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A recent clinicopathologic study of a series of patients with monocytoid B-cell lymphoma (MBCL) indicated that there is a frequent association between MBCL and Sjogren's syndrome (SS) and raised the possibility of a relationship between these two disease entities. To further investigate the possible relationship of MBCL and SS, we studied pathologic and clinical characteristics of 13 patients with MBCL who had clinically documented SS. In all patients, the lymphoma had the characteristic morphologic features of MBCL, and immunologic and molecular hybridization studies confirmed the B-cell nature of the lymphoma. Twelve of the 13 patients were female, with a median age of 66 years at diagnosis. Eleven had localized disease and presented with either salivary gland or cervical lymph node enlargement; one patient presented with a breast mass, and another with generalized lymphadenopathy and hepatosplenomegaly. In five of 13 patients, the MBCL was associated with or progressed to large cell lymphoma. In two patients, there was bilateral involvement of the parotid gland; one had a synchronous high-grade lymphoma in both parotid glands. In two patients, bone marrow biopsies showed involvement by MBCL. Eleven patients are alive 2 to 55 months after the diagnosis of MBCL. One patient died with the disease 8 months after the initial diagnosis. Another patient died of an unrelated cause without evidence of disease 16 months after the diagnosis of MBCL. We conclude that there is a more than fortuitous association between MBCL and SS. This concept is consistent with previously reported observations of reactive monocytoid B cells in patients with benign lymphoepithelial lesions of salivary glands, which may result from selective homing of reactive monocytoid B lymphocytes to the benign lymphoepithelial lesions and their subsequent neoplastic transformation.

The cytogenetics of Hodgkin's disease (HD) is poorly understood. However, a t(2;5) is a common finding in CD30+ anaplastic large cell lymphoma (ALCL), a neoplasm thought by some to be closely related to HD. Recently, the t(2;5) has been cloned and found to represent fusion of the NPM gene with the ALK gene. Using Southern blot hybridization, one group has reported finding rearrangements of NPM in a proportion of cases of both ALCL and HD. In the current study, we used a highly sensitive reverse transcriptase-polymerase chain reaction methodology to analyze 34 cases of HD for the t(2;5). We were unable to find polymerase chain reaction evidence for the t(2;5) in any of the cases of HD, a result significantly different from our previous study of CD30+ non-Hodgkin's lymphomas (P < .02) including ALCL (P < .04), using identical methods. Our results do not support the hypothesis that the t(2;5) represents a common chromosomal abnormality for both HD and ALCL.

In its late stage, Alzheimer's disease results in progressive muscle weakness in the arms and legs. The aim of this study was to determine whether mice expressing the skeletal muscle-specific mutant PS2 gene (a model of Alzheimer's disease) are a useful experimental system to study the protective effect of exercise on A beta-42 reduction, improvement of behavioural function and changes in metabolic parameters. With this aim in mind, the transgenic mice were subjected to treadmill exercise for 3 months. The results showed that in transgenic mice, but not in normal mice, treadmill exercise resulted in a reduction of A beta-42 deposits and an improvement in behavioural function, thereby restoring normal concentrations of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglyceride. Thus, exercise may represent a practical therapeutic strategy for use with human patients with Alzheimer's disease.

Apoptosis is an important process in the variety of different biological system including cell death and embryonic development. Inappropriate apoptosis is implicated in many human diseases such as Alzheimer's disease. Central component of the machinery of apoptosis program in neurons of patients with Alzheimer's disease includes proteins of caspases and Bcl-2 families. We examined whether endogenous protein levels of caspases and Bcl-2 families are expressed in a differential manner during the embryonic and postnatal development of BDF1 strain. Here, all four proteins with caspases-3, -9, Bcl-2 and Bax were highly expressed between embryonic day 19 and 1 week age of early postnatal development, but thereafter the expression dramatically declined. These patterns are needed to compare the proteins in the brains of APPsw-transgenic mice that are expected to be expressed highly in the brain of adult mice. Thus, the results are useful to understand fundamentally the mechanisms of the apoptotic changes during the embryonic and postnatal development of Alzheimer's model mice.

The dose and time effect of nine xenobiotics, including 17β-estradiol, corticosterone, dexamethasone, progesterone, nifedipine, bisphenol A, rifampicin, methamphetamine, and nicotine were investigated, in vitro, using human steroid and xenobiotics receptor (SXR)-binding sites on the human CYP3A4 promoter, which can enhance the linked lac Z reporter gene transcription. To test this, liver-specific SAP (human serum amyloid P component)-SXR (SAP/SXR) and human CYP3A4 promoter-regulated lac Z (h CYP3A4/lac Z) constructs were transiently transfected into Hep G2 and NIH3T3 cells to compare the xenobiotic responsiveness between human and nonhuman cell lines. In the Hep G2 cells, rifampicin, followed by corticosterone, nicotine, methamphetamine, and dexamethasone, exhibited enhanced levels of the lac Z transcript, whereas those of bisphenol A and nifedipine were found to be reduced. No significant responses were observed with 17β-estradiol or progesterone. In addition, 17β-estradiol and progesterone did not change the levels of the lac Z transcripts in the Hep G2 cells, but did induce significant increases in the transcripts of the NIH3T3 cells. Treatment with corticosterone and dexamethasone, which were highly expressed in the Hep G2 cells, did not affect the levels of the lac Z transcript in NIH3T3 cells. These results show that lac Z transcripts can be measured, rapidly and reproducibly, using reverse transcriptase–polymerase chain reaction (RT-PCR) based on the expression of the h CYP3A4/lac Z reporter gene, and was mediated by the SXR. Thus, this in vitro reporter gene bioassay is useful for measuring xenobiotic activities, and is a means to a better relevant bioassay, using human cells, human genes and human promoters, in order to get a closer look at actual human exposure.

Apoptosis is an important process in the variety of different biological system including cell death and embryonic development. Inappropriate apoptosis is implicated in many human diseases such as Alzheimer's disease. Central component of the machinery of apoptosis program in neurons of patients with Alzheimer's disease includes proteins of caspases and Bcl-2 families. We examined whether endogenous protein levels of caspases and Bcl-2 families are expressed in a differential manner during the embryonic and postnatal development of BDF1 strain. Here, all four proteins with caspases-3, -9, Bcl-2 and Bax were highly expressed between embryonic day 19 and 1 week age of early postnatal development, but thereafter the expression dramatically declined. These patterns are needed to compare the proteins in the brains of APPsw-transgenic mice that are expected to be expressed highly in the brain of adult mice. Thus, the results are useful to understand fundamentally the mechanisms of the apoptotic changes during the embryonic and postnatal development of Alzheimer's model mice.

Induction of c-Fos has previously been used to map locations of cells in the central nervous system (CNS) that are activated by ethanol administration. Only a few studies examining a restricted range of CNS areas have identified brain areas activated by nitrous oxide (N(2)O). Because ethanol and N(2)O have overlapping physiological, psychological and behavioral effects, we hypothesized that these drugs act on similar sites in the CNS. To test this hypothesis, we assessed c-Fos-like immunoreactivity in brain slices from male Long-Evans rats that received a 2-h exposure of 0, 20, 40 or 60% N(2)O (n=5 each) immediately prior to sacrifice. N(2)O administration produced significant (P0.05) dose-related increases of c-Fos expression in several forebrain regions, including the hypothalamic supraoptic and paraventricular nuclei, the thalamic paraventricular nucleus, the amygdala, and in retrosplenial cortex. In the midbrain, N(2)O caused significant dose-related c-Fos expression in the Edinger-Westphal nucleus. Finally, the pontine locus coeruleus, and two medullary regions, the nucleus of the solitary tract and ventrolateral medulla, also showed significant dose-related N(2)O-induced c-Fos expression. Most of the brain areas identified as targets of N(2)O are also activated by ethanol administration. The overlapping pattern of c-Fos induced by ethanol and N(2)O suggests that these drugs may cause comparable central activity by acting on similar neuronal pathways.

The Arabidopsis ethylene-overproducing mutants eto1, eto2, and eto3 have been suggested to affect the post-transcriptional regulation of 1-aminocyclopropane-1-carboxylic acid synthase (ACS). Here, we present the positional cloning of the gene corresponding to the dominant eto3 mutation and show that the eto3 phenotype is the result of a missense mutation within the C-terminal domain of ACS9, which encodes one isoform of the Arabidopsis ACS gene family. This mutation is analogous to the dominant eto2 mutation that affects the C-terminal domain of the highly similar ACS5. Analysis of purified recombinant ACS5 and epitope-tagged ACS5 in transgenic Arabidopsis revealed that eto2 does not increase the specific activity of the enzyme either in vitro or in vivo; rather, it increases the half-life of the protein. In a similar manner, cytokinin treatment increased the stability of ACS5 by a mechanism that is at least partially independent of the eto2 mutation. The eto1 mutation was found to act by increasing the function of ACS5 by stabilizing this protein. These results suggest that an important mechanism by which ethylene biosynthesis is controlled is the regulation of the stability of ACS, mediated at least in part through the C-terminal domain.

Forced immobilization is a simple and effective stressor which produces large increases in heart rate (HR), blood pressure (BP), and plasma levels of norepinephrine (NE) and epinephrine (EPI). This study investigated the effects of electroacupuncture on BP, HR, and plasma catecholamine levels in rats challenged with immobilization stress. Male Sprague-Dawley rats received electroacupuncture (3 Hz, 0.2 ms pulses, 20 mA) for 30 min after start of immobilization stress (180 min). Needlepoints corresponded to Shaohai (HT3) and Neiguan (PC6) on the heart and pericardium channel. BP and HR were monitored with an indwelling carotid catheter, and blood samples were taken from the jugular vein. Blood (for HPLC determination of NE and EPI), mean BP, and HR were sampled at rest and during the immobilization stress at 15, 30, 60, 90, 120, 150, and 180 min. Electroacupuncture at HT3 and PC6 points but not at control points (TE5, LI11, and tail) significantly reduced the expected increases in BP, HR, and attenuated plasma levels of NE and EPI in response to 3 h of immobilization stress. Results provide strong evidence that electroacupuncture effectively reduces BP and HR increases and plasma catecholamine increases in rats challenged with immobilization stress.

Alzheimer's disease (AD) occurs when neurons in the memory and cognition regions of the brain are accompanied by an accumulation of the long amyloid beta-proteins of the 39 to 43 amino acids derived from the amyloid precursor protein (APP) by cleavage with beta- and gamma-secretase. An increased production of Abeta-42 by mutation of PS2 genes promotes caspase expression and is associated with the Cox-2 found in the brain of AD patients. To address this question in vivo, we expressed the human mutant PS2 (hPS2m) (N141I) as well as wild PS2 (hPS2w) as a control in transgenic (Tg) mice under control of the neuron-specific enolase (NSE) promoter. Water maze tests were used to demonstrate the behavioral defect; dot blot, Western blot, and immunohistochemical analyses were performed on the brain with the hPS2, Abeta-42, caspase-3, and Cox-2 antibody. We concluded that 1) Tg mice showed a behavioral dysfunction in the water maze test, 2) levels of hPS2, Abeta-42, caspase-3, and Cox-2 expression were modulated in the brains of both Tg mice, 3) dense staining with antibody to hPS2, Abeta-42, caspase-3, and Cox-2 was visible in the brains of Tg mice compared with age-matched control mice, and 4) distinguishable AD phenotypes between hPS2w- and hPS2m-Tg mice did not appear. These results suggest that an elevation of Abeta-42 by overexpression of hPS2 and mutation of hPS2m might induce the behavioral deficit and caspase-3 and Cox-2 induction, which could be useful in the therapeutic testing of compounds to have considerable clinical effects.

We compared radioligand binding and functional data for histamine H3 receptor ligands across different tissues or species to evaluate the basis for pharmacological evidence of receptor heterogeneity previously reported. Agonist binding affinities showed correlation coefficients near unity in comparing human, dog, rat, and guinea pig cerebral cortical histamine H3 receptors. Antagonist binding affinities revealed lower correlations for human compared to dog, rat, or guinea pig, suggesting species-based pharmacological differences. The functional potencies of histamine H3 receptor antagonists in field-stimulated guinea pig ileum were highly correlated to binding affinities for guinea pig, dog, and, to a lesser extent, rat cerebral cortex. However, antagonist binding affinity at human cerebral cortex did not correlate well with guinea pig ileum functional potency. These results suggest significant interspecies histamine H3 receptor heterogeneity, consistent with recent receptor gene sequence data. Therefore, genetic heterogeneity, rather than peripheral and central histamine H3 receptor diversity, is responsible for the pharmacological differences observed.

The distinction between mantle cell lymphoma (MCL) and other low-grade B-cell neoplasms is important because MCL has a more aggressive clinical course. In bone marrow biopsy specimens, this distinction can be especially difficult. We examined 70 bone marrow biopsy specimens involved by various B-cell lymphoid neoplasms to assess the utility of cyclin D1 immunostaining in distinguishing MCL from other B-cell lymphoproliferative disorders. We used a cocktail of two monoclonal anti-cyclin D1 antibodies and a heat- and sonication-induced epitope retrieval procedure. The neoplasms assessed included MCL (32 cases), small lymphocytic lymphoma/chronic lymphocytic leukemia (18 cases), follicular lymphoma (11 cases), hairy cell leukemia (5 cases), splenic marginal zone lymphoma (2 cases), and small lymphocytic lymphoma with plasmacytoid differentiation (2 cases). The diagnosis of MCL in bone marrow was confirmed by review of the original diagnostic biopsy specimens along with additional data, such as immunophenotypic or molecular studies. Most MCL (23/32; 72%) cases expressed cyclin D1 protein. In contrast, one case of small lymphocytic lymphoma/chronic lymphocytic leukemia (1/18; 6%) and one case of hairy cell leukemia (1/5; 20%) expressed cyclin D1 protein. These findings demonstrate that immunostaining for cyclin D1 protein expression is useful in distinguishing MCL from other B-cell lymphoid neoplasms in the bone marrow.

Five cases of clinically aggressive, keratin-positive malignant lymphomas of B-cell type with unusual immunophenotypes were studied. All cases were extranodal: two from the stomach, one from soft tissue, one from the skin, and one from the spleen. These tumors were undifferentiated large-cell neoplasms that showed reactivity for low-molecular-weight keratin 8, but they were negative for keratin 19; three cases were also positive for epithelial membrane antigen. The immunohistochemical diagnosis was complicated by the fact that two of these cases lacked reactivity for leukocyte common antigen and three were CD20 negative. These findings simulated the immunophenotype of a carcinoma and led to an initial misdiagnosis of carcinoma. Although only two cases showed immunohistochemical evidence of B-cell lineage (CD20+), all five cases were documented as B-cell lymphomas on the basis of the clonal immunoglobulin heavychain gene rearrangement, as demonstrated by polymerase chain reaction (PCR) in all the cases and by Southern blot hybridization in three cases; all cases were negative for T-cell markers, and three cases showed germline configuration for T-cell receptor beta-chain. One case was strongly CD30 positive and represented large-cell anaplastic lymphoma of B-cell type. Our results show that some B-cell lymphomas can have unusual and confusing immunophenotypes, including keratin positivity and leukocyte antigen negativity. Use of PCR-based molecular genetic demonstration of clonal immunoglobulin heavychain gene rearrangement is helpful in establishing the correct diagnosis in such cases.