A novel t(2;6)(p12;q23) appearing during transformation of follicular lymphoma with t(18;22)(q21;q11) to diffuse large cell lymphoma

Follicular lymphoma is characterized genetically by t(14;18)(q32;q21), whereas t(18;22)(q21;q11), a rare variant form of t(14;18), has been preferentially observed in chronic lymphocytic leukemia (CLL). We describe here an unusual case of follicular lymphoma with a t(18;22)(q21;q11), that progressed to diffuse large cell lymphoma with a novel t(2;6)(p12;q23). Spectral karyotyping revealed that add(2)(p12) and add(6)(q23) were derived from a t(2;6)(p12;q23). Fluorescence in situ hybridization analysis confirmed rearrangements of the BCL2 gene at 18q21 and the BCL6 gene at 3q27. Our results indicate that a reciprocal translocation involving 6q23 could be implicated in the progression of follicular lymphoma and that t(18;22) may have a specific role in the pathogenesis of follicular lymphoma as well as CLL.     

Central command and the cutaneous vascular response to isometric exercise in heated humans

Cutaneous vascular conductance (CVC) decreases during isometric handgrip exercise in heat stressed individuals, and we hypothesized that central command is involved in this response. Seven subjects performed 2 min of isometric handgrip exercise (35% of maximal voluntary contraction) followed by postexercise ischaemia in normothermia and during heat stress (increase in internal temperature ∼1°C). To augment the contribution of central command independent of force generation, on a separate day the protocol was repeated following partial neuromuscular blockade (PNB; i.v. cisatracurium). Forearm skin blood flow was measured by laser-Doppler flowmetry, and CVC was the ratio of skin blood flow to mean arterial pressure. The PNB attenuated force production despite encouragement to attain the same workload. During the heat stress trials, isometric exercise decreased CVC by ∼12% for both conditions, but did not change CVC in either of the normothermic trials. During isometric exercise in the heat, the increase in mean arterial pressure (MAP) was greater during the control trial relative to the PNB trial (31.0 ± 9.8 versus 18.6 ± 6.4 mmHg, P < 0.01), while the elevation of heart rate tended to be lower (19.4 ± 10.4 versus 27.4 ± 8.1 b.p.m., P = 0.15). During postexercise ischaemia, CVC and MAP returned to pre-exercise levels in the PNB trial but remained reduced in the control trial. These findings suggest that central command, as well as muscle metabo-sensitive afferent stimulation, contributes to forearm cutaneous vascular responses in heat stressed humans.     

Osteopontin affects the persistence of beta-glucan-induced hepatic granuloma formation and tissue injury through two distinct mechanisms

Osteopontin (OPN) plays a pivotal role in various immune responses and inflammatory diseases. OPN is expressed in various granulomatous diseases; however, the cellular and molecular role of OPN in these diseases is not well known. We analyzed the role of OPN in a beta-glucan-induced hepatic granuloma model. First, we found that neither OPN deficiency nor overexpression of OPN affected the number and the size of hepatic granulomas at day 7, indicating that OPN is not involved in the formation of hepatic granulomas at the early stages. Importantly, OPN did not influence the liver tissue damage as defined by alanine aminotransferase and aspartate aminotransferase levels at early stages. Second, OPN deficiency resulted in the reduction of IL-12 and IFN-gamma production at early stages. Third, at late stages, OPN deficiency resulted in a decrease in the number and size of hepatic granulomas, and a reduction of liver tissue injury. This was due to the reduction of the cellular recruitment including macrophages, CD4 T cells and dendritic cells into the liver, and the reduction of tumor necrosis factor (TNF)-alpha production in the liver. In contrast, overexpression of OPN resulted in the persistence of granuloma formation. These data suggest that OPN affects the persistence of hepatic granuloma formation. Our results indicate that OPN up-regulates the production of IL-12 and IFN-gamma within the granulomas at early stages, and OPN has an additional role in the regulation of cellular recruitment and TNF-alpha production at late stages that determine the severity of liver tissue injury.     

Whole genome association study of rheumatoid arthritis using 27 039 microsatellites

A major goal of current human genome-wide studies is to identify the genetic basis of complex disorders. However, the availability of an unbiased, reliable, cost efficient and comprehensive methodology to analyze the entire genome for complex disease association is still largely lacking or problematic. Therefore, we have developed a practical and efficient strategy for whole genome association studies of complex diseases by charting the human genome at 100 kb intervals using a collection of 27,039 microsatellites and the DNA pooling method in three successive genomic screens of independent case-control populations. The final step in our methodology consists of fine mapping of the candidate susceptible DNA regions by single nucleotide polymorphisms (SNPs) analysis. This approach was validated upon application to rheumatoid arthritis, a destructive joint disease affecting up to 1% of the population. A total of 47 candidate regions were identified. The top seven loci, withstanding the most stringent statistical tests, were dissected down to individual genes and/or SNPs on four chromosomes, including the previously known 6p21.3-encoded Major Histocompatibility Complex gene, HLA-DRB1. Hence, microsatellite-based genome-wide association analysis complemented by end stage SNP typing provides a new tool for genetic dissection of multifactorial pathologies including common diseases.     

A Gln/Arg polymorphism at codon 349 of the hBUBR1 gene

We found a glutamine/arginine polymorphism at codon 349 of the hBUBR1 gene, encoding a protein kinase required for spindle assembly checkpoint function. The observed heterozygosity was estimated to be 45% in the Japanese population. This polymorphism may be helpful for genetic studies of many cancer types in which chromosomal instability is observed. Received: October 19, 1998 / Accepted: October 24, 1998     

Analysis of wild-type and e antigen-defective hepatitis B viruses during the course of a short-term corticosteroid therapy in chronic hepatitis B

Hepatitis B virus (HBV), with a G-to-A point mutation at nucleotide 83 in the precore region (mutant HBV83), accounts for most cases of hepatitis B e antigen (HBeAg)-defective HBV. However, it is still not clear how mutant HBV83 is associated with HBe seroconversion. Twenty-six HBeAgpositive patients with chronic hepatitis B who received oral prednisolone (30 mg/day) for 3 weeks were studied to clarify the prevalence of mutant HBV83 during the treatment using polymerase chain reaction with a restriction fragment length polymorphism assay. Twelve (46%) patients seroconverted to anti-HBe 1 year after treatment, whereas 14 (54%) did not. The proportion of mutant HBV83 to whole HBV remained unchanged in both groups during an acute exacerbation induced by withdrawal of corticosteroids. Among 12 anti-HBe-0seroconverted patients, five (56%) of nine patients with only wild-type HBV at baseline developed detectable levels of mutant HBV83 while all three patients with a mixed viral population of wild-type HBV and mu tant HBV83 at baseline developed a higher pro portion of mutant HBV83 one year after treat ment. In contrast, these changes were observed in only one (14%) of seven who failed to seroconvert. The results indicate that a flare-up of hepa titis precedes emergence or selection of mutant HBV83, followed by HBe seroconversion in patients with chronic hepatitis B. © 1995 WiIey-Liss, Inc.     

Numerical aberrations of chromosome 9 in bladder cancer. A possible prognostic marker for early tumor recurrence

Bilharzial bladder cancer is one of the most common types of malignancy in both men and women in several developing countries including Egypt. It has several unique clinical, epidemiological, and histological characteristics, suggesting that it is an entity distinct from bladder cancer seen in Western countries. Genetic alterations in bilharzial-related bladder cancer have been studied infrequently, especially in the advanced stages of disease, that is, T3 and T4 classifications. The objective of this study was to extend establishing the baseline cytogenetic profile of this type of malignancy to early T1 and T2 classifications. For this purpose, fluorescence in situ hybridization was applied to interphase nuclei of frozen-stored samples with biotinylated repetitive DNA probes specific for all chromosomes to detect numerical chromosome changes in 35 patients presenting with relatively early-stage pT1 and pT2 disease. Eleven cases had squamous cell carcinoma (SCC) and 24 had transitional cell carcinoma. Six of 24 transitional cell carcinomas had diploid chromosome counts with all the probes. Numerical chromosome aberrations were detected in 18 cases (75%). In 12 cases, a loss of chromosome 9 was observed. In three cases, an additional loss of chromosome 17 was detected. One case demonstrated a loss of chromosome 10, whereas another two cases showed a gain of chromosome 7, next to a loss of chromosome 9. Loss of chromosome Y was observed in nine of the 27 male cases studied (33.3%), in which only one case showed an abnormality whereas four cases were detected next to loss of chromosome 9, and one case showed gain of chromosome 7. Five cases showed loss of chromosome 19 whereas gain of chromosome 4 was detected in two cases. Two of 11 samples of SCC had normal diploid chromosome counts with all the probes used. In four of 11 cases (36.4%) underrepresentation of chromosome 9, compared with the other chromosomes, was detected. An additional loss of chromosome 17 and gain of chromosome 7, next to loss of chromosome 9, was detected in three cases. One case showed loss of chromosome 17 as the only numerical aberration. Loss of the Y chromosome was detected in three cases of which one case had gain of chromosome 7 and one case had loss of chromosome 19. No correlation was found between any of the clinicopathologic parameters examined in this study and the presence or absence of any numerical chromosomal aberrations except for the significant association between schistosomal history and loss of Y chromosome (P=0.007).