Antivaccinia activities of acyclic nucleoside phosphonate derivatives in epithelial cells and organotypic cultures.

Organotypic "raft" cultures of epithelial cells allow the reconstitution of a skin equivalent that is easily infectible with different viruses with cutaneous tropism. Among these, poxvirus and particularly vaccinia virus (VV) are good candidates for use in antiviral tests, giving histological pictures comparable to those observed in humans infected with smallpox. Therefore, we decided to evaluate a series of phosphonate derivatives for their ability to inhibit VV growth in epithelial cell monolayers, and the most powerful derivatives were tested in the organotypic cultures. The most active compound was 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine [(S)-HPMPA], followed by 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine, cyclic (S)-HPMPA, 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine [(S)-HPMPC; cidofovir, Vistide], and cyclic (S)-HPMPC. Cidofovir, which is on the market for the treatment of human cytomegalovirus retinitis in immunocompromised patients, is potentially a good candidate for the treatment of a poxvirus outbreak, in the absence of any vaccination.

Hodgkin's disease in a patient with Von Hippel-Lindau disease. A case report.

Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited disorder with a predisposition to develop a wide variety of lesions: retinal, cerebellar, spinal and medullar hemangioblastomas, renal cell carcinomas, phaeochromocytomas, and renal, pancreatic and epididymal cysts are the most frequent manifestations of the disease. The prevalence of VHL disease has been estimated to be 1 per 36,000 persons. We report the case of a 68-year-old woman with Von Hipple-Lindau disease who developed high fever with pulmonary and hepatic lesions proven to be Hodgkin's disease on biopsy. To our knowledge, this is the first report of Hodgkin's disease in a patient with Von Hippel-Lindau.

Mutation analysis of the rearranged immunoglobulin heavy chain genes of marginal zone cell lymphomas indicates an origin from different marginal zone B lymphocyte subsets.

Marginal zone cell lymphoma is a recently described entity among the non-Hodgkin's lymphomas. It likely originates from the marginal zone B cells in the spleen and equivalent cells in the lymph node and extranodal tissues. Recent evidence indicates that marginal zone B cells are functionally heterogeneous and may differ with respect to the pattern of somatic hypermutation in their Ig variable genes. To test whether marginal zone lymphomas may originate from different subsets of marginal zone B cells, we performed a sequence and mutation analysis of the rearranged Ig heavy chain (IgH) variable genes (VH) of a series of 14 cases of marginal zone lymphoma, occurring in the spleen (4), the lymph node (4), the stomach (2), the orbit (2), the tongue (1), and the skin (1). Our data show that marginal zone cell lymphomas preferentially rearrange the VH4, VH3, and VH1 family genes, without preference for any particular VH gene. Somatic mutations are present in 13 cases; one case of marginal zone cell lymphoma of the skin showed a germline configuration of the rearranged VH gene. Mutation analysis shows evidence of antigen selection in three cases of marginal zone cell lymphoma, one of the spleen, stomach, and orbit, respectively. No evidence of antigen selection was present in the other cases. These data indicate that marginal zone cell lymphomas may arise from different subsets of marginal zone B cells. In addition, lymphomagenesis may not be triggered by antigen in all cases of marginal zone cell lymphoma.

Primary rat lacrimal cells undergo acinar-like morphogenesis on reconstituted basement membrane and express secretory component under androgen stimulation.

Single cells or small cell clusters, isolated from the rat lacrimal gland, were incubated on reconstituted basement membrane (matrigel) in a well-defined serum-free medium. During the first days of culture, cells reassociated and reorganized in structures resembling acini. These multicellular structures, maintained in culture for 2 weeks, consisted of well-polarized cuboidal cells surrounding a central lumen and exhibiting apically located microvilli. Myoepithelial cells were observed at the periphery of the acinar structures. Both in the native lacrimal and in the cultured aggregates, epithelial cells displayed strong immunoreactivity for cytokeratin 8, while myoepithelial cells were immunoreactive for vimentin and alpha-smooth muscle isoactin. These data indicate that the cultured aggregates closely mimic the in vivo architecture of lacrimal glands both by morphology and immunohistochemistry. We further demonstrated the presence of an intact androgen receptor and the ability of the cultured aggregates to respond to androgens with increased secretion of the secretory component. Comparable androgen responses were observed in lacrimal gland cultures of 5-week-old male and female rats. In conclusion, we report a morphologically and functionally differentiated culture system of primary rat lacrimal cells, in which androgen-regulated gene expression was observed. This culture model provides a unique experimental paradigm for studying the effects of hormones, cytokines, and growth factors on the morphogenesis, growth, and functional differentiation of lacrimal glands.

Workshop report on Hodgkin's disease and related diseases ('grey zone' lymphoma).

Despite advances in immunohistochemistry and molecular biology, the distinction between classical Hodgkin's lymphoma and related diseases such as nodular lymphocyte-predominant Hodgkin's disease, T-cell rich large B-cell lymphoma or anaplastic large cell lymphoma has remained difficult in rare cases. Lack of clear-cut diagnostic criteria represents a problem for both the pathologist and the clinician. To delineate this 'grey zone' between classical Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL) and to develop criteria for classification of such cases, 12 expert hematopathologists each submitted one to five borderline cases to a workshop. Cases were reviewed and classified at a multiheaded microscope and criteria were established for the diagnosis of questionable cases. Well established entities such as classical Hodgkin's lymphoma, anaplastic large-cell lymphoma and TCRBCL were defined more strictly and cases with unusual morphology or antigen expression could be identified. A distinctive subset of cases representing mediastinal large B-cell lymphomas with features of Hodgkin's lymphoma was identified.

Fever of unknown origin due to inflammatory pseudotumour of lymph nodes.

The clinical features of inflammatory pseudotumour of lymph nodes, a distinct non-malignant histopathological entity firstly described in 1988, are summarized based upon a detailed analysis of 4 personal cases and 47 cases reported in the literature. The mean age of the patients is 38 years (range 8 to 82 years) and there is no gender predilection. One third present with asymptomatic lymphadenopathy and 47% present with fever, nearly all meeting the criteria of fever of unknown origin. Abdominal complaints are occasionally present. Intermittence of symptoms is common. Hepatosplenomegaly is unusual. All lymph node areas may be involved but abnormalities are mostly confined to one or two anatomic regions. No extranodal involvement has been reported although inflammatory pseudotumour may occur in several organs with similar morphological features and identical signs of inflammations. Routine blood tests are normal except for signs of inflammation. The lesions are Gallium-avid. Diagnosis is based upon typical histopathological features. The prognosis is favorable and surgical resection frequently leads to cure. Spontaneous resolution of symptoms has been reported and nonsteroidal anti-inflammatory drugs may suppress the clinical manifestations.

Increased expression of the PRAD-1/CCND1 gene in hairy cell leukaemia.

The PRAD-1/CCND1 gene encodes Cyclin D1, a cyclin involved in cell cycle regulation at the G1-S transition. Over-expression of this gene is a highly specific molecular marker of mantle cell lymphomas (MCLs), but it may also be up-regulated in some chronic lymphoproliferative disorders, mainly chronic lymphocytic leukaemia. We have examined PRAD-1/CCND1 gene expression by Northern blot and Western blot analysis in a series of 18 hairy cell leukaemias (HCLs), nine other splenic malignant lymphoproliferative disorders, and three normal/reactive spleens. Over-expression of the mRNA PRAD-1/CCND1 gene was observed in 16/18 HCLs, including one case of hairy cell leukaemia variant, whereas this molecular alteration was not found in other cases examined. mRNA levels varied from case to case, but they were lower than those observed in MCLs. At the protein level, Western blotting analysis showed Cyclin D1 protein expression in the 11 HCLs analysed. No bcl-1 rearrangements were seen with the MTC, p94PS and PRAD-1 (lambda-P1-4) probes used, and no PRAD-1/CCND1 gene amplification was detected in any case. These findings indicate that PRAD-1/CCND1 is over-expressed at mRNA and protein levels in a high number of HCLs. However, the levels of expression are much lower than in MCLs, and this expression is not associated with bcl-1 rearrangements or PRAD-1/CCND1 gene amplification.

A case of Omenn-like immunodeficiency syndrome.

We report the case of a child with a variant of the Omenn immunodeficiency syndrome. He presented with erythroderma, lymphadenopathy, hepatosplenomegaly, failure to thrive, and recurrent purulent infections. The immunological studies showed marked disturbances in the subpopulations and functions of T lymphocytes, which suggests a defect in T cell differentiation as the cause of the disease.

Phytohemagglutinin-conditioned medium modulates adherence properties and morphology of hairy cells.

The effect of a PHA-conditioned medium was tested on a population highly enriched in hairy cells obtained from spleens of patients with hairy cell leukemia. Under PHA-CM treatment hairy cells adhered to both plastic and glass and spread assuming a typical stellate shape, without changing their enzymatic and antigenic properties. Provided PHA-CM was present, stellate adherent hairy cells remained viable in culture for several months. Mononuclear splenic cells from patients with various hematological disorders never showed similar phenotypic modifications after PHA-CM treatment.

Morphological study of the reticular erythematous mucinosis syndrome.

Histopathological studies were conducted on skin biopsies of 4 patients with the reticular erythematous mucinosis (REM) syndrome. The diagnosis was made on the basis of the clinical picture in 3 of the cases and from histological characteristics in the 4th. These morphological studies were done parallel with a study of skin biopsies with quite a similar histological picture but in which the clinical picture clearly indicated differing entities. The nosologic place of REM syndrome is questioned and the impression arises that there is a clear-cut histogenetical connection with several inflammatory skin diseases.

Pseudotumor orbitae and myasthenia gravis. A case report.

A case of myasthenia gravis in association with benign orbital pseudotumor of lymphoid origin is described. To our knowledge, this is the second report of such a case.