Brain pathology induced by infection with the human immunodeficiency virus (HIV)

Summary Neuropathological examination of brain tissue of 100 patients with infection by the human immunodeficiency virus (HIV), including 98 with clinically manifest acquired immune deficiency syndrome (AIDS), revealed distinct multifocal-disseminated and diffuse brain tissue lesions, which can be regarded as HIV-induced brain lessions: multifocal giant cell encephalitis (MGCE; 4) and progressive diffuse leukoencephalopathy (PDL; 25). These lesions were found in 38 brains, and in 17 in absence of infectious, necrotizing or inflammatory changes of other types. In 13 brains, a combination of MGCE with PDL was seen, suggesting a spectrum of HIV-induced brain lesions. MGCE is characterized by perivascular accumulations predominantly of rod cells, monohistiocytes and macrophages, all of which are strongly labeled with a monoclonal antibody to macrophages. Most conspicuous are multinucleated giant cells which are also labeled by anti-macrophage antibody, and which can be regarded as evidence of the local presence of HIV, as confirmed by electron microscopical detection of HIV particles in four MGCE brains, and by immunocytochemical detection of HIV proteins in two MGCE brains. PDL is characterized by a triad: diffuse myelin loss, astroglial proliferation, and infiltration by mono- and multinucleated macrophages. HIV-induced lesions can be morphologically differentiated from histopathological brain lesions known in immunosuppression, including what is called here nodular encephalitis [subacute encephalitis of the literature, in most cases attributable to cytomegalovirus (CMV) or toxoplasmosis], by their characteristic histopathology including the hallmark presence of multinucleated giant cells, by direct immunocytochemical and electron microscopical demonstration of HIV in the lesions, and by the absence of opportunistic agents (bacteria, fungi, Toxoplasma, CMV, HSV or papovaviruses). Diffuse poliodystrophy (diffuse proliferation of astroglia with swollen nuclei, occasionally minor neuronal loss and rod cell proliferation) was found in the cerebral cortex and other gray matter in half of all brains, including cases with gyral atrophy, and may be another correlate of HIV damage to the brain. Morphological delineation of HIV-induced brain lesions is a necessary prerequisite for a meaningful clinical definition of HIV-induced cerebral disease.Part of this study was presented at the International Scientific Meeting: Medical Brain Research — State and Perspectives, in Vienna, Austria, June 18–20, 1987     

Follicular center-cell lymphoma with plasmacytic differentiation, monoclonal paraprotein, and peripheral blood involvement. Recapitulation of normal B-cell development

A patient with a nodular and diffuse small-cleaved follicular center-cell lymphoma that exhibited definite plasmacytic differentiation, a related monoclonal gammopathy, and circulating population of small lymphocytes is presented. Aside from showing that the presence of numerous plasma cells is not a reliable criterion for the diagnosis of a reactive follicular proliferation, the case is an example of a lymphoma without a block in maturation. The "neoplastic" B-cells show development to follicular center cells and beyond, to functioning plasma cells, and probably also to recirculating "memory" cells. It also suggests that plasmacytoid lymphocytic lymphomas (Lukes-Collins classification) might represent a heterogeneous group of lymphoid neoplasms with some closely related to follicular center-cell lymphomas and others more closely related to small lymphocytic lymphoma/B-cell chronic lymphocytic leukemia.     

High Prevalence of Hypovitaminosis D among Free-Living Postmenopausal Women Referred to an Osteoporosis Outpatient Clinic in Northern Italy for Initial Screening

To establish the prevalence of hypovitaminosis D among free-living postmenopausal women referred to an osteoporosis outpatient clinic in Northern Italy, we evaluated 25-hydroxyvitamin D (25(OH)D) levels in 570 postmenopausal women who had been consecutively referred to our clinic in the 12 months beginning October 1995. Parathyroid hormone (PTH), serum calcium (Ca), creatinine (Cr) and osteocalcin (OC), urinary calcium (Ca24h) and creatinine (Cr24h), and the bone mineral density of the lumbar spine (LBMD) and femur (FBMD) were also measured. 1,25-Dihydroxyvitamin D (1,25(OH)₂D) concentrations were measured in 23 women. All women had normal electrolyte serum concentrations and kidney function. Mean ± SD 25(OH)D concentration was 18.3 ± 8.3 ng/ml. A significant (p<0.001) seasonal variation was seen for both 25(OH)D and PTH. Women were divided into two groups based on their vitamin D status: low vitamin D status (25(OH)D <12 ng/ml, n= 161, 28%) and normal vitamin D status (25(OH)D ≥12 ng/ml, n= 409, 72%). Hypovitaminosis D was found in 38.5% of all the women in the time period December–May and in 12.5% in the other half-year; among women >70 years old 51% had hypovitaminosis D in the time period December–May and 17% in the other half-year. PTH was significantly (p<0.05) increased, and Ca24h, OC and FBMD significantly (p<0.05) decreased in women with hypovitaminosis D. 1,25(OH)₂D positively correlated with 25(OH)D (p<0.0001), but did not correlate with PTH, age or creatinine clearance. In conclusion, hypovitaminosis D is an important, underestimated problem in Italian free-living postmenopausal women referred to an outpatient osteoporosis clinic. Received: 9 February 1998 / Accepted: 8 July 1998     

Determination, by in situ hybridization on interphasic nucleus, a cytogenetic DNA index; application to breast cancer; comparison of this DNA index to DNA indexes determined by imaging and flow cytometry

In oncology, flow cytometry (FCM) and image cytometry (ICM) are commonly used to detect DNA aneuploid cell populations in solid tumors. Agreement between these two approaches is good. The use of both techniques in association minimizes the rate of FCM and ICM false negatives and gives better DNA pattern characterization, particularly for detection of any tumoral component in the FCM DNA diploid peak. Nevertheless, discrepancies exist between the FCM and the ICM DNA index values: the ICM DNA index is often greater than the FCM DNA index. The aim of the present study was to establish a cytogenetic DNA index by determining the chromosomal ploidy using a molecular cytogenetic approach and to compare it to the FCM and ICM DNA indexes. We present here the fluorescence in situ hybridization (FISH) technique we have adapted to the study of breast cancer in order to count the number of copies of the 22 + X human chromosomes in interphasic nuclei. This was achieved using a panel of 21 indirect FITC labeled probes which recognize specific chromosomic DNA sequences. Preliminary results obtained from DNA diploid and DNA aneuploid tumors are discussed.     

Molecular detection of Chlamydia trachomatis and HPV infections in cervical samples with normal and abnormal cytopathological findings

It has been suggested that Chlamydia trachomatis (CT) and human papillomaviruses (HPV) co-infection could contribute to development of intraepithelial lesions. In this study, HPV and CT-DNA were investigated in 250 cervicovaginal samples of patients from Minas Gerais, Brazil. The cytological analysis revealed that 70% of samples (175) were negative, 5.2% (13) presented atypical squamous or glandular cells of undetermined significance (ASCUS/AGUS), 12.4% (31) presented low-grade squamous intraepithelial lesion (LSIL), 10.8% (27) high-grade squamous intraepithelial lesion (HSIL), and 1.6% (4) invasive carcinoma. HPV-DNA and HPV/CT co-infection was observed in 40% (100/250) and in 5.2% (13/250) of samples, respectively. Among the positive cytological samples, HPV-DNA was detected in 73.3% and CT-DNA in 9.33% and in 13%, if only the HPV positive samples were considered. The highest co-infection rate (15.4%) was observed among ASCUS/AGUS samples. Although a significant association was found for HPV infection and the precursor lesions of cervical cancer, it was not possible to establish a significant association between these lesions and CT or HPV/CT co-infection.     

Cytomegalovirus infection of the central nervous system in patients with AIDS: diagnosis by DNA amplification from cerebrospinal fluid.

A nested polymerase chain reaction (PCR) was evaluated for the detection of cytomegalovirus (CMV) DNA in cerebrospinal fluid (CSF). CSF and serum samples from 19 AIDS patients with intracerebral CMV infection diagnosed at autopsy were retrospectively examined. As controls, CSF and serum samples from 15 AIDS patients with only extracerebral CMV involvement at autopsy, from 10 AIDS patients without CMV infection at autopsy, and from 10 anti-human immunodeficiency virus-negative patients without ongoing CMV infection, were studied. CMV DNA was detected from patients with intracerebral CMV infection in 9 of 9, 5 of 6, and 1 of 4 CSF samples collected, respectively, 1-30, 30-90, and 90-300 days before death. Twelve of 13 sera from these patients were CMV PCR-positive. None of the control patients had CMV DNA in CSF. PCR was positive in 6 of 8 sera from AIDS patients with only extracerebral CMV infection and in serum from 1 AIDS patient without CMV involvement at autopsy. CMV PCR on CSF is highly sensitive and specific. It should be considered a rapid and reliable diagnostic method for CMV infection of the central nervous system.     

Experts’ considerations on HLA‐haploidentical stem cell transplantation

Recently, novel strategies to control graft‐versus‐host disease and facilitate engraftment have allowed an increasing number of human leukocyte antigen (HLA)‐haploidentical hematopoietic stem cell transplantation (haploHSCT) to be performed. A meeting was convened to review the biological rationale and the clinical results of various T‐cell‐depleted (TCD) and T‐cell‐replete (TCR) HLA‐haploidentical ‘transplant platforms’. The objective of the meeting was to promote discussion and consent among leading researchers in the field on three main crucial issues for haploHSCT: (i) eligibility criteria, (ii) choice of the most suitable donor, and (iii) choice of the most appropriate transplant platform. The experts in attendance agreed that a patient who is eligible for an allogeneic transplant and lacks an HLA‐identical sibling or an HLA‐matched unrelated donor should be considered for an alternative donor transplant. Together with the experience of the individual center, the most important decision criteria in choosing an alternative donor source should be the rapidity of transplantation so as to avoid disease relapse/progression. The choice of the mismatched donor should be driven by younger age, ABO blood group compatibility, and Cytomegalovirus status. If a TCD transplant is planned, NK‐alloreactive donors and/or the mother should be preferred. Prospective comparative studies are needed to establish the relative efficacy of different transplant platforms. However, expertise in stem cell manipulation and in adoptive immunotherapy is essential if a TCD transplant platform is chosen.