[Head of the WHO declares war against mental illness].
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Global Health↗
Biomedical subjects
M Pettersson
Publications and source records attributed to M Pettersson.
Prognostic significance of proliferative and apoptotic fractions in low grade follicle center cell-derived non-Hodgkin's lymphomas.
BACKGROUND: The biologic parameters, DNA ploidy and proliferative activity, have been suggested as prognostic factors in non-Hodgkin's lymphoma (NHL). However, reports on the prognostic importance of these factors in follicle center cell-derived (FCC) centroblastic/centrocytic (CB/CC) NHL patients with long follow-up are scarce. METHODS: Apoptotic fractions were quantified in 60 patients with CB/CC NHL by in situ labeling of DNA strand breaks in nuclei [TdT-mediated dUTP/dATP in situ 3'OH--end labeling (TUNEL)]. The findings were related to S-phase and MIB-1 counts, DNA ploidy, and clinical outcome. RESULTS: In CB/CC NHL, the percentages of proliferating and apoptotic cells were lower than in reactive germinal centers (GC; P < 0.05; mean, 0.188 vs 3.263% and 19.05 vs. 69.4% for TUNEL and MIB-1 positive cells in CB/CC and GC, respectively). Significantly higher percentages of MIB-1 and TUNEL positive cells were observed in patients with complete remission when compared with the partial remission / no response group (P < 0.01). The size of proliferative and apoptotic fractions did not correlate with the overall survival of the patients. However, follicular and diffuse growth pattern, elevated serum lactic dehydrogenase, advanced stage, and age indicated a lower probability of 5- and 10-year survival. CONCLUSIONS: The investigation of proliferative and apoptotic fractions in FCC lymphomas may help to define groups of patients to who would benefit from aggressive, high dose therapy protocols and patients to whom less aggressive strategies can be applied safely.
Adult↗
Omeprazole and visual disorders: seeing alternatives.
In the WHO data base, visual disorders reported spontaneously with omeprazole, ranitidine and cimetidine, are very rare in the context of the widespread use of these drugs. There is a maximum reporting rate of severe visual impairment possibly ascribed to i.v. omeprazole of 0.94 reports per million treatment days in one year and in one country, Germany. This gives the worst quantitative case scenario for omeprazole by a single route of administration, to be compared with the worldwide reporting rate of all severe visual disorders by all routes of administration--0.008 reports per million treatment days. Moreover, the reported visual abnormalities have a varied pathophysiological aetiology and their number increased in Germany after the first signal was raised in that country. Thus, apart from a direct causal relationship, solicited reporting artifact is one alternate plausible explanation for the apparent excess of cases of visual disturbance to omeprazole compared with cimetidine and ranitidine. That reporting rates of clinical events on newly marketed drugs are generally higher than with older drugs is a second factor for higher reporting rates with omeprazole. Vasculitis has been suggested as an aetiological factor, but the even lower reporting rate of this reaction makes this an unlikely hypothesis without any other supporting evidence. The authors are unaware of any drug that has caused a vasculities solely affecting the eye. Information on the prevalence of relevant visual disorders in the community would have been of considerable help in interpreting this signal, and a case control study of visual events in relationship to severe illness would be of public health interest, since no data seems to exist concerning this.
Journal Article↗
Amniotic fluid antibacterial activity and nutritional parameters in term Mozambican and Swedish pregnant women.
Randomly selected parturients with term singleton pregnancies from two different settings, 83 from Mozambique and 90 from Sweden, entered the study. All of them underwent elective cesarean section, which enabled sterile harvesting of amniotic fluid (AF). AF samples were then tested for antibacterial activity (ABA). Background data and nutritional status were compared. Average age was 32.7 and 30.7 years (n.s.), average parity 6.6 and 1.6 (p < 0.0001), average number of antenatal visits 4.9 and 11.6 (p < 0.0001), and average birthweight 3,194 and 3,688 g (p < 0.01), respectively. Body mass index, mid-upper-arm circumference and hemoglobin did not show any significant differences. The average ABA of AF was more than 50% higher in Swedish than in Mozambican specimens (p < 0.0001). Less than one-sixth of MoZambican women reached the average ABA of AF from Swedish women. Bacterial outgrowth delay equal to or above 3 h was encountered in 13% of Mozambican AF as against 61% of Swedish AF (OR 0.10; 95% CI 0.05-0.19). Histopathological examinations of the placenta, nonplacental membranes and umbilical cord showed inflammatory lesions in 29% of the Mozambican parturients and in 13% of Swedish parurients (OR 2.65; 95% 1.00-6.98). It is probable that the lower antibacterial activity in Mozambican AFs reflects an increased vulnerability to ascending genital infections during late pregnancy.
Adolescent↗
Amniotic fluid interleukins in Swedish and Mozambican pregnant women.
The aim of the study was to investigate inflammatory cytokines, interleukin-1 beta (IL-1 beta), interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-8 in amniotic fluid, in a cohort of Swedish pregnant women from early to late pregnancy and Mozambican late pregnant women with and without signs of histologic chorioamnionitis. Eleven Swedish women were studied from early pregnancy (week 16-17) to late pregnancy (week 37-38). Amniotic fluid was collected via amniocentesis in early pregnancy and also in late pregnancy during elective Caesarean section. From Mozambican women, amniotic fluid was harvested transmurally through the uterus wall during elective Caesarean section. Half of the group of 30 women showed histological signs of chorioamnionitis and half of the group did not show such signs. A statistical, significant increase in IL-1ra, Il-6 and IL-8 values from early to late pregnancy was seen in the Swedish pregnant women. Among the Mozambican women, no statistically significant increase in the above-mentioned interleukins was observed when comparing women with and without histological signs of chorioamnionitis. Term Swedish and Mozambican women did not show differences in cytokine levels. There were no detectable values of IL-1 beta in either Swedish or Mozambican women. IL-1ra, IL-6 and IL-8 increased in amniotic fluid from the second to the third trimester in the Swedish cohort. No correlation was found between histological chorioamnionitis and elevated cytokine levels of amniotic fluid in term pregnant women not in labour. An equally good cytokine response was found among Swedish and Mozambican third-trimester non-labouring women.
Amniocentesis↗
The hematopoietic transcription factor PU.1 is downregulated in human multiple myeloma cell lines.
PU.1 is a hematopoietic transcription factor belonging to the Ets-family. It is identical to the Spi-1 oncogene, which is implicated in spleen focus-forming virus-induced murine erythroleukemias. PU.1 seems to be required for early development of multiple hematopoietic lineages, but its expression in mature cells is preferentially observed in cells of the B-cell-and monocyte/macrophage-differentiation lineage. It binds the so-called Pu box, an important tissue-specific regulatory DNA element present in a number of genes expressed in these cell lineages. We have analyzed the expression and activity of PU.1 during human B-cell development using a panel of B-cell lines representing different stages of maturation, from early precursors to differentiated plasma cells. PU.1 mRNA expression and PU.1 DNA binding activity, as measured by Northern blot analysis and electrophoretic mobility shift assay, respectively, were evident in cell lines representing pro-B, pre-B, and mature B cells. We could also show Pu box-dependent transactivation of a reporter gene in transient transfections in these cell lines. In contrast, in a number of multiple myeloma cell lines, representing differentiated, plasma cell-like B cells, PU.1 DNA binding activity, mRNA expression, and Pu box-dependent transactivation were absent or detectable at a very low level. In lymphoblastoid cell lines, which exemplify an intermediate stage of B-cell differentiation, a reduced expression and activity were observed. The findings in the human multiple myeloma cell lines represent the first examples of B cells with downregulated PU.1 expression and apparently contradict observations in the murine system in which PU.1 is expressed and active in plasmacytoma cell lines. At present, it is unclear whether the lack of PU.1 expression and activity in human multiple myeloma cell lines represents a malignancy-associated defect in these cells or exemplifies a normal developmental regulation in terminally differentiated B cells.
B-Lymphocytes↗
Surfactant protein A modulates release of reactive oxygen species from alveolar macrophages.
The production and release of reactive oxygen species (the respiratory burst) is a common metabolic pathway linked to several macrophage-related reactions. The most abundant surfactant protein A (SP-A) binds to alveolar macrophages (AM) through a specific surface receptor with high affinity. Because such binding might initiate or modulate the respiratory burst, we wanted to know whether and how SP-A affects the oxygen radical release from AM. To answer these questions, we measured the release of reactive oxygen species from rat AM under various in vitro conditions using enhanced chemiluminescence systems. We prepared SP-A from pulmonary surfactant isolated either from silica-treated rats or adult dogs. Resident AM were harvested from pathogen-free Wistar rats by lung lavage. Adhered and nonadhered AM were assessed on protein-free or protein-coated surfaces of 96-well microtiter plates. On protein-free surfaces, the sole addition of SP-A failed to induce measurable oxygen radical release from 2 x 10(5) adhered or nonadhered AM, while zymosan opsonized with SP-A induced a marked increase over control. On protein-coated surfaces, AM respond differently depending on the coated protein: on SP-A-coated surfaces, a dose-dependent enhancement of oxygen radical release with a mean effective concentration of approximately 1.15 micrograms/ml was found. No such enhancement was seen on plates coated with similar amounts of either human fibronectin or collagen, and the enhancement with serum albumin was not dose related. Our data demonstrate that SP-A only enhances oxygen radical release from AM if SP-A is fixed to zymosan or the surface of the reaction vial in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Expression of mad, mxi1, max and c-myc during induced differentiation of hematopoietic cells: opposite regulation of mad and c-myc.
The Myc proto-oncoprotein family is considered to play an important role in the control of cell growth and differentiation. It appears that the interaction of Myc with its heterodimeric partner Max is essential for Myc function. Recently two other partners of Max, called Mad and Mxi1, have been identified. In an effort to gain insight into the network of these four proteins we have started to analyse the expression of the c-myc, max, mad and mxi1 genes at the mRNA level during hematopoietic cell growth and differentiation. In the human myeloid cell lines U-937, HL-60 and ML-1 c-myc expression was down-regulated as shown previously after induction of differentiation, whereas the expression of max was only slightly affected. In contrast to these two genes the expression of mad was induced upon differentiation in the three cell lines by TPA, retinoic acid, vitamin D3, dimethyl sulfoxide, and interferon-gamma and remained elevated for at least 3 days. A kinetic analysis showed that the induction of mad in U-937 in response to TPA was rapid (15 min) and at least in part transcriptional, reminiscent of immediate early genes. The expression of mxi1 was induced in U-937 by some inducers but not in HL-60 or ML-1. Its induction occurred slowly, peaking around 48 h. These analysis thus suggest that the expression of mad and c-myc is inversely regulated during induced hematopoietic differentiation.
Cell Differentiation↗
Ice hockey injuries: a 4-year prospective study of a Swedish élite ice hockey team.
In this prospective study, we have investigated the incidence of injuries of different severity, types of injury, and mechanisms of injury during ice hockey practice and games. One Swedish élite hockey team was closely observed during four seasons (1986-1990). There were 376 injuries, of which 148 resulted in absence from practice or games. The incidence of injury (injuries associated with later absence) during practice was 2.6 per 1000 player-practice hours and 74.1 per 1000 player-game hours. Nuisance injuries (without any later absence) and minor injuries (absence < 1 week) constituted the vast majority (95.2%) and only 4.8% (18 cases) were classified as moderate or major injuries (absence > 1 week). Of the injuries 85% were caused by trauma and 15% by overuse. Injuries were most often localized to the lower limb (37.8%) and head/face (31.4%). The commonest injuries were contusions, lacerations/wounds, strains and sprains. Most injuries resulted from stick or player contact (predominantly checking). The results are in close agreement with those of a previous investigation of another Swedish élite hockey team covering the years 1982-1985. It should be possible to reduce the number of injuries by stricter enforcement of the hockey rules, especially against stick violations, and a more widespread use of visors.
Adult↗
Expression of myc-family genes in established human multiple myeloma cell lines: L-myc but not c-myc gene expression in the U-266 myeloma cell line.
Deregulated c-myc expression, as a consequence of translocation of the c-myc gene to one of the immunoglobulin loci, appears to play an important role in the pathogenesis of several B-cell tumors, including Burkitt's lymphoma, mouse plasmacytoma and rat immunocytoma. This study investigated the expression of c-myc and 2 other members of the myc gene family, L- and N-myc, at the mRNA and protein level, and analyzed for possible rearrangements of these genes in the human counterpart to the mouse plasmacytoma--multiple myeloma (MM). Nine well-characterized MM cell lines were examined by using Northern- and Southern-blot analysis and immunoprecipitation. The c-myc gene was found to be highly expressed in most MM cell lines. The level of expression was comparable to that observed in the COLO 320 and HL-60 cell lines, carrying amplified c-myc genes, and to that of B-cell lines with a higher proliferative activity than the MM cell lines. In the U-266 MM cell line, L-myc, but no c-myc mRNA or protein, was found. The L-myc gene was expressed in both early- and late-passage U-266 cells, suggesting that the L-myc expression was not the result of the in vitro cultivation. N-myc was not expressed in any of the MM cell lines. No rearrangements of c-myc or L-myc genes were found. We thus conclude that (a) in contrast to the corresponding mouse and rat B-cell tumors, c-myc is not frequently rearranged in MM; (b) c-myc is highly expressed in most MM lines; and (c) L-myc but not c-myc is expressed in the U-266 MM cell line.
DNA, Neoplasm↗
Expression of the bcl-2 gene in human multiple myeloma cell lines and normal plasma cells.
The bcl-2 gene, encoding a mitochondrial membrane protein suggested to play an important role in cell survival, is translocated into the Ig loci in about 80% of human follicular lymphomas, which results in a high level of expression. This report shows that bcl-2 was expressed in eight of eight human multiple myeloma cell lines and in normal lymph node and bone marrow plasma cells. In the majority of the myeloma lines, the level of expression was comparable with that observed in Karpas 422, a follicular lymphoma cell line carrying a 14;18 translocation of the bcl-2 gene. DNA rearrangements of the bcl-2 locus were evident in only one of the myeloma cell lines, U-266-1970. In this cell line, which exhibited the highest bcl-2 expression, a fourfold increased copy number of the bcl-2 gene was estimated by Southern analysis. This amplification was lost in cells of later passages (U-266-1984), suggesting that bcl-2 might possibly have played a role in the tumor development in vivo. Our results are in contrast to previous observations in murine plasmacytoma, in which bcl-2 was shown to be silent. The results also contradict the published observation that bcl-2 is not expressed at terminal stages of B-cell differentiation. It is at present unclear whether the high expression of bcl-2 in human myeloma is the result of a deregulated expression associated with the malignant phenotype or a mere reflection of the bcl-2 expression typical of normal plasma cells.
Blotting, Southern↗
Increase in interleukin 6 (IL-6) and IL-6 receptor expression in a human multiple myeloma cell line, U-266, during long-term in vitro culture and the development of a possible autocrine IL-6 loop.
A human multiple myeloma (MM) cell line, U-266, has developed the ability to grow independently of exogenous interleukin 6 (IL-6) during long-term cultivation in vitro. The early passage, feeder-cell dependent U-266 cell line (U-266-1970) was compared with the late passage U-266-1984 cell line with respect to response to IL-6, IL-1 beta and tumour necrosis factor alpha and expression of IL-6 and IL-6 receptor (IL-6R) mRNA and protein. The results showed that; (a) only the U-266-1970 cell line was stimulated to growth by IL-6, (b) IL-6 and IL-6R mRNA were expressed in both cell lines, (c) the level of IL-6 mRNA was increased in the U-266-1984 cell line and only this line produced IL-6 and, (d) the level of IL-6R mRNA was highest in the U-266-1984 cell line and the number of IL-6R about ten times higher than in U-266-1970. The growth of the IL-6-producing U-266-1984 cell line was inhibited by 30% by anti-IL-6R antibodies suggesting the possibility that an autocrine IL-6 loop might have developed during the long-term cultivation. In addition to many other phenotypic alterations of the U-266 cell line, having developed as a consequence of tumor progression in vitro, its growth factor requirement seems to have evolved from a dependence on IL-6 as a paracrine growth factor to a capacity for autonomous growth, dependent on autocrine IL-6 stimulation. Whether such a development also may take place in MM clones in vivo remains to be established.
Blotting, Northern↗
Effects of cholecystokinin (CCK)-8, CCK-33, and gastric inhibitory polypeptide (GIP) on basal and meal-stimulated pancreatic hormone secretion in man.
Gastrointestinal hormones with insulinotropic effects, like cholecystokinin (CCK) and gastric inhibitory polypeptide (GIP) might tentatively be used in the treatment of non-insulin-dependent diabetes mellitus. We therefore examined the effects of intravenous injection of pharmacological dose levels of CCK-8 (100 and 300 pmol/kg), CCK-33 (100 pmol/kg), GIP (100 pmol/kg), and CCK-8 plus GIP (100 pmol/kg of each) on plasma levels of glucose, insulin, somatostatin, glucagon, and pancreatic polypeptide (PP) in healthy human volunteers. The peptides were given under basal conditions or in combination with a mixed meal. CCK-8, CCK-33, and GIP were all found to increase the basal plasma levels of insulin, somatostatin, and PP; the increases were observed already in samples taken at 2 min after the injection. In contrast, the plasma glucagon levels were unaffected by the peptides. CCK-8, CCK-33, and GIP (100 pmol/kg) all potentiated the meal-induced plasma responses of insulin and PP, whereas plasma levels of glucagon after the meal were not affected. Plasma somatostatin levels after the meal were increased by GIP but not affected by CCK-8 or CCK-33. CCK-8 and GIP together (100 pmol/kg for both) increased plasma levels of insulin, PP and somatostatin as much as each of the peptides given alone, both under basal conditions and after the meal intake. Plasma levels of glucagon were not affected by CCK-8 and GIP together. We conclude that in man, both CCK-8, CCK-33, and GIP moderately stimulate basal and meal related insulin release without any synergistic effects and that the peptides do not inhibit the secretion of glucagon.
Adult↗
Recombinant interferon-gamma inhibits the growth of IL-6-dependent human multiple myeloma cell lines in vitro.
Recombinant human IFN-gamma (100-1000 U/ml) inhibited the IL-6-induced growth of 2 human IL-6-dependent multiple myeloma (MM) cell lines U-1958 and U-266-1970 in vitro. In contrast, the U-1996 line, independent of IL-6 for maintenance at a slow growth rate but responding to IL-6 by increased proliferation, and the IL-6-independent U-266-1984 were refractory to the anti-proliferative effect of IFN-gamma. The effect of IFN-gamma in the sensitive MM cell lines was cytostatic in U-266-1970, and cytostatic and cytotoxic in U-1958. Northern blot analysis revealed that the growth inhibition of the IL-6-dependent MM cell line U-1958 was not due to down-regulation of IL-6 receptor mRNA expression and that the differential sensitivity to IFN-gamma was not due to differences in IFN-gamma receptor expression. The growth inhibition was not a consequence of an IFN-gamma-induced terminal differentiation as flow cytometric analyses demonstrated an arrest in all phases of the cell cycle. IFN-alpha inhibited the growth in 3 of the 4 cell lines tested. The results thus suggest that the particular MM phenotype, which includes IL-6 dependency for survival and growth, may also be characterized by IFN-gamma sensitivity. Furthermore, the study demonstrates that MM cell lines are not simultaneously sensitive to IFN-gamma and alpha, indicating that the mechanisms of action of the two types of IFN are distinct.
Cell Division↗
Every enhancer works with every promoter for all the combinations tested: could new regulatory pathways evolve by enhancer shuffling?
The promoters and enhancers of cell type-specific genes are often conserved in evolution, and hence one might expect that a given enhancer has evolved to work best with its own promoter. While this expectation may be realized in some cases, we have not found evidence for it. A total of 27 combinations of different promoters and enhancers were tested by transfection into cultured cells. We found that the relative efficiency of the enhancers is approximately the same, irrespective of the type of promoter used, i.e., there was no strong preference for any given enhancer/promoter combination. Notably, we do not see particularly strong transcription when the immunoglobulin kappa enhancer (or the immunoglobulin heavy chain enhancer) is used to activate a kappa gene promoter. We propose that a generally permissive enhancer/promoter interaction is of evolutionary benefit for higher eukaryotes: by enhancer shuffling, genes could be easily brought under a new type of inducibility/cell type specificity.
B-Lymphocytes↗
Heterogeneity in response to interleukin 6 (IL-6), expression of IL-6 and IL-6 receptor mRNA in a panel of established human multiple myeloma cell lines.
The controversial role of interleukin-6 (IL-6) as an auto- or paracrine growth factor for human multiple myeloma (MM) cells was studied using a panel of six well characterized feeder-cell dependent and independent MM cell lines as models. With respect to the effect of IL-6 on growth and survival, three types of lines were found: (1) U-1958, dependent on IL-6 both for growth and survival; (2) U-1996, dependent on IL-6 for growth but not survival; and (3) U-266-1984, Fravel, L363, and Karpas 707, independent of IL-6. Feeder-cell supernatants were as efficient as feeder-cell monolayers in stimulating growth and contained IL-6 as the only growth promoting activity. IL-6 was growth stimulatory and sustained the growth of U-1958 only when the medium contained fetal calf serum. The nature of the serum factor(s) is unknown, but it was excluded to be the IL-6 carrier protein a2-macroglobulin. IL-1, IL-2, IL-3, TNF-alpha, GM-CSF, IGF-1, and insulin were neither co-stimulatory with IL-6 nor stimulated growth on their own. Only U-266-1984 expressed IL-6 mRNA. IL-6 receptor mRNA was expressed in all lines except the L363 and Fravel. We conclude that the response to IL-6 is heterogeneous among the MM lines and that IL-6 acts as a paracrine growth factor for two of six lines. In a third line, U-266-1984, the IL-6 mRNA expression suggests the possibility of an autocrine growth stimulation.
Antibodies↗
[Intrauterine infection an important cause of pregnancy complications].
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Amniotic Fluid↗
Synergistic activation of transcription by multiple binding sites for NF-kappa B even in absence of co-operative factor binding to DNA.
Regulation of eukaryotic genes is largely governed by multiple cis-acting DNA sequences recognized by specific transcription factors. The transcription factor NF-kappa B has been implicated as an important regulator of cellular and viral genes, including those of immunoglobulin kappa light chain, interleukin-2, beta-interferon, HIV-1 and cytomegalovirus. We have analyzed the effect of increasing the number of NF-kappa B sites, located directly upstream from the TATA box. Four copies of the sequence gave a more than 100-fold stimulation relative to a single copy, suggesting that NF-kappa B proteins act synergistically to bring about this dramatic increase in transcription. By DNase I footprinting we demonstrated factor binding to two adjacent NF-kappa B sites in vitro. However, we found no evidence for co-operative binding to these DNA sites. We propose that the high transcriptional activity results from another type of co-operation, based on multiple weak interactions of the NF-kappa B factors with another component of the transcription apparatus, perhaps RNA polymerase II itself.
Animals↗