Occurrence of the t(2;5)(p23;q35) in non-Hodgkin's lymphoma

Primary CD30(Ki-1)-positive anaplastic large-cell lymphoma (ALCL) is considered by some to be a distinct clinicopathologic entity associated with the t(2;5) (p23;q35). However, the specificity of t(2;5) for ALCL has not been carefully studied. Therefore, we performed a detailed analysis of all cases of ALCL with abnormal cytogenetics results in the Nebraska Lymphoma Study Group registry, as well as all other cases of non-Hodgkin's lymphoma with t(2;5) in the registry. We found the t(2;5) in only five of 10 cases of ALCL, four of whom were young patients. However, we also found the t(2;5) in 11 other cases of nonanaplastic lymphoma, including eight children with typical peripheral T-cell lymphomas of various types. The t(2;5) was also found in three older adults with B-cell lymphomas of various types. Thus, the t(2;5) was not specific for CD30+ ALCL. However, t(2;5) may define a clinicopathologic entity in children and young adults characterized by variable morphologies with a T-cell or indeterminate phenotype, CD30-positivity, nodal disease with frequent extranodal involvement, advanced stage, and an excellent response to therapy, including bone marrow transplantation for relapsed disease. The clinical relevance of the t(2;5) in older patients requires further study.     

Modulation of calcium-activated chloride current via pH-induced changes of calcium channel properties in cone photoreceptors.

The activity of calcium-activated chloride channels is controlled through the complex interaction of cellular mechanisms affecting calcium entry, buffering, and extrusion, and an unknown stoichiometric relation between intracellular Ca concentration and Cl channel activation. Here, we show that calcium-activated chloride current [ICl(Ca)] in cone photoreceptors is also highly sensitive to external pH, being strongly reduced by acidification and enhanced by alkylinization of the bathing medium. We propose that this modulation is accounted for by the pH sensitivity of Ca channel activation and permeation, already well characterized in other cells, which we now extend to cone photoreceptor Ca channels. Acidification of the external medium from a control pH of 7.4 shifts the Ca channel activation range positively by about 10 mV at pH 6.8, reducing the magnitude of calcium current with a consequent reduction of chloride current. Alkylinization shifts the Ca channel activation range negatively by about 8 mV at pH 8 and produces larger calcium currents during step depolarizations that in turn elicit larger chloride tail currents. Modulation of ICl(Ca) by pH suggests other consequences of the pH-induced shift in Ca channel gating, for one, modification of Ca-dependent transmitter release, which could be especially significant in photoreceptors where the cell's operating voltage range overlaps only the lower end of the Ca channel activation range.     

Modulation of high-dose methotrexate toxicity by a non-toxic level of 5-fluorouracil

High-dose methotrexate (MTX) toxicity is reduced by a non-toxic dose of 5-fluorouracil (FU) when these agents are used in combination. Changes in the hematopoietic system (platelets, erythrocytes, leukocytes, hemoglobin, and hematocrit), ileal tissue, body weight, and mean survival were used as parameters to assess toxicity. For all parameters studied, there were no significant differences between the scheduling of MTX (245 mg/kg) after a priming dose of FU (25 mg/kg), simultaneous MTX and FU, FU alone, and control. However, sequential treatment with MTX followed by FU, and MTX alone resulted in: a marked decrease in the hematopoietic parameters; significant morphological changes in ileal tissue; a reduction of body weight; and increased mortality of animals. Hence, this study suggests that FU, a cytotoxic agent, may protect against MTX toxicity and improve its therapeutic index when FU administration precedes MTX or when these agents are given simultaneously.     

Hemorrhagic and nonhemorrhagic brain lesions: evaluation with 0.35-T fast MR imaging

Two fast magnetic resonance (MR) imaging techniques, advanced Fourier and partial-flip imaging, were used at 0.35 T to examine 21 patients with suspected intracranial lesions; the results were quantitatively compared with a conventional spin-echo study. Both of the fast MR techniques yielded a fourfold reduction in imaging time per section. The advanced Fourier sequence showed contrast that was identical to the conventional spin-echo study with signal-to-noise ratios of 58% and 57% for the first and second echoes, respectively. The partial-flip sequence showed a contrast of 109% and 57% for lesions versus substantia alba, and 107% and 78% for substantia grisea versus substantia alba relative to the first and second echoes of the conventional spin-echo study. The partial-flip sequence was particularly sensitive to magnetic susceptibility; this produced artifacts that may undermine the usefulness of partial flip for routine screening in certain parts of the brain. However, this susceptibility significantly improved the detection of intracranial hemorrhage when compared with the spin-echo sequence, particularly when combined with phase mapping of the partial-flip study.     

Genetic diversity among clinical isolates of Acremonium strictum determined during an investigation of a fatal mycosis

Primarily saprophytic in nature, fungi of the genus Acremonium are a well-documented cause of mycetoma and other focal diseases. More recently, a number of Acremonium spp. have been implicated in invasive infections in the setting of severe immunosuppression. During the course of routine microbiological studies involving a case of fatal mycosis in a nonmyeloablative hematopoietic stem cell transplant patient, we identified a greater-than-expected variation among strains previously identified as Acremonium strictum by clinical microbiologists. Using DNA sequence analysis of the ribosomal DNA intergenic transcribed spacer (ITS) regions and the D1-D2 variable domain of the 28S ribosomal DNA gene (28S), the case isolate and four other clinical isolates phenotypically identified as A. strictum were found to have <99% homology to the A. strictum type strain, CBS 346.70, at the ITS and 28S loci, while a sixth isolate phenotypically identified only as Acremonium sp. had >99% homology to the type strain at both loci. These results suggest that five out of the six clinical isolates belong to species other than A. strictum or that the A. strictum taxon is genetically diverse. Based upon these sequence data, the clinical isolates were placed into three genogroups.     

CD1d deficiency exacerbates inflammatory dermatitis in MRL-lpr/lpr mice

Mechanisms responsible for the development of autoimmune skin disease in humans and animal models with lupus remain poorly understood. In this study, we have investigated the role of CD1d, an antigen-presenting molecule known to activate natural killer T cells, in the development of inflammatory dermatitis in lupus-susceptible MRL-lpr/lpr mice. In particular, we have established MRL-lpr/lpr mice carrying a germ-line deletion of the CD1d genes. We demonstrate that CD1d-deficient MRL-lpr/lpr mice, as compared with wild-type littermates, have more frequent and more severe skin disease, with increased local infiltration with mast cells, lymphocytes and dendritic cells, including Langerhans cells. CD1d-deficient MRL-lpr/lpr mice had increased prevalence of CD4(+) T cells in the spleen and liver and of TCR alpha beta (+)B220(+) cells in lymph nodes. Furthermore, CD1d deficiency was associated with decreased T cell production of type 2 cytokines and increased or unchanged type 1 cytokines. These findings indicate a regulatory role of CD1d in inflammatory dermatitis. Understanding the mechanisms by which CD1d deficiency results in splenic T cell expansion and cytokine alterations, with increased dermal infiltration of dendritic cells and lymphocytes in MRL-lpr/lpr mice, will have implications for the pathogenesis of inflammatory skin diseases.     

A critical function for type I interferons in cancer immunoediting

'Cancer immunoediting' is a process wherein the immune system protects hosts against tumor development and facilitates outgrowth of tumors with reduced immunogenicity. Although interferon-gamma (IFN-gamma) is known to be involved in this process, the involvement of type I interferons (IFN-alpha/beta) has not been elucidated. We now show that, like IFN-gamma, endogenously produced IFN-alpha/beta was required for the prevention of the growth of primary carcinogen-induced and transplantable tumors. Although tumor cells are important IFN-gamma targets, they are not functionally relevant sites of the actions of the type I interferons. Instead, host hematopoietic cells are critical IFN-alpha/beta targets during development of protective antitumor responses. Therefore, type I interferons are important components of the cancer immunoediting process and function in a way that does not completely overlap the functions of IFN-gamma.     

Choline acetyltransferase activity and cognitive domain scores of Alzheimer's patients

Choline acetyltransferase activity and cognitive domain scores of Alzheimer's patients. Item scores from the Mattis Dementia Rating Scale (MDRS) and the Mini-Mental State Examination (MMSE) from 389 patients with probable Alzheimer's disease were submitted to principal component analysis with orthogonal rotation. The optimal solution identified four factors that reflected the cognitive domains of attention/registration, verbal fluency/reasoning, graphomotor/praxis and recent memory. A subgroup of patients was identified for whom both the MDRS and the MMSE had been administered within the 12 months before death. Scores were assigned to these patients for the four factors. These cognitive-domain scores were then correlated with postmortem choline acetyltransferase (ChAT) activity in the medial frontal cortex, inferior parietal cortex, and hippocampus. ChAT activity in both the medial frontal and the inferior parietal cortex significantly correlated with scores on the graphomotor/praxis factor. Medial frontal ChAT also correlated significantly with the attention/registration scores. Hippocampal ChAT correlated significantly only with recent memory scores. These results are consistent with current animal research regarding the effect of selective cholinergic lesions on behavior.