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PubMed2005

Effects of locoweed on serum swainsonine and selected serum constituents in sheep during acute and subacute oral/intraruminal exposure.

A study was conducted to evaluate the effects of acute and subacute locoweed exposure on serum swainsonine concentrations and selected serum constituents in sheep. Thirteen mixed-breed wethers (BW = 47.5 +/- 9.3 kg) were assigned randomly to 0.2, 0.4, or 0.8 mg of swainsonine x kg BW(-1) x d(-1) treatments. During acute (24 h) and subacute (19 d) exposure, serum swainsonine was detected in all treatments and was greatest (P < 0.03) in the 0.8 mg treatment. Serum alkaline phosphate (ALK-P) activity was increased (P < 0.01) for the 0.8 mg treatment compared with baseline (0 h) by 7 h and continued to increase throughout the initial 22 h following acute exposure to locoweed. A linear increase (P < 0.01) in serum ALK-P activity was noted, with the rate being 3.00 +/- 0.56 U x L(-1) x h(-1). Serum ALK-P activity was increased (P < 0.05) across treatments on d 7 over d -19, -12, 0, 1, 21, and 26; on d 14 over d -19, -12, 0, and 26; and on d 19 over d -19, -12, 0, 1, 21, and 26. By d 20, approximately 48 h after last exposure to swainsonine, serum ALK-P activities were no longer different (P = 0.13) than baseline (d -19, -12, and 0), and by d 26 values had generally returned to baseline. No linear (P = 0.98), quadratic (P = 0.63), or cubic effects of swainsonine with time from exposure were noted for serum aspartate aminotransferase. Similar to serum ALK-P activities, serum aspartate aminotransferase activities were increased (P < 0.05) across treatment levels on d 7, 14, 19, 20, 21, and 26 over those on d -19, -12, 0, and 1. Total serum Fe was decreased (P < 0.05) within the initial 22 h following the swainsonine exposure. On d 21 (48 h after swainsonine feeding ended), serum Fe increased to 472 mg/L. Concentrations of ceruloplasmin were lower (P < 0.10) on d 14 and 19 following exposure to locoweed. Recovery of ceruloplasmin levels coincided with similar changes in serum Fe. There was a linear (slope = 0.33 mg x dL(-1) x d(-1); P < 0.01) effect with time of exposure to locoweed (i.e., swainsonine) on serum triglyceride concentrations. Rapid changes in serum ALK-P and Fe concentrations without parallel changes in other damage markers indicate that acute exposure to swainsonine induces metabolic changes that may impair animal production and health before events of cytotoxicity thought to induce clinical manifestation of locoism.

Administration, Oral↗
PubMed1977

Alkaline phosphatase reaction of canine mammary mixed tumours: a light and electron microscopic study.

Alkaline phosphatase (ALK-P) reactions at the light and electron microscopic levels were performed on eight canine mammary mixed tumours. In the morphologically normal gland next to the tumours, the myoepithelial cells and the stromal tissues near the acinar basement membranes both showed a positive ALK-P reaction by light microscopy. At the electron microscopic level, those parts of the myoepithelial cell membrane that were in contact with other cells--myoepithelial or lumenal epithelial--showed an ALK-P-positive reaction, as did the adjacent stromal tissue. The characteristic tumour cells, at sites of early proliferation, were ALK-P-positive, while in the mucoid and chondroid areas of the mixed tumours they were largely ALK-P-negative by light microscopy. By electron microscopy, those neoplastic cells which were in contact with other cells typically showed a positive ALK-P reaction, while those cells which were in contact with mucoid or chondroid matrix were largely negative. Although the cytoplasmic filaments of the neoplastic cells were 10 nm thick, and those of normal myoepithelial cells were 6 to 8 nm thick, the observations reported provide further evidence for the view that the essential cells of the canine mammary mixed tumour are derived from myoepithelial cells.

Alkaline Phosphatase↗
PubMed1996

Amplification of genomic DNA demonstrates the presence of the t(2;5) (p23;q35) in anaplastic large cell lymphoma, but not in other non-Hodgkin's lymphomas, Hodgkin's disease, or lymphomatoid papulosis.

Anaplastic large cell lymphoma (ALCL) is a distinct clinicopathologic variant of intermediate grade non-Hodgkin's lymphomas (NHL) composed of large pleomorphic cells that usually express the CD30 antigen and interleukin (IL)-2 receptors, and is characterized by frequent cutaneous and extranodal involvement. With variable frequency ALCL bear the t(2;5)(p23;q35) chromosomal translocation that fuses the nucleophosmin (NPM) gene on chromosome 5q35 to a novel protein kinase gene, Anaplastic Lymphoma Kinase (ALK), on chromosome 2p23. We determined the frequency of this translocation with a novel DNA polymerase chain reaction (PCR) technique using 0.5 microgram of genomic DNA, 5'-primers derived from the NPM gene and 3'-primers derived from the ALK gene and hybridization with internal probes. The presence of amplifiable DNA in the samples was tested with the inclusion in the PCR reaction of oligonucleotide primers designed to amplify a 3016-bp fragment from the beta-globin locus. NMP-ALK fusion amplicons were detected using DNA isolated either from all three ALCL cell lines tested, or from all four primary ALCL tumors known to contain the t(2;5)(p23;q35) translocation. Nested amplicons were detected by hybridization in 100% of specimens diluted 10(4)-fold and in 20% of those diluted 10(5)-fold. We subsequently examined archival genomic DNA from 20 patients with ALCL, 39 with diffuse large cell, 2 with mantle cell, 20 with peripheral T cell, 13 with low-grade NHL, 31 with Hodgkin's disease (HD), and 6 with lymphomatoid papulosis. Fusion of the NPM and ALK genes was detected in three of 18 patients with ALCL who had amplifiable DNA (17%, 95% confidence intervals 4% to 41%), but not in any patients with other NHL, HD, or lymphomatoid papulosis. The amplicon sizes were different in all cell lines and patients reflecting unique genomic DNA breakpoints. We conclude that with genomic DNA-PCR the rearrangement of the NPM and ALK loci is restricted to patients with ALCL. Further studies are needed to determine the prognostic significance of the NPM-ALK rearrangement, to determine whether its detection can aid in the differential diagnosis between ALCL. Hodgkin's disease, and lymphomatoid papulosis, and to establish the usefulness of the genomic DNA PCR in the monitoring of minimal residual disease in those patients whose tumors bear the t(2;5).

Adolescent↗
PubMed1997

Type I (RI) and type II (RII) receptors for transforming growth factor-beta isoforms are expressed subsequent to transforming growth factor-beta ligands during excisional wound repair.

Transforming growth factor (TGF)-beta isoforms (TGF-beta 1, -beta 2, and -beta 3) regulate cell growth and differentiation and have critical regulatory roles in the process of tissue repair and remodeling. Signal transduction for TGF-beta function is transmitted by a heteromeric complex of receptors consisting of two serine/threonine kinase transmembrane proteins (RI and RII). We have previously shown that each TGF-beta isoform is widely expressed in a distinct spatial and temporal pattern throughout the processes of excisional and incisional wound repair. As the presence of TGF-beta receptors determines cellular responsiveness, we have currently examined, by immunohistochemistry, the localization of RI (ALK-1, ALK-5) and RII throughout repair of full-thickness excisional wounds up to 21 days after wounding. The expression of RI (ALK-5) and RII co-localized in both the unwounded and wounded skin and was present in the same cell types as TGF-beta ligands. However, immunoreactivity for TGF-beta receptors, throughout repair, occurred 1 to 5 days later than TGF-beta isoform immunostaining. This implies that the presence of TGF-beta ligands may up-regulate TGF-beta receptors for function and/or may reflect a lag due to local processing of latent TGF-beta. As observed for the immunohistochemical localization of TGF-beta isoforms in unwounded skin, RI and RII were expressed throughout the four layers of the epidermis, showing a wavy pattern of slight to moderate immunostaining, and hair follicles, sweat glands, and sebaceous glands were moderately immunoreactive. The extracellular matrix, fibroblasts, and blood vessels in the dermis were not immunoreactive. After injury, as observed for TGF-beta ligands, RI and RII expression was increased in the epidermis adjacent to the wound and the epithelium migrating over the wound was completely devoid of TGF-beta receptor immunoreactivity until re-epithelialization was completed by day 7 after wounding. The dermis was only slightly immunoreactive for RI and RII until day 5 when, immediately under the wound, immunostaining for fibroblasts, connective tissue cells, and newly forming vasculature began to increase and remained intense until day 14. Consistent with the role for TGF-beta in scarring, numerous fibroblasts, ostensibly active in the production of extracellular matrix components, continued to be slightly immunoreactive for RI and RII at 21 days. The ALK-1 (TSR-1) type I receptor, which binds both activin and TGF-beta, showed slight immunostaining early in repair (days 1 to 7) that progressively became more intense later in repair after day 10 and through day 21. This suggests that there may be a switch to a different type I receptor, implying different functions for the ALK-1 and ALK-5 receptors. The concomitant expression of TGF-beta isoforms and their signal-transducing receptors denote potential spatial and temporal activity of TGF-beta. Thus, although TGF-beta ligand is present, TGF-beta would not function in wound repair until a later time when RI and RII appear. This information should aid in the development of receptor antagonists as a therapeutic approach to scarring and fibrosis. In addition, these studies underscore the importance of defining the expression of proteins in vivo to establish a basis for the analysis of mechanisms in vitro.

Animals↗
PubMed1997

The monoclonal antibody ALK1 identifies a distinct morphological subtype of anaplastic large cell lymphoma associated with 2p23/ALK rearrangements.

Anaplastic large cell lymphoma (ALCL) is a heterogeneous group of diseases by morphology, phenotype, genotype, and clinical presentation. Using a new monoclonal antibody (ALK1) that recognizes the native anaplastic lymphoma kinase (ALK) protein as well as the fusion product of the t(2;5)(p23;q35), nucleophosmin (NPM)/ALK, we investigated for ALK expression cases diagnosed as ALCL as well as lympho-proliferative disorders possessing overlapping features with ALCL. Thirteen cases showed cytoplasmic staining of the neoplastic cells. These cases were characterized by a fairly uniform morphology and occurred in children and young adults as a systemic disease. All other cases comprising T or null ALCL (17 cases), B ALCL (8 cases), Hodgkin's disease (HD) (15 cases), HD-like ALCL (23 cases), and lymphomatoid papulosis (9 cases), were negative for ALK expression. Translocation t(2;5)(p23;q35) was found by classical cytogenetics or interphase fluorescence in situ hybridization in 8 of the ALK1-positive cases and by reverse transcription-polymerase chain reaction in 1 other case. Two additional ALK1-positive cases with an abnormal karyotype, but without t(2;5)(p23;q35), showed by fluorescence in situ hybridization analysis a cryptic NPM/ALK gene fusion caused by an insertion of ALK near NPM in one case and a translocation of ALK to 2q35 as a result of an indiscernible inv(2)(p23q35) in the other. The latter variant translocation points to a localization of an unknown gene at 2q35 that, like NPM, might deregulate ALK and be involved in the pathogenesis of ALCL. In summary, immunohistochemistry with ALK1 antibody allows the identification of a distinct subgroup within the ALCL of T or null phenotype that is associated with 2p23 abnormalities and lacks the marked histological pleomorphism described in ALCL in general. Whereas immunostaining is the most sensitive method to identify this group, it does not help to additionally clarify the relationship among ALCL, HD, and HD-like ALCL.

Adolescent↗
PubMed1998

Characterization of t(2;5) reciprocal transcripts and genomic breakpoints in CD30+ cutaneous lymphoproliferations.

NPM-ALK chimeric transcripts, encoded by the t(2;5), lead to an aberrant expression of ALK by CD30+ systemic lymphomas. To determine if t(2;5) is involved in cutaneous lymphoproliferative disorders, we studied 37 CD30+ cutaneous lymphoproliferations, 27 mycosis fungoides (MF), and 16 benign inflammatory disorders (BID). NPM-ALK transcripts were detected by nested reverse transcription-polymerase chain reaction (RT-PCR) in 1 of 11 lymphomatoid papulosis (LyP), 7 of 15 CD30+ primary cutaneous T-cell lymphoma (CTCL), 3 of 11 CD30+ secondary cutaneous lymphoma, 6 of 27 MF, and 1 of 16 BID. However, the expression of NPM-ALK transcripts was not associated with ALK1 immunoreactivity in MF, LyP, or BID cases. Only 1 CD30+ primary CTCL and 3 CD30+ secondary cutaneous lymphoma were ALK1 immunoreactive. The ALK1+ cases were also characterized by amplification of tumor-specific genomic breakpoints on derivative chromosome 5. These cases, except for 1 secondary cutaneous lymphoma, were also characterized by reciprocal breakpoints on derivative chromosome 2, leading to the expression of reciprocal ALK-NPM transcripts. Amplification of chromosomal breakpoints on both derivative chromosomes could represent an alternative to conventional cytogenetics for the diagnosis of t(2;5) and seems to be more reliable than the detection of cryptic NPM-ALK transcripts by nested RT-PCR.

Base Sequence↗
PubMed1998

Hyperopic automated lamellar keratoplasty: complications and visual results.

OBJECTIVE: To examine the long-term safety and efficacy of hyperopic automated lamellar keratoplasty (H-ALK) for correction of primary hyperopia and for consecutive hyperopia following overcorrected myopic refractive surgery. METHODS: A prospective study was done on 67 eyes of 50 consecutive patients who underwent H-ALK between March 17, 1993, and August 18, 1995. Hyperopic automated lamellar keratoplasty was performed for primary hyperopia in 25 eyes (group 1) and for consecutive hyperopia after myopic refractive surgery in 42 eyes (group 2, radial keratotomy, 41 eyes, and myopic automated lamellar keratoplasty, 1 eye). The eyes were followed up for a mean+/-SD of 19.2+/-12.8 months (range, 3-49 months), 58 (87%) of them with 6 months' follow-up, and 45 (67%) of them with at least 1 year's follow-up. Twenty-one eyes were followed up for 2 to 4 years. RESULTS: The overall mean+/-SD preoperative spherical equivalent was +2.87+/-1.28 diopters (D). The mean+/-SD postoperative spherical equivalent was -0.03+/-1.42 D at 3 months, -0.42+/-2.25 D at 6 months, -0.55+/-3.00 D at 1 year, -1.58+/-1.53 D at 2 years, and -0.35+/-1.79 D at the last follow-up. A mean myopic shift of 0.50 D was noted between 3 months and 1 year, and of 1.00 D between 1 and 2 years. Hyperopia was meaningfully reduced and visual acuity was improved by H-ALK, especially for patients with primary hyperopia. Long-term refractive instability, however, is a serious problem with this procedure. In this series, 11 (26%) of 42 eyes in which H-ALK was performed for consecutive hyperopia developed iatrogenic keratoconus. CONCLUSION: Based on this study, the long-term instability of H-ALK and the high incidence of iatrogenic keratoconus following the procedure should discourage its use, especially for consecutive hyperopia following radial keratotomy.

Adult↗
PubMed1994

Differential effects of retinoic acid and growth factors on osteoblastic markers and CD10/NEP activity in stromal-derived osteoblasts.

The effects of retinoic acid (RA) on the expression of osteoblastic-related cell markers was examined. A marrow stromal osteogenic cell line, MBA-15, was analyzed by Northern blotting for the expression of bone matrix proteins. These cells constitutively express mRNA encoding for procollagen alpha 2 (I), osteonectin, osteopontin, biglycan, and alkaline phosphatase (ALK-P). Gene expression was unchanged in response to RA triggering for 24 hr. Furthermore, cell growth and enzymatic activities of ALK-P and neutral endopeptidase (CD10/NEP) were studied. These parameters were examined in MBA-15 and clonal populations representing different stages of differentiation. The cell's growth rate was unchanged, while ALK-P activity was greatly increased during the culture period under RA treatment in MBA-15 and in the clonal cell lines examined while CD10/NEP activity displayed a different pattern. MBA-15.4, a preosteoblast cell line, exhibited an inhibition in CD10/NEP activity at the beginning of the culture period, reaching basal level with time. This activity was greatly increased over control level in MBA-15.6, a mature stage of osteoblasts. Furthermore, the response of cell lines to various growth factors was tested subsequent to priming the cultures with RA. A synergistic effect was monitored for ALK-P activity in MBA-15.4 and MBA-15.6 cells under rh-bone morphogenic protein (BMP-2) and purified osteogenin (BMP-3), and an antagonist effect was measured when cells were exposed to transforming growth factor beta (TGF beta). Contrarily, BMP-2 and BMP-3 inhibited the CD10/NEP activity that had remained unchanged following priming of the cell with RA. Insulin-like growth factor I (IGF-I) and basic fibroblast growth factors (bFGF) did not affect either ALK-P nor CD10/NEP activities in both cloned cells. Cellular response to bone-seeking hormone, parathyroid hormone (PTH), and prostaglandin E2 (PGE2) was monitored by activation of intracellular cAMP. Treatment with RA caused a dramatic decrease in MBA-15.6 cell responses to PTH and PGE2, but no significant effects could be observed in other clonal lines.

1-Methyl-3-isobutylxanthine↗
PubMed2003

BCL-2 family proteins in peripheral T-cell lymphomas: correlation with tumour apoptosis and proliferation.

The present study investigated expression levels of the anti-apoptotic proteins BCL-2, BCL-XL and MCL-1 and the pro-apoptotic proteins BAX and BCL-XS in a series of 112 peripheral T-cell lymphomas (PTCLs) classified according to the WHO classification. Using immunohistochemical methods and a 10% cut-off, each protein was detected in a subset of PTCLs: BCL-2 in 46%, BCL-XS in 49%, BAX in 57%, BCL-XL in 57%, and MCL-1 in 65%. The mean percentage of positive cells for these proteins varied significantly among the PTCL types. Only two types of PTCL, ALK-positive anaplastic large cell lymphoma (ALCL) and enteropathy-type T-cell lymphoma, had a distinctive pattern of expression; all were BCL-2-negative and MCL-1-positive. The mean percentage of BAX-positive and BCL-XS-positive tumour cells was higher in ALK-positive ALCL than in ALK-negative ALCL or other types of PTCL (p = 0.06 and p = 0.01, respectively, Kruskal-Wallis test). MCL-1 was detected significantly more frequently (p = 0.01, chi-square test) and at higher levels (p = 0.0001, Kruskal-Wallis test) in ALK-positive ALCL and ALK-negative ALCL than in other PTCL types. The apoptotic rate, evaluated by the TUNEL assay, correlated inversely with BCL-2 expression (p = 0.035). The proliferation index, assessed by the MIB-1 antibody, correlated with expression levels of MCL-1 (R = 0.42, p = 0.003), BCL-2 (R = 0.32, p = 0.027), BAX (R = 0.33, p = 0.014), and BCL-XL (R = 0.34, p = 0.015) (Spearman rank). In conclusion, BCL-2 family proteins are expressed by a subset of PTCLs and their levels correlate with some histological types, apoptotic rate, and proliferation index. Expression of these proteins may explain the poor response of many types of PTCL to standard chemotherapy. These proteins may also provide novel targets for experimental therapy.

Anaplastic Lymphoma Kinase↗
PubMed1983

1-O-alkyl-linked phosphoglycerides of human platelets: distribution of arachidonate and other acyl residues in the ether-linked and diacyl species.

In this study, the 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine content of human platelets was determined. The distribution of arachidonate among the 1,2-diacyl, 1-O-alkyl-2-acyl, and 1-O-alk-l'-enyl-2-acyl classes of choline- and ethanolamine-containing phosphoglycerides was also assessed. The major platelet phospholipids were choline-containing phosphoglycerides (38%), ethanolamine-containing phosphoglycerides (25%) and sphingomyelin (18%), with smaller amounts of phosphatidylserine (11%) and phosphatidylinositol (4%). In addition to the diacyl class, the choline-linked fraction was found to contain both 1-O-alkyl-2-acyl (10%) and 1-O-alk-l'-enyl-2-acyl (9%) species. The ethanolamine-linked fraction, on the other hand, had an elevated level of the 1-O-alk-1'-enyl-2-acyl (60%) species and a small amount of the 1-O-alkyl-2-acyl component (4%). The major fatty acyl residues found in all classes of the choline and ethanolamine phospholipids were 16:0, 18:0, 18:1 (delta 9), 18:2(n-6) and 20:4(n-6). The 1-O-alkyl and 1-O-alk-1'-enyl fraction of the ethanolamine-linked phospholipids also contained substantial amounts of 22:5(n-3) and 22:6(n-3) acyl chains. Arachidonate comprised 44% of the acyl residues in the sn-2 position of 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine. Corresponding values for the diacyl and 1-O-alk-1'-enyl-2-acyl species were 23% and 25%, respectively, based on all 20:4(n-6) being linked to the sn-2 position of all classes.(ABSTRACT TRUNCATED AT 250 WORDS)

Arachidonic Acid↗
PubMed1985

In vitro generation of human activated lymphocyte killer cells. II. N-acetyl-D-galactosamine inhibits a distinct subpopulation of human activated lymphocyte killer cells generated in mixed lymphocyte culture.

A range of monosaccharides was tested for its ability to inhibit the generation of cytotoxic cells during mixed lymphocyte culture. The most discriminatory effect was produced by N-acetyl-D-galactosamine (NADG). The presence of this sugar at the initiation of the coculture significantly inhibited in a dose-dependent manner the induction of a subset of nonspecific activated lymphocyte (ALK) cells preferentially able to lyse the K562 target cell (natural killer, NK-like cells) but had no effect on the generation of either specific cytotoxic T lymphocytes or another separate subset of ALK cells mediating lysis of an NK-insensitive melanoma cell line. The addition of conditioned medium containing interleukin 2 and interferon (IFN) at the start of culture reversed the inhibitory effect of the sugar. Under conditions of limiting dilution, the frequency of NK-like precursors ranged from 1/50 to 1/1200 with different mononuclear cells (MNC) and in all cases the presence of NADG from Day 0 of culture selectively decreased the frequency of these precursors. At the concentrations used NADG had no effect on NK-like cell cytolysis once generated. The addition of recombinant gamma-IFN did not abrogate the inhibitory effect of NADG and in MLC of some individuals decreased the frequencies of ALK cell precursors. These data provide further evidence for the heterogeneity of ALK cells and indicate that what is usually referred to as NK-like cell activity in in vitro culture is mediated by a subpopulation of MNC which are activated and induced to differentiate along a pathway independent of that of other ALK subsets.

Acetylglucosamine↗
PubMed1989

Alkaline phosphatase activity in striated muscle: the effect of aging and long-term training in female mice.

Alkaline pNPPase (Alk'ase) activity was measured in bicarbonate buffer and in Triton buffer of striated muscles of aging mice. Between young age (4-9 months) and middle age (13-15 months) the enzyme specific activity increased by 41.8% in the bicarbonate buffer and by 22.6% in the Triton extraction. Thereafter, between middle age and old age (32 months), a marked decrease in enzyme activity took place in both the bicarbonate and Triton extractions (23.5% and 31.4%, respectively). Alk'ase activity in muscles of old mice that had been exposed for prolonged training (12-18 months), did not differ from that of age-matched controls in both types of extracts. However, cysteine, an Alk'ase inhibitor, affected the enzymatic activity in the various samples tested differently: in the bicarbonate buffer its inhibitory effect increased with age and training, whereas in the Triton extraction its effect decreased with age and following training. Thus, it seems conceivable that with age and following long-term physical exercise an overall functional change is taking place in muscle which makes Alk'ase more vulnerable. The membranous Alk'ase, however, appears more resistant to external inhibitors in the form of endurance training and to the aging process.

Age Factors↗
PubMed2006

Effects of bile diversion in rats on intestinal sphingomyelinases and ceramidase.

Alkaline sphingomyelinase (Alk-SMase) and neutral ceramidase (N-CDase) in the intestinal microvillar membrane are responsible for dietary sphingomyelin digestion. The activities of the enzymes require the presence of bile salt, and the enzymes can be released into the gut lumen in active forms by bile salts and trypsin. It is unclear to what extent that the intestinal presence of bile salts is critical for the intraluminal activity of these enzymes. We compared the activities of Alk-SMase, N-CDase, and other types of SMases in control and permanently bile diverted rats. In the intestinal tract of control rats, the activity of Alk-SMase was profoundly higher than those of acid and neutral SMases. Bile diversion reduced Alk-SMase activity by 85% in the small intestinal content, and by 68% in the faeces, but did not significantly change the activity in the intestinal mucosa. Western blot showed a marked reduction of the enzyme in the intestinal lumen but not mucosa. N-CDase activities both in the intestinal mucosa and content were reduced by bile diversion. Bile diversion also decreased aminopeptidase N activity in the content and increased that in the mucosa, but had no effects on that of alkaline phosphatase. In conclusion, the presence of bile salts is important for maintaining high intraluminal levels of Alk-SMase and N-CDase, two key enzymes for hydrolysis of sphingomyelin in the gut. We speculate that the sphingomyelin hydrolysis in cholestatic conditions is impaired not only by reduced hydrolytic activity but also by deficient dissociation of the enzymes from the membrane.

Amidohydrolases↗
PubMed2005

Inflammatory myofibroblastic tumor in children: clinical review with anaplastic lymphoma kinase, Epstein-Barr virus, and human herpesvirus 8 detection analysis.

BACKGROUND/PURPOSE: Inflammatory myofibroblastic tumor (IMT) is considered as an intermediate neoplasm that may present malignant features. Differential diagnosis with other tumor processes is sometimes difficult. Similar anaplastic lymphoma kinase (ALK) gene abnormalities as in anaplastic large cell lymphoma have been reported. Human herpesvirus 8 (HHV-8) DNA sequences have been described in adult pulmonary IMTs and Epstein-Barr virus (EBV) has been reported in splenic and hepatic IMTs, suggesting the importance of both viruses in IMT development. This article aims to evaluate ALK, EBV, and HHV-8 expression in children with IMT and to correlate our findings with clinical features. METHODS: Sixteen children (range, 1-15 years) who had surgery for IMT between 1978 and 2003 were evaluated retrospectively. Formalin-fixed, paraffin-embedded archival tissues were stained for HHV-8 and ALK with immunohistochemistry. Epstein-Barr virus was detected by in situ hybridization (EBER probes). RESULTS: Tumors were located in the pulmonary lobe (n = 4), urinary tract (n = 4), mesentery or bowel (n = 4), hepatic lobe (n = 1), vena cava (n = 1), spinal cord (n = 1), and soft tissue (n = 1). Five children were treated with steroids and/or antibiotics before surgery, with no substantial result. IMT was excised totally in all but 2 cases. Four patients presented aggressive IMT with recurrence or metastasis requiring new surgery. ALK was positive in 3 (18.8%) cases and EBV in 1 pulmonary and 1 bladder tumor, all of them without recurrence or metastasis. None of the cases were positive for HHV-8. All patients are now disease-free with a mean follow-up of 4.2 years. CONCLUSIONS: Considering the present lack of efficient medical treatment, surgery should still be considered as the mainstay therapy in IMT, even in cases of recurrence or metastases. Larger multicentric studies would be necessary to understand the prognostic significance of ALK, EBV, and HHV-8 and their relationships with the origins of the tumor.

Adolescent↗
PubMed2005

Sleep disturbances before and after parathyroidectomy for secondary hyperparathyroidism.

BACKGROUND: The prevalence of insomnia in patients with symptomatic secondary hyperparathyroidism and the improvements of sleep disturbances after parathyroidectomy have not been previously reported. METHODS: Thirty-one patients who had undergone successful total parathyroidectomy and autotransplantation for symptomatic secondary hyperparathyroidism were enrolled in the study. The symptoms of skin itching, bone pain, and general weakness were recorded. Preoperatively, serum levels of calcium, phosphorus, alkaline phosphatase (Alk-ptase), intact parathyroid hormone (iPTH), am melatonin (noon), and pm melatonin (midnight) were measured in association with a simple yes/no questionnaire of 5 items about sleep disturbances as described previously. The severity of insomnia was the sum of positive items of sleeping disturbances. The sleep hours per night and the habit of taking sleeping pills were also recorded. One week after surgery, serum levels of calcium, phosphorus, Alk-ptase, iPTH, am melatonin, and pm melatonin were measured again. Three months after surgery, symptoms of skin itching, bone pain, and general weakness were recorded, and serum levels of calcium, phosphorus, Alk-ptase and iPTH were measured in association with a yes/no questionnaire of sleep disturbances. The severity of insomnia, sleep hours per night, and the habit of taking sleeping pills were recorded again. RESULTS: One week after parathyroidectomy, serum levels of calcium, phosphorus, and iPTH decreased significantly; serum levels of Alk-ptase and am melatonin increased significantly; serum levels of pm melatonin did not change significantly. Three months after parathyroidectomy, symptoms of skin itching, bone pain, and general weakness decreased significantly; serum levels of calcium, phosphorus, Alk-ptase, and iPTH decreased significantly; sleeping disturbances and severity of insomnia improved significantly in association with longer sleep hours per night. A significant reduction of the habit of taking sleeping pills was also noted. Preoperatively, the severity of insomnia was correlated with skin itching, general weakness, and levels of iPTH. Postoperatively, the severity of insomnia was correlated with skin itching, general weakness, and bone pain. CONCLUSIONS: Preoperatively, a high prevalence of sleep disturbances (97%) was found in patients with symptomatic secondary hyperparathyroidism. We conclude that nocturnal melatonin levels do not change after parathyroidectomy; the improvements in sleep disturbance and the decreases in severity of insomnia are found 3 months after surgery in association with longer sleep hours per night. Decreases of symptoms such as skin itching, bone pain, and general weakness may be the reasons for the improvement in sleep and the decrease in insomnia.

Adult↗
PubMed2004

Genomic profiling of peripheral T-cell lymphoma, unspecified, and anaplastic large T-cell lymphoma delineates novel recurrent chromosomal alterations.

To characterize genetic alterations in peripheral T-cell lymphoma, not otherwise specified (PTCL NOS), and anaplastic large T-cell lymphoma (ALCL), 42 PTCL NOS and 37 ALCL [17 anaplastic large cell kinase (ALK)-negative ALCL, 9 ALK-positive ALCL, 11 cutaneous ALCL] were analyzed by comparative genomic hybridization. Among 36 de novo PTCL NOS, recurrent chromosomal losses were found on chromosomes 13q (minimally overlapping region 13q21, 36% of cases), 6q and 9p (6q21 and 9p21-pter, in 31% of cases each), 10q and 12q (10q23-24 and 12q21-q22, in 28% of cases each), and 5q (5q21, 25% of cases). Recurrent gains were found on chromosome 7q22-qter (31% of cases). In 11 PTCL NOS, high-level amplifications were observed, among them 3 cases with amplification of 12p13 that was restricted to cytotoxic PTCL NOS. Whereas cutaneous ALCL and ALK-positive ALCL showed few recurrent chromosomal imbalances, ALK-negative ALCL displayed recurrent chromosomal gains of 1q (1q41-qter, 46%), and losses of 6q (6q21, 31%) and 13q (13q21-q22, 23%). Losses of chromosomes 5q, 10q, and 12q characterized a group of noncytotoxic nodal CD5+ peripheral T-cell lymphomas. The genetics of PTCL NOS and ALK-negative ALCL differ from other T-NHLs characterized genetically so far, among them enteropathy-type T-cell lymphoma, T-cell prolymphocytic leukemia, and adult T-cell lymphoma/leukemia.

Adolescent↗
PubMed2004

Retinoblastoma protein is frequently absent or phosphorylated in anaplastic large-cell lymphoma.

The possible role of retinoblastoma protein (Rb) in the pathogenesis of anaplastic large-cell lymphoma (ALCL) is unknown. We investigated Rb protein expression, both total (phosphorylated and underphosphorylated) and active (underphosphorylated), in four anaplastic lymphoma kinase (ALK)-positive ALCL cell lines (Karpas 299, JB-6, SU-DHL1, and SR-786) by Western blot analysis, and in 67 ALCL tumors (30 ALK-positive, 37 ALK-negative) using immunohistochemical methods. We also used fluorescence in situ hybridization and polymerase chain reaction methods to assess for loss of heterozygosity of the rb gene. The findings were correlated with apoptotic rate assessed by the terminal dUTP nick-end labeling assay. Immunoblots showed high total Rb levels in Karpas 299, SU-DHL1 and SR-786 and relatively lower levels in and JB-6. Underphosphorylated Rb was negative or expressed at low levels in all cell lines. In ALCL tumors, total Rb was detected in 44 (66%) and absent in 23 (34%). The mean apoptotic rate was 3.2% in Rb-negative tumors compared with 2.7%, 2.2%, and 1.2% in tumors with <10%, 10 to 50%, and >50% Rb-positive cells, respectively (P = 0.2, Kruskall-Wallis test). In a subset of 25 total Rb-positive tumors we assessed for underphosphorylated Rb, which was detected in 12 tumors. The detection of only total Rb in the remaining 13 tumors suggests that Rb was phosphorylated. Fluorescence in situ hybridization showed allelic loss of the rb gene in 10 (40%) of 25 tumors analyzed and was significantly associated with absence of Rb expression (P = 0.003). Similar results were obtained for loss of heterozygosity of the 13q14 locus. Five-year progression-free survival for patients with Rb-negative ALCL was 89.4% compared with 47.7% for patients with total Rb-positive ALCL (P = 0.006, log-rank test). Similar trends for progression-free survival held true for patients with ALK-positive and ALK-negative tumors analyzed separately. In conclusion, Rb is absent or phosphorylated in most ALCL cell lines and tumors and absence of Rb expression is associated with better clinical outcome in patients with ALCL.

Aged↗
PubMed2002

Phosphorylation regulation of the interaction between Smad7 and activin type I receptor.

Signal transduction of activin, one of the members in the transforming growth factor-beta superfamily, is initiated by ligand binding with two distinct membrane receptors (type II and type I) followed by activation of Smad2 or Smad3. We report here that activin-induced signaling is negatively regulated by another Smad molecule, Smad7. When expressed in Chinese hamster ovary cells, Smad7 inhibited the transcriptional response induced by either activin treatment or a constitutively active activin type I receptor (ALK-4). In addition, Smad7 also inhibited mouse FAST-2-mediated transactivation of the Xenopus Mix.2 promoter stimulated by the constitutively active ALK-4. Smad7 was able to directly associate with ALK-4 and this association was dependent on the phosphorylation of the type I receptor in its GS domain by activin type II receptors. Expression of kinase defective activin type II receptors decreased the association of Smad7 with ALK-4. Correspondingly, Smad7 bound poorly to a mutant ALK-4 bearing serine to alanine substitutions in four putative phosphorylation sites in its GS domain. These studies not only illustrated the counter regulatory function of Smad7 on activin signaling, but also indicated the involvement of phosphorylation at activin type I receptor in the inhibitory action of Smad7.

Activin Receptors, Type I↗