Kaposi's sarcoma-associated herpesvirus/human herpesvirus type 8-positive solid lymphomas: a tissue-based variant of primary effusion lymphoma

Kaposi's sarcoma-associated herpesvirus (KSHV), also termed human herpesvirus type 8, is consistently identified in Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. Here we report four cases of KSHV-bearing solid lymphomas that occurred in AIDS patients (cases 1 to 3) and in a human immunodeficiency virus (HIV)-seronegative person (case 4). The patients presented extranodal masses in the abdomen (cases 1, 3, and 4) or skin (case 2), and nodal involvement, together with Kaposi's sarcoma (case 3). The gastrointestinal tract was involved in two patients (cases 1 and 3). The patients did not develop a lymphomatous effusion. KSHV was detected in the tumor cells of all cases by immunohistochemistry and by polymerase chain reaction. Epstein-Barr virus was detected in two of the HIV-related cases. All KSHV-positive solid lymphomas exhibited PEL-like cell morphology. To investigate the relationship of these disorders to PEL and to other AIDS-associated diffuse large cell lymphomas, KSHV-positive solid lymphomas were tested for the expression of a set of genes that were previously shown by gene profiling analysis to define PEL tumor cells. The results showed that expression of this set of genes in KSHV-positive lymphomas is similar to that of PEL but distinct from KSHV-negative AIDS-associated diffuse large cell lymphomas. Because pathobiological features of KSHV-positive solid lymphomas closely mimic those of PEL, our results suggest that KSHV-positive solid lymphomas should be considered as a tissue-based variant of classical PEL, irrespective of HIV status.     

Report: workshop on mediastinal grey zone lymphoma

There are several indications that classical Hodgkin lymphoma (cHL) and at least a proportion of cases of Primary Mediastinal B cell Lymphoma (PMBL) are derived from B cells at similar stages of differentiation and share common pathogenic mechanisms. The first indication was the existence of mediastinal grey zone lymphomas as identified in the 4th International Symposium on HL, with clinical, histological and immunohistochemical features intermediate between cHL and PMBL. Second, both tumor types resemble a cell that is developmentally situated in-between the germinal center reaction and a plasma cell. Third, cHL and PMBL were found to have similar gene expression profiles, including the lack of immunoglobulin expression and low levels of B cell receptor signalling molecules, and the secretion of molecules like the chemokine TARC and the prominent expression of IL-13 receptors. Fourth, both entities were found to have common genomic aberrancies, notably in 2p15 and 9p24, the sites of the REL oncogene and the tyrosine kinase gene JAK2, respectively. Further comparison of both lymphoma types may provide further insight in the pathogenic mechanisms and allow the design of diagnostic algorithms to sort out the small number of so-called mediastinal grey zone lymphomas, that appear to be intermediate between PMBL and cHL.     

Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3',5'-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-Kinase/Akt signaling

Among its pleiotropic actions, ghrelin modulates insulin secretion and glucose metabolism. Herein we investigated the role of ghrelin in pancreatic beta-cell proliferation and apoptosis induced by serum starvation or interferon (IFN)-gamma/TNF-alpha, whose synergism is a major cause for beta-cell destruction in type I diabetes. HIT-T15 beta-cells expressed ghrelin but not ghrelin receptor (GRLN-R), which binds acylated ghrelin (AG) only. However, both unacylated ghrelin (UAG) and AG recognized common high-affinity binding sites on these cells. Either AG or UAG stimulated cell proliferation through Galpha(s) protein and prevented serum starvation- and IFN-gamma/TNF-alpha-induced apoptosis. Antighrelin antibody enhanced apoptosis in either the presence or absence of serum but not cytokines. AG and UAG even up-regulated intracellular cAMP. Blockade of adenylyl cyclase/cAMP/protein kinase A signaling prevented the ghrelin cytoprotective effect. AG and UAG also activated phosphatidyl inositol 3-kinase (PI3K)/Akt and ERK1/2, whereas PI3K and MAPK inhibitors counteracted the ghrelin antiapoptotic effect. Furthermore, AG and UAG stimulated insulin secretion from HIT-T15 cells. In INS-1E beta-cells, which express GRLN-R, AG and UAG caused proliferation and protection against apoptosis through identical signaling pathways. Noteworthy, both peptides inhibited cytokine-induced NO increase in either HIT-T15 or INS-1E cells. Finally, they induced cell survival and protection against apoptosis in human islets of Langerhans. These expressed GRLN-R but showed also UAG and AG binding sites. Our data demonstrate that AG and UAG promote survival of both beta-cells and human islets. These effects are independent of GRLN-R, are likely mediated by AG/UAG binding sites, and involve cAMP/PKA, ERK1/2, and PI3K/Akt.     

Mild hyperuricemia and subclinical renal damage in untreated primary hypertension

BACKGROUND: Subclinical renal damage and hyperuricemia are not uncommon in patients with primary hypertension. Whether mild hyperuricemia reflects a subclinical impairment of renal function or contributes to its development is currently debated. We investigated the relationship between serum uric-acid levels and the occurrence of early signs of kidney damage. METHODS: Four hundred eighteen patients with primary hypertension were studied. Albuminuria was measured as the albumin-to-creatinine ratio, and creatinine clearance was estimated by the formula of Cockcroft and Gault. Interlobar resistive index and renal abnormalities, ie, the renal volume-to-resistive index ratio, were evaluated by renal Doppler and ultrasound. RESULTS: Uric acid was directly related to resistive index (P = .007) in women and to albuminuria (P = .04) in men, and was inversely related to the renal volume-to-resistive index ratio in both men (P = .005) and women (P = .02). Patients with uric-acid levels above the median showed a higher prevalence of microalbuminuria (14% v 7%, P = .012) and of renal abnormalities (41% v 33%, P = .007). Moreover, when creatinine clearance was taken as a covariate, patients with increased uric-acid levels showed higher albuminuria and resistive indices, and a lower renal volume-to-resistive index ratio. Even after adjustment for several risk factors, each standard deviation increase in serum uric acid entailed a 69% higher risk of microalbuminuria, and a 39% greater risk of ultrasound detectable renal abnormalities. CONCLUSIONS: Mild hyperuricemia is associated with early signs of renal damage, ie, microalbuminuria and ultrasound-detectable abnormalities, regardless of the glomerular filtration rate in primary hypertension.     

Patient risk of contact with respiratory pathogens from inanimate surfaces in a cystic fibrosis outpatient clinic. A prospective study over a four-year period

Acquisition of respiratory pathogens such as Pseudomonas aeruginosa (PA) is associated with increased morbidity and mortality in cystic fibrosis (CF). Research on the prevalence of these pathogens on environmental surfaces of a CF Center is scanty, and so far no study has determined what risk CF patients have of coming in contact with them during their visits to the CF Center. This study is aimed at assessing the prevalence of some respiratory pathogens in samples taken systematically during a 4-year period from inanimate surfaces and sinks in a CF Outpatient Clinic, and to estimate the risk that a non-PA colonized CF patient has of contact with PA when visiting the CF Center. Microbiological samples were taken and cultured from the inanimate surfaces and sinks of the Outpatient clinic of a CF Center once a month from 2001 to 2005. Four hundred and sixty environmental specimens were collected: 36.3% were positive for respiratory pathogens (23% of rooms' inert surfaces, 49.5% of sinks). Achromobacter xylosoxidans was found in 0.8% of surface samples. PA was isolated in 22.8% samples. The estimated risk for each non-colonized patient of coming in contact with PA on the surfaces in the Clinic at each visit was 5.4 per thousand (CI95% 0.9-30.1). Genotyping of a sample of environmental PA strains revealed a genetic relation between environmental and clinical isolates in most cases. Micro-organisms relevant for CF patients can be found on inanimate surfaces of a CF Center, although the risk for patients of coming in contact with PA during their visits to the CF center seems low.