovered by bronchoalveolar lavage from normal and HIV-infected subjects, and their ability to phagocytose and kill Staphylococcus aureus. PAM from HIV-infected subjects who did not have pneumonia were present in greater numbers and phagocytosed significantly more opsonized Staphylococcus aureus (32.5% and 27.3% for nonsmokers and smokers, respectively) than did PAM from healthy controls (19.5% and 18.2%). In 15 patients with AIDS and pneumonia (due to Pneumocystis carinii in 13/15), viability of PAM and their phagocytic capacity were significantly reduced; in smokers with AIDS and pneumonia, the PAM yield was also dramatically decreased. Killing of S. aureus was similar by PAM from all patient groups. HIV infection was associated with the electron microscopic finding in PAM of extensively ruffled PAM cell-surfaces and ingestion of lymphocytes. Thus, HIV infection stimulates the phagocytic capacity and produces morphologic changes consistent with the possibility that PAM are activated by this retroviral infection. In patients with AIDS who develop pneumonia, especially in smokers, the number, viability and phagocytic capacity of PAM are significantly decreased; our study could not determine whether this diminished activity reflects evolution of the HIV infection or a secondary effect of the pneumonia.

Spontaneous, nontraumatic gangrene due to Clostridium septicum.

Clostridium septicum is a major cause of spontaneous, nontraumatic gas gangrene. Unlike Clostridium perfringens, C. septicum is relatively aerotolerant and thus appears to be more capable of initiating infection in the absence of obvious damage to tissues. Six cases illustrate the clinical setting and fulminant nature of spontaneous gangrene caused by C. septicum. A lesion in the colon such as carcinoma is often present and is presumed to serve as a portal of entry to the bloodstream. Diabetes and leukopenia are also common predisposing conditions; compromise of vital host responses may facilitate proliferation of those organisms that settle out in the tissues. Acute lymphoma or leukemia during a course of chemotherapy is accompanied by damage to bowel mucosa and granulocytopenia, thus predisposing to spontaneous clostridial gangrene. Infection progresses in a fulminating manner; the majority of patients die within 24 hours of onset. Characteristic symptoms and signs include excruciating pain (although a sense of heaviness may be the only early symptom), swelling of tissues, crepitance, and bulla formation. A hallmark of C. septicum infection is the absence of acute inflammatory cells in involved tissues or in bulla fluid. A series of laboratory investigations demonstrated that fluid obtained from a bulla adversely affected the viability, morphology, and function of polymorphonuclear leukocytes (PMNs), which may explain the paucity of PMNs in involved tissues and may in part contribute to the fulminant progression observed in infection due to this organism.

Identification and characterization of a human proliferation-associated nucleolar antigen with a molecular weight of 120,000 expressed in early G1 phase.

Tumor nucleoli were treated with polyclonal antisera to normal human tissue nucleoli to block some determinants common to tumor and normal tissue nucleoli. Immunization of mice with these immune complexes resulted in the development of a monoclonal antibody (FB2) to a novel Mr 120,000 nucleolar proliferation-associated antigen. By indirect immunofluorescence, antibody FB2 produced bright nucleolar staining in a variety of malignant tumors, including cancers of the breast, liver, gastrointestinal tract, genitourinary tract, blood, lymph system, lung, and brain. Although specific nucleolar immunofluorescence was not detectable in most normal tissues, it was detectable in some proliferating nonmalignant tissues including spermatogonia of the testes, ductal regions of hypertrophied prostates, and phytohemagglutinin-stimulated lymphocytes. The Mr 120,000 antigen was not detectable in 48-h serum-deprived HeLa cells but was readily detectable (within 30 min) following serum refeeding. The Mr 120,000 antigen was not detected in retinoic acid-treated HL-60 cells following morphological differentiation but was detectable in 48-h phytohemagglutinin-treated lymphocytes. These studies suggest that the Mr 120,000 antigen is a proliferation-associated antigen which plays a role in the early G1 phase of the cell cycle.

Human immunodeficiency virus in brain biopsies of patients with AIDS and progressive encephalopathy.

Human immunodeficiency virus (HIV) has been identified in patients with AIDS in their circulating and tissue lymphocytes and in their monocyte-macrophages, an arm of the cell-mediated immune system. We report our findings of HIV in brain biopsies. Virus was detected in oligodendroglial and astroglial cells. Virus was also present in the brain capillaries, both in lumens and at the endothelial gaps. Virus was also found in extracellular spaces. Budding forms of the developing virus and bar-shaped nucleoids of mature virus, the diagnostic hallmark of the HIV retrovirus, were identified in brain tissue of five of seven patients with AIDS studied. We believe that HIV may enter the the brain via the vascular capillaries (through the endothelial gaps), bind to brain cells containing T4 receptors, enter the cells, and replicate. There follows a reactive hyperplasia and degeneration of oligodendroglial and astroglial cells. The oligodendroglial cells are the myelin-forming cells, and thus, the result is myelin degeneration.

Bacterial remnants in an aortic valve after treatment for staphylococcal endocarditis.

A patient with staphylococcal endocarditis was treated for 6 weeks with high doses of nafcillin. Despite a prompt clinical response and bacteriologic cure, residual damage to the aortic valve led to severe congestive heart failure necessitating surgery. Valve tissue obtained at surgery was sterile, but organisms consistent with staphylococci were observed in the inflammatory infiltrate by light and electron microscopy.

Cimetidine hepatitis.

A 62-year-old man developed asymptomatic anicteric hepatitis during cimetidine therapy for duodenal ulcer disease. Liver biopsy revealed zonal (centrolobular) necrosis, bile stasis, and mononuclear cell infiltration. Electron microscopy featured mitochondrial hyperplasia, giant mitochondria, and liver cell bile inclusions. The diagnosis of cimetidine-related hepatitis was confirmed by re-exposure to cimetidine, which prompted a rapid rise in serum transaminases while under observation in the hospital. Cimetidine hepatitis is rarely reported, and routine monitoring of the patient's liver tests during therapy does not seem cost-effective as a general practice.

Identification and partial characterization of a nucleolar antigen with a molecular weight of 145,000 found in a broad range of human cancers.

Previous studies in our laboratory have indicated the presence of nucleolar antigens in tumors which were not detected in normal tissues. Some of the polyclonal antisera produced in these studies were shown to identify a Mr, 145,000 nucleolar antigen on immunoblots of tumor nucleoli but not in normal human liver nucleoli. A monoclonal antibody to a Mr 145,000 nucleolar protein (p145) was produced by immunization of mice with a nucleolar extract of HeLa cells which is enriched with this antigen. The monoclonal antibody showed bright nucleolar immunofluorescence localization in a broad range of human tumors including cancers of the gastrointestinal tract, genitourinary tract, lung, liver, muscle, cartilage, and blood. The p145 nucleolar antigen was not detected in most normal human tissues or in benign tumors, with only weak nucleolar staining observed in spermatogonia of the testes and in ductal regions of some hypertrophied prostates. Nucleolar antigen p145 was extracted from HeLa cell nucleoli by homogenization in a 0.01 M Tris buffer containing 0.2% deoxycholate. On sucrose density gradient centrifugation, the antigen remained sedimented with the nucleolar ribonucleoprotein fraction. Nucleolar antigen p145 was released from ribonucleoproteins following treatment with 4 M guanidinium hydrochloride or RNase. Peptide mapping of nucleolar antigen p145 showed that it was distinct from other known nucleolar antigens. Although it remains to be determined if the p145 antigen plays a role in cell transformation, maintenance of the malignant phenotype, or in cell division, it may have value as a tumor marker or as a therapeutic target.

Progressive multifocal leukoencephalopathy and magnetic resonance imaging.

Progressive multifocal leukoencephalopathy developed in a homosexual man with underlying Hodgkin's disease. Computed tomography and magnetic resonance imaging of the brain demonstrated multiple lesions, more in gray than white matter. Brain biopsy established the diagnosis of progressive multifocal leukoencephalopathy. Magnetic resonance imaging was found useful for detecting brain lesions and for localizing an accessible lesion for biopsy.

Emergence of bactericidal and opsonizing antibody to Vibrio vulnificus following bacterial infection.

Virulent isolates of Vibrio vulnificus resist the bactericidal and opsonizing effects of normal human serum, in contrast to environmental isolates, which are highly serum susceptible. Immune responses to bacteremic V. vulnificus infections in human subjects have not been characterized. Serum from a patient who survived sepsis caused by V. vulnificus had substantial bactericidal and opsonizing immunoglobulin G (IgG) for his own bloodstream isolate. Killing was mediated by the classical complement pathway, whereas opsonization was effected by either the classical or the alternative pathway. IgG that reacted strongly with 55-, 58-, and 68-kilodalton outer membrane proteins was present in the patient's convalescent-phase serum but was absent from normal human serum. These findings suggest that humoral immunity to V. vulnificus, mediated by bactericidal and opsonizing antibody, emerges during infection and may be due, in part, to IgG directed against identifiable outer membrane proteins.