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This study addresses the different types and implications of linguistic indeterminacy in Chinese law. It firstly draws on the studies of scholars of different disciplines, such as linguistics and philosophy of language, to provide a taxonomy of indeterminacy in language. It then provides examples of each type, highlighting the implications in law and legal interpretation. It uses linguistic data from various texts, such as statutory laws and judgements, and analyses them with various methods, including discourse analysis and corpus linguistics. This study argues that when the language of the law is indeterminate, the legal outcomes may be particularly uncertain. It suggests that although it is difficult to ascertain whether the degree of indeterminacy is higher in some languages more than in others, some linguistic mechanisms at the word-formation level in Chinese, such as portmanteaus and the modifier-modified structure, are remarkably ambiguous. When uncertain terms are in key parts of the law, the consequences may be more serious. The study of linguistic indeterminacy in Chinese has implications for the study of forensic linguistics, and Chinese studies in general.

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Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650–85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.

In this study we determined whether human stromal cells could be engineered with a retroviral vector carrying the interleukin 7 (IL-7) gene and investigated the effects on T cells in vitro and in vivo in a murine model. Transduced mesenchymal cells strongly express CD90 (98.15%), CD105 (87.6%), and STRO-1 (86.7%). IL-7 production was 16.37 (±2 SD) pg/ml, which remained stable for 60 days. In vitro-immunoselected naive T cells maintained the CD45RA+CD45RO− naive phenotype (4.2 times more than controls) after 7 days of culture with IL-7-engineered stromal cells. The apoptosis rate (4.7%) of the naive T cells cultured with transduced stromal cells overlapped with that of freshly isolated cells. Immunohistological analysis detected stromal cells in bone marrow, spleen, and thymus. Cotransplantation of IL-7-engineered stromal cells with CD34+ cells improved engraftment in terms of CD45+ cells and significantly increased the CD3+ cell count in peripheral blood, bone marrow, and spleen. These data demonstrate the following: (1) human stromal cells can be transduced, generating a normal layer; (2) transduced stromal cells in vitro maintain the naive T cell phenotype; and (3) IL-7-transduced stromal cells in vivo home to lymphoid organs and produce sufficient IL-7 in loco, supporting T cell development in a cotransplantation model. Because of their efficient cytokine production and homing, IL-7-engineered stromal cells might be an ideal vehicle to hasten immunological reconstitution in T cell-depleted hosts.

In 2004, Georges Méliès's granddaughter Madeleine Malthête-Méliès ceded the totality of her archival and object collection to the Centre National de la Cinématographie (CNC), which acquired it for the state via the acquisitions commission: the Patrimony Division of the CNC and the Patrimony Collection of the Ministry of Culture. This dossier provides a historical overview and the description of this collection. [ABSTRACT FROM AUTHOR]

Genetic modification of primary tumor cells by gene transfer is of major interest to study the role of specific genes in the biology of a given malignancy and to modify tumor cells for therapeutic use. Multiple myeloma (MM) is a low-proliferating cancer, with often less than 1% of the cells in the S phase of the cell cycle. As primary myeloma cells are notoriously difficult to transduce, we conducted a comparison of various viral vectors, known to integrate the transgene of interest into the target genome, for their ability to stably promote the expression of an enhanced green fluorescent protein (EGFP) transgene. We compared three murine leukemia virus-based vectors, differing only in their viral envelope, a human immunodeficiency virus (HIV)-based vector pseudotyped with the vesicular stomatitis virus glycoprotein (VSV-G), and an adeno-associated virus type 2 vector. Transduction characteristics of these vectors were evaluated in human myeloma cell lines and in primary myeloma cells. Unequivocally, we observed that the VSV-G/HIV vector was the most efficient vector for transducing the cell lines and the only one able to transduce primary myeloma cells reproducibly. The mean percentage of transduced primary myeloma cells was 43.6% (range, 16.3-77.6%), with one round of infection at a low multiplicity of infection, including MM cell samples with less than 1% of cells in the S phase. A quantitative polymerase chain reaction assay demonstrated that this more efficient EGFP expression was associated with a higher GFP copy number in the targeted cell. We propose that lentiviral vectors should be used for transduction of nonproliferating primary tumor cells such as myeloma cells.

Objective. To validate a translated version of the revised and expanded Arthritis Impact Measurement Scales (AIMS2) to be used by Italian patients with osteoarthritis (OA) of the knee.
Methods. The AIMS2 was translated into Italian and administered to a cohort of 178 outpatients with symptomatic OA of the knee who attended 12 participating rheumatological institutes in northern, central and southern Italy. A random sample of 71 patients were readministered the AIMS2, 7 days after the first visit, to evaluate the instrument's test-retest reliability. After 6 months, the subjects were asked to return to the institutes for a second administration of the questionnaire.
Results. The internal consistency reliability of each scale score, as estimated by Cronbach's alpha coefficient, was high and indicated that the components of the scale measured the same construct. The items all correlated with each other, but there was no redundancy; this indicates that each domain addressed a somewhat different aspect of functional disability. The test-retest reliability equalled or exceeded 0.80 for eight of the 12 scales. Factor analysis provided a three-factor health status model explaining 63.5% of the variance. Arthritis pain and psychological scale were loaded on the first factor, together with physical scales for mobility level and walking and bending. The upper limb function scales formed the second factor. The third factor was determined by the social dimension. These results demonstrate that the physical health status scales of the AIMS2 are valid, as shown by the significant, moderate to high correlations between the AIMS2 subscales and the majority of the clinical measures.
Conclusion. Our data suggest that, like the original questionnaire, the translated version of AIMS2 is a reliable, consistent and valid instrument for measuring health status and physical functioning in patients with OA of the knee.

V pre-B and λ-like genes are selectively expressed in human pre-B cells and encode polypeptide chains that associate in a μ-pseudolight chain complex that may regulate some crucial steps of early B-cell differentiation. We have followed by polymerase chain reaction and Northern blot analysis the expression of these “pre-B-specific” genes in correlation with the status (rearranged v germline) of Ig gene loci (H, κ, λ) in a panel of 32 leukemias pertaining mostly to the B lineage and including a number of ambiguously characterized samples. All cells that had rearranged the H locus only expressed V pre-B and λ-like transcripts, in agreement with a pre-B status. In this group, some biphenotypic leukemias (mostly My/B) might, in fact, be already engaged in the B lineage. Rearrangement of Vκ or Vλ loci correlated with the disappearance of the pre-B gene products. In a pre-B acute lymphoblastic leukemia cell line that was induced to mature to the B-cell stage in culture upon κ gene rearrangement, the μ-pseudolight chain complex was actually replaced by the classical μ-Κ molecule. Finally, V pre-B and λ-like genes were found expressed in two leukemic cells that had retained all Ig loci in germline configuration. This finding raises the possibility of having an early pro-B progenitor in which V pre-B and λ-like products associate with a H chain surrogate in a complex that would trigger an early event of B-cell differentiation such as the H locus rearrangements. © 1991 by The American Society of Hematology.

The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the growth of multiple myeloma (MM) was investigated in 21 patients with MM. In 17 patients with proliferating myeloma cells in vivo, recombinant GM-CSF significantly increased the endogenous-IL-6-mediated spontaneous myeloma cell proliferation occurring in 5-day cultures of tumor cells in vitro (P less than .01). Furthermore, GM-CSF was detected in 5-day culture supernatants of myeloma bone marrow cells. This endogenous GM-CSF was produced by the myeloma bone marrow microenvironment but not by myeloma cells and contributed to the spontaneous myeloma-cell proliferation observed in 5-day cultures. In fact, this proliferation was partially blocked (67%) by anti-GM-CSF monoclonal antibodies. The stimulatory effect of rGM-CSF was mediated through IL-6 because it was abrogated by anti-IL-6 monoclonal antibodies. rGM-CSF did not reproducibly increase the endogenous IL-6 production in short-term cultures of bone marrow cells of MM patients. Using an IL-6-dependent myeloma cell line (XG-1 cell line), rGM-CSF was shown to act directly on myeloma cells stimulating by twofold their IL- 6 responsiveness. rGM-CSF did not induce any IL-6 production in XG-1 cells, nor was it able to sustain their growth alone. Although no detectable GM-CSF levels were found in the peripheral or bone marrow blood of MM patients, it is possible that GM-CSF, produced locally by the tumoral environment, enhances the IL-6 responsiveness of myeloma cells in vivo in a way similar to that reported here in vitro.

Induction of proliferation and differentiation in response to the addition of recombinant human granulocyte colony-stimulating factor (G- CSF) was studied by both suspension and semisolid cultures in a series of acute myeloid leukemias (AML). Induction of proliferation by G-CSF alone was observed in six of 27 cases of AML. All acute promyelocytic leukemias with the specific chromosomal translocation t(15;17) and one case of myelomonocytic leukemia with balanced chromosomal translocation involving chromosome 17 at band q12q21 were induced to proliferate strongly by the G-CSF. However, contrary to the long-term proliferative effect observed with granulocyte/macrophage colony-stimulating factor (GM-CSF), G-CSF activity can be characterized by its capability to initiate and promote the growth of responding AML cells but not to sustain long-term proliferation. Finally, no terminal differentiation was found, as assessed by morphology, cytochemistry, and cell surface marker analysis. These results indicate that G-CSF may be sufficient to provide a specific signal for induction of a transient proliferation in AML without induction of terminal differentiation. The cells with the highest response are clonal leukemia cells, all bearing a translocation involving the chromosome region 17q12q21 in which the G-CSF gene has been recently located.

Interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) are two biochemically distinct, but distantly related, polypeptidic cytokines that play a key role in inflammation, immunologic reactions, and tissue repair. Recently, it has been shown that IL-1 alpha is identical to hematopoietin 1, which was described as a hematopoietic growth factor acting on early progenitor cells in synergy with other hematopoietic growth factors. In this report we discuss our use of in situ hybridization on human prometaphase cells with a human IL-1 alpha cDNA probe to localize the human IL-1 alpha gene on the proximal part of the long arm of chromosome 2 at band q13, in the same chromosomal region as the IL-1 beta gene.

Previous studies have shown that tumor necrosis factors (TNFs) inhibit the proliferative effects of crude or purified colony-stimulating factors (CSFs) on low density human bone marrow cell fractions. In the present study we investigated the effects of TNF alpha on the growth of highly purified CD34+ human hematopoietic progenitor cells (HPC) in response to recombinant CSFs. In short-term liquid cultures (5 to 8 days), TNF alpha strongly potentiates interleukin-3 (IL-3) and granulocyte-macrophage-CSF (GM-CSF)-induced growth of CD34+ HPC, while it has no proliferative effect per se. Within 8 days, the number of viable cells obtained in TNF alpha-supplemented cultures is threefold higher than in cultures carried out with IL-3 or GM-CSF alone. Secondary liquid cultures showed that the potentiating effect of TNF alpha on IL-3-induced proliferation of CD34+ HPC does not result from an IL-3-dependent generation of TNF alpha responsive cells. Limiting dilution analysis indicates that TNF alpha increases both the frequency of IL-3 responding cells and the average size of the IL-3-dependent clones. The potentiating effect of TNF alpha on IL-3- and GM-CSF- dependent growth of CD34+ HPC is also observed in day 7 colony assays. Under these short-term culture conditions, TNF alpha does not appear to accelerate cell maturation as a precursor morphology is retained. Finally, TNF alpha inhibits the relatively weak growth-promoting effect of granulocyte-CSF (G-CSF), which acts on a more committed subpopulation of CD34+ HPC different from that recruited by IL-3 and GM- CSF. TNF beta displays the same modulatory effects as TNF alpha. Thus, TNFs appear to enhance the early stages of myelopoiesis.

Induction of proliferation and differentiation in response to recombinant human interleukin-3 (hIL-3) was studied in liquid and semisolid cultures of umbilical cord blood and bone marrow cells that were fractionated by “panning” with anti-My10 antibody according to expression of CD34 antigen. Cells from enriched fractions (70% to 90% CD34+) were found to proliferate strongly in response to hIL-3. Phenotypic analysis and morphologic characterization of the proliferating cells demonstrated a rapid decrease in CD34+ cells and an exponential increase in the number of cells belonging to the neutrophilic, eosinophilic, monocyte/macrophage, and thrombocytic lineages. When combined with recombinant human erythropoietin, burst colonies and cells expressing glycophorin-A were detected, thereby demonstrating the effects of hIL-3 on erythroid progenitors. Further, the development of mixed-erythroid colonies indicated that multipotential cells within CD34-enriched fractions responded to hIL-3. In addition, we examined the effect of hIL-3 on the proliferation of primary acute myeloblastic leukemia cells in liquid culture. We found that hIL-3 was able to induce cell proliferation in a proportion of the cases tested. Heterogeneity of the responses to hIL-3 was in part related to French-American-British classification but could not be correlated with CD34 antigen expression by the leukemic cells. These results indicate that, although the effects of hIL-3 on proliferation and differentiation of cells obtained from normal hematopoietic specimens were primarily borne by CD34+ cells, expression of the CD34 molecule per se is an insufficient condition to determine a growth response to this lymphokine.

FLT3, a receptor belonging to the FMS/KIT family and localized to 13q12, could play a role in the biology of early hematopoietic progenitor cells. Because FMS and KIT are expressed in both normal progenitors and myeloid leukemias, we looked for FLT3 expression in fresh human leukemic cells using Northern blot analysis. High levels of FLT3 expression were detected in 92% of the cases of acute myeloid leukemia (AML) tested, ranging from the M1 to the M5 stages of differentiation assessed in the French-American-British classification. Immature (MO) AML cells, biphenotypic leukemias, and AML with megakaryocytic differentiation (M7 subtype) also expressed the FLT3 transcript. FLT3 was also expressed at high levels in acute lymphoid leukemias of T and B origins. Finally, it was not expressed in chronic myeloid leukemias in chronic phase, whereas it was expressed in most blast crisis samples. This pattern of expression of FLT3 contrasts with the expression of FMS and KIT restricted to myeloid leukemias, and suggests that the FLT3 product could play a role in the expansion of the leukemic blasts of both the myeloid and lymphoid lineages.

We have previously shown that tumor necrosis factor-a (TNFa) strongly potentiates interleukin-3 (IL-3)-induced short-term proliferation of human CD34+hematopoietic progenitor cells (HPC). Using longer term cultures of CD34+HPC, we demonstrate here that this initial potentiation ceases after 10 to 12 days; whereupon TNFα displays inhibitory effects. Thus, TNFα was found to inhibit cells of granulocytic affiliation while it potentiates the development of maturing cells of the monocytic lineage both in liquid and semi-solid (day 14 colony-forming unit) cultures. TNFα was demonstrated to reversibly block granulocytic differentiation at the level of uncommitted CD13-, CD15-blast cells that accumulate in IL-3 + TNFα cultures. Furthermore, growth of committed granulocytes (CD15+) from IL-3 cultures was also inhibited by TNFa through an arrest of cell cycle in G0/G1. Finally, the use of neutralizing anti-TNFα monoclonal antibody and limiting dilution studies indicate that the inhibitory effects of TNFα are direct. Taken together, our data demonstrate that, following a phase of potentiation of proliferation of early HPC, TNFa displays direct inhibitory effects due to negative interference with both granulocytic differentiation and proliferation of granulocytic cells.

Previous studies have shown that tumor necrosis factors (TNFs) inhibit the proliferative effects of crude or purified colony-stimulating factors (CSFs) on low density human bone marrow cell fractions. In the present study we investigated the effects of TNFα on the growth of highly purified CD34 human hematopoietic progenitor cells (HPC) in response to recombinant CSFs. In short-term liquid cultures (5 to 8 days), TNFα strongly potentiates interleukin-3 (IL-3) and granulocyte-macrophage-CSF (GM-CSF)-induced growth of CD34+HPC, while it has no proliferative effect per se. Within 8 days, the number of viable cells obtained in TNFα-supplemented cultures is threefold higher than in cultures carried out with IL-3 or GM-CSF alone. Secondary liquid cultures showed that the potentiating effect of TNFα on IL-3-induced proliferation of CD34+HPC does not result from an IL-3-dependent generation of TNFα responsive cells. Limiting dilution analysis indicates that TNFα increases both the frequency of IL-3 responding cells and the average size of the IL-3-dependent clones. The potentiating effect of TNFα on IL-3- and GM-CSF-dependent growth of CD34+HPC is also observed in day 7 colony assays. Under these short-term culture conditions, TNFα does not appear to accelerate cell maturation as a precursor morphology is retained. Finally, TNFα inhibits the relatively weak growth-promoting effect of granulocyte-CSF (G-CSF), which acts on a more committed subpopulation of CD34+HPC different from that recruited by IL-3 and GM-CSF. TNFβ displays the same modulatory effects as TNFα. Thus, TNFs appear to enhance the early stages of myelopoiesis.

The expression of class II MHC and CD34 antigens on human cord blood hematopoietic progenitor cells (HPC) was investigated upon culturing in the presence of inter-leukin-3 (IL-3). HPC isolated by “panning” according to their expression of CD34 coexpressed HLA-DR and HLA-DP, and the majority of the CD34+HPC also expressed HLA-DQ. In the presence of IL-3, the expression of CD34 and class II MHC antigens was found to be gradually lost in culture. Loss of CD34 expression preceded loss of HLA-DR expression. After eight days of culture, CD34−, HLA-DR+blast cells were obtained that strongly proliferated in response to IL-3, GM-CSF, G-CSF, and M-CSF, and that had the capacity to generate macrophage and granulocyte colonies. After ten days of culture in IL-3, a population of CD34−cells that expressed low levels of HLA-DR (HLA-DR10) was obtained by FACS-sorting. These CD34−, HLA-DR10cells lacked colony-forming activity while the population expressing high levels of HLA-DR (HLA-DRhi) contained great numbers of colony-forming cells, and proliferated stronger in response to CSFs than the HLA-DR10fraction. Finally CD34−, HLA-DR−cells that appeared later in the cultures (14 to 16 days) represented more differentiated cells with only marginal proliferative and no clonogenic capacity. These data indicate that whereas CD34 expression is associated with the multilineage potential of the HPC, HLA-DR expression correlates with overall proliferative capacity of hematopoietic cells during culture in IL-3.

lnterleukin-2 (IL-2) is able to induce the regression of metastatic cancers when administered in vivo. IL-2-activated natural killer cells and lymphocytes show, in vitro, activities against leukemic cells. To assess if in vitro observations could have significant clinical relevance, we evaluated the in vivo activity of high-dose recombinant IL-2 (6 to 8 x 106IU/m2/8Hintravenous bolus for 5 days) in 10 patients with acute myeloid leukemias (AML) in relapse after chemotherapy (n = 7) or autologous bone marrow transplantation (n = 3). Two patients achieved a complete remission and one had a minimal improvement in his marrow blast cells. Response was observed after one cycle of IL-2 in the two patients achieving a complete remission. These two patients relapsed at 3 and 4 months. These results showing clinical activity of high-dose recombinant IL-2 in AML invite further evaluation of this new form of immunotherapy in other clinical situations, like an adjuvant setting for selected groups of high-risk patients.

Serial cytogenetic studies were performed on 60 leukemic recipients of HLA-matched bone marrow transplants (BMT) who were prepared by high doses of alkylating agents and fractionated total body irradiation (TBI). Forty-three patients were recipients of untreated BMT and 17 were recipients of T-depleted BMT. Donor or host mitoses were identified by examination of sex chromosomes in 54 patients or by evaluation of the polymorphism of other chromosomes after specific banding in six patients. Mixed lymphoid chimerism (MLC) was identified in 29 patients and full donor lymphoid chimerism (FDLC) in 29 patients. Complete donor hematopoiesis was recovered in most patients after 12 months, but two T-depleted patients had persistent host cells at 46 and 52 months after the graft. Acute graft-versus-host disease was significantly less frequent in patients with MLC, especially when more than 10% of residual lymphoid cells were detected. The probability of relapse and survival was identical in patients with MLC and FDLC, except in patients with chronic myeloid leukemia where MLC was significantly associated with an increased risk of relapse.