Obstetric cholestasis in Hong Kong--local experience with eight consecutive cases.

Obstetric cholestasis is associated with maternal morbidity and adverse foetal outcomes. No information on local incidence is available. We present our experience with eight consecutive cases of obstetric cholestasis diagnosed between January 2003 and December 2005 in a regional hospital in Hong Kong. Three patients presented with pruritus without rash, three with impaired liver function, and two with elevated blood pressure postpartum. Meconium-stained liquor was present in five patients and four had spontaneous preterm delivery (between 34 and 36 weeks). The higher the bile acid level, the more marked the prematurity (correlation coefficient, -0.771; P=0.025). All those presenting with itchiness delivered preterm. Two patients developed pre-eclampsia. The rates of labour induction and abdominal delivery were both 38%. Heightened awareness among clinicians is required to recognise patients with obstetric cholestasis. Affected pregnancies are associated with meconium passage and prematurity. In our locality, affected women may also have an increased risk of pre-eclampsia. In affected women, the bile acid level is useful in assessing the risk of prematurity.

Successful treatment of recurrent, intractable hyperemesis gravidarum with methylprednisolone. A case report.

BACKGROUND: Severe and persistent hyperemesis gravidarum is a disabling condition. Women may request termination of pregnancy because of the intolerable symptoms and stress. CASE: A woman requested termination of pregnancy because of severe hyperemesis gravidarum. Her first three pregnancies were also complicated by severe and persistent vomiting. The vomiting was successfully treated with a short course of methylprednisolone. CONCLUSION: Methylprednisolone is an effective treatment for severe hyperemesis gravidarum and should be considered for women whose vomiting is persistent and refractory to conventional therapy.

A tumor derived motility factor that stimulates cell migration on extracellular matrix.

A factor that stimulates migration of lung carcinoma cells on biological substrata was purified from the human lung adenocarcinoma cell line WART. A partially purified autocrine motility factor-like substance, termed haptotaxin, was added to the lower compartment of Boyden chambers and the filters were coated on the upper, lower or both sides with different concentrations of the extracellular matrix (ECM) components fibronectin, laminin or collagen type IV. These adhesive proteins coated on the lower surface of the filter promoted the migration (haptotaxis) of lung carcinoma cells. This effect was greatly enhanced by the addition of haptotaxin. In contrast, ECM components (including gelatin) coated on the upper surface or on both filter surfaces did not stimulate tumor cell migration. However, the addition of haptotaxin also timulated cell migration under these conditions. Haptotaxin did not stimulate migration on filters coated with bovine serum albumin or on uncoated filters. Haptotaxin could not be absorbed by fibronectin, laminin, collagen type IV or gelatin, and soluble ECM components did not affect the locomotor effect of haptotaxin. Substrata coated with fibronectin, laminin and collagen type IV induced adhesion and spreading of lung carcinoma cells in a dose dependent fashion. Haptotaxin potentiated adhesion and spreading of tumor cells on these substrata but did not in itself mediate adhesion and spreading of the cells. Anti-VLA 2 antibodies inhibited migration to haptotaxin on gelatin and laminin coated filters but did not affect haptotaxin-induced migration on fibronectin or collagen type IV substrata. Anti-VLA-5 monoclonal antibodies inhibited haptotaxin-induced migration on fibronectin coated filters but not such migration on filters coated with other ECM molecules showing that tumor cells must interact specifically with ECM components in order to migrate to haptotaxin.

Production of a motility factor by a newly established lung adenocarcinoma cell line.

We have established and characterised a cell line, designated WART, from a patient with primary adenocarcinoma of the lung. This cell line grows with a doubling time of approximately 15 hours, forms colonies in soft agarose, is tumorigenic in athymic nude mice, and has a complex karyotype with both structural and numerical abnormalities. WART serum free conditioned medium (SFCM) contains a factor which stimulates motile behavior of WART cells. This factor with an apparent molecular weight of 67 kDa induced in an autocrine fashion prominent pseudopodia, and chemotactic and chemokinetic responses. Heparin affinity chromatography, ion exchange and molecular sieve chromatography accompanied by SDS-PAGE analysis showed that the motility inducing activity was associated with a major band with molecular weight 67 kDa. The motility inducing activity of the 67 kDa protein was not sensitive to reduction with either dithiotreitol or mercaptoethanol which distinguishes it from A-2058 melanoma autocrine motility factor (AMF)/autotaxin, HT-1080 fibrosarcoma AMF and scatter factor which lose their biological activity upon reduction. This 67 kDa motility inducing factor did not augment DNA synthesis indicating that its locomotor activity is independent of mechanisms regulating cell growth. Pertusis toxin inhibited the motile response induced by the 67 kDa protein indicating a signal transduction pathway involving G proteins. Due to its production of the motility stimulating protein the cell line could facilitate studies of invasion and metastasis of human lung tumors.

Low-dose ara-C in myelodysplastic syndromes (MDS) and acute leukemia following MDS: proposal for a predictive model.

Patients with myelodysplastic syndromes (MDS) comprise an extremely heterogeneous group. There is a need for decision models both for predicting the natural course of the disease and the outcomes of different treatment alternatives. In 102 consecutive patients with MDS or acute myelogenous leukemia (AML) following MDS, pre-treatment variables were studied in relation to the response to treatment with low-dose ara-C. Thirty patients (29%) responded with either a complete remission or a significant rise in the hemoglobin level. For the remaining 71%, the treatment was ineffective and in some cases hazardous. The factors associated with a poor response to treatment could be divided into two groups: one included low platelet counts and the presence of chromosomal aberrations, both signs of progressive MDS with a short survival, and the other comprised morphological findings, indicating ineffective hemopoiesis. Patients with platelet counts > 150 x 10(9)/l had a response rate of 55%, compared to 24% in patients with subnormal platelet counts. Logistic regression identified low bone marrow cellularity, absence of ring sideroblasts and < 2 chromosomal aberrations as predictors of a favourable response in patients with platelet counts < 150 x 10(9)/l. These factors and the platelet count were combined in a predictive model which divided patients into three groups with different probabilities of response: one favourable (38% of the patients), with a response rate of > 50%; a second, intermediate group (33% of the patients), with a response rate of 24%; and a third, unfavourable group (29% of the patients) with only 3% responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemotaxis and haptotaxis of human malignant mesothelioma cells: effects of fibronectin, laminin, type IV collagen, and an autocrine motility factor-like substance.

A human malignant pleural mesothelioma cell line (STAV) was studied with respect to production of the extracellular matrix components laminin, type IV collagen, and fibronectin, and interactions with these proteins in vitro. We also analyzed STAV cell serum-free conditioned medium with respect to the possible presence of "autocrine motility factor-like" substance. Sodium dodecylsulfate-polyacrylamide gel electrophoresis of biosynthetically labeled STAV serum-free conditioned medium showed that STAV cells released several proteins into the medium, including components with molecular weights of 850,000, 540,000 and 440,000. Using Western blotting we identified these proteins as laminin, type IV collagen, and fibronectin, respectively. By immunocytochemistry laminin, type IV collagen, and fibronectin were detected as a matrix surrounding the cells. Plastic culture dishes coated with microgram quantities of laminin, type IV collagen, and fibronectin induced attachment and spreading of STAV cells. Laminin, type IV collagen, and fibronectin stimulated directional (chemotactic) migration of STAV cells in Boyden chambers fitted with 8 microns filters. The same cells also migrated to insoluble step gradients of filter-bound extracellular matrix components (haptotaxis). When STAV serum-free conditioned medium was separated by using fast protein liquid chromatography Superose 6 gel filtration, two motility-inducing protein peaks were detected. The first peak contained proteins with molecular weight > 220,000 that had both chemotactic and haptotactic properties, while the second peak contained material with apparent molecular weights of approximately 67,000 that had chemotactic and chemokinetic (random motility) but not haptotactic properties. Analysis of the M(r) 67,000 material indicated that it was a heat-sensitive and trypsin-digestible protein. The production of both soluble and insoluble extracellular matrix components by human mesothelioma cells and the motile response to these molecules as well as the production of a M(r) 67,000 autocrine motility factor-like substance may be important for the highly invasive motile behavior of this tumor.

A predictive model for the clinical response to low dose ara-C: a study of 102 patients with myelodysplastic syndromes or acute leukaemia.

The response to treatment with low-dose ara-C was studied in 102 consecutive patients; 79 with myelodysplastic syndrome (MDS) and 23 with acute myelogenous leukaemia (AML) following MDS. The aim was to find variables that could predict the response to treatment. All patients had clinical symptoms related to cytopenia. Peripheral blood values, bone marrow morphology histology and chromosomes were analysed before the start of treatment. The median survival of the patients was 9 months and a poor survival was predicted by advanced age, low platelet counts, the presence of pseudo-Pelger morphology and > or = 2 chromosomal aberrations. Thirty patients (29%) responded with either a complete remission or a significant increase in haemoglobin level. For the remaining 71%, the treatment was ineffective and in some cases hazardous. The factors associated with a poor response to treatment could be divided into two groups: one included low platelet counts and the presence of chromosomal aberrations, both signs of progressive MDS with a short survival, and the other comprised morphological findings, indicating ineffective haemopoiesis. Patients with platelet counts > 150 x 10(9)/l had a response rate of 55% compared to 23.5% in patients with subnormal platelet counts. Logistic regression identified low bone marrow cellularity, absence of ring sideroblasts and < 2 chromosomal aberrations as predictors of a favourable response in patients with platelet counts < 150 x 10(9)/l. These factors and the platelet count were combined in a predictive model which can divide patients into three groups with different probabilities of response: a favourable group, 38.6% of the patients, with a response rate of > 50%, an intermediate group, 32.7% of the patients, with a response rate of 24%, and an unfavourable group, 28.7% of the patients, with only 3% responses. While low-dose ara-C is an effective treatment for some patients, it is ineffective and hazardous for others. We present a model that can facilitate therapeutic decision making in two-thirds of patients with MDS and MDS-AML by identifying patients who should not be treated with low-dose ara-C as well as patients with a relatively high probability of response.

In vitro suspension culture reactions to 1,25 dihydroxyvitamin D3 in relation to bone marrow morphology and prognosis in patients with myelodysplastic syndromes.

Thirty-four patients with MDS or AML following MDS were studied with regard to survival, peripheral blood values and bone marrow morphology. The effects of 1,25 dihydroxyvitamin D3 (D3) on differentiation (NBT positivity) and proliferation (3H-thymidine incorporation) were studied in suspension cultures of bone marrow cells. Twelve bone marrow donors served as controls. Normal cells showed spontaneous differentiation in vitro, but only 2/12 were induced to differentiation by D3. Myelodysplastic cells did not differentiate spontaneously, but cells from 18/34 patients differentiated after incubation with D3. Normal cells showed increased proliferation, myelodysplastic cells showed a heterogeneous response and leukemic cells reacted with decreased proliferation after D3 incubation. Poor survival was associated with low platelet counts, high percentage of bone marrow blasts (BM blast %), low spontaneous in vitro proliferation and absence of hypogranulation of myeloid cells. Platelet counts and hypogranulation retained their predictive value in a multi-variate analysis. Progression to AML was predicted by a high BM blast % and low scores for erythroid and total dysplasia. In conclusion, the pattern of in vitro proliferation showed prognostic value while the pattern of vitamin D3-induced differentiation failed to correlate to other parameters. An estimation of bone marrow dysplasia can be used to predict the development of AML. Our results add to the information about the biology of MDS and may be important for the evaluation of therapeutic trials.

Nucleokinesis: distinct pattern of cell translocation in response to an autocrine motility factor-like substance or fibronectin.

Human lung adenocarcinoma cells develop bipolar shape with prominent pseudopodia (greater than or equal to 200 microns) when cultured in the presence of autocrine motility factor (AMF)-like substance or on fibronectin-coated substrata. AMF was partially purified from a human lung adenocarcinoma cell line and has a peak biological activity at a molecular mass of 67 kDa. Using time-lapse photography, we observed that during AMF- or fibronectin-induced cell translocation, the nuclei of some bipolar cells are transported to the opposite end of the cell, while gross cell shape and position remain unchanged. Following this nuclear movement, which we call "nucleokinesis," the posterior pseudopodium is retracted behind the nucleus. Thus, extension of a pseudopodium followed by nucleokinesis in the same direction and retraction of the cell body behind the nucleus is a normal motile sequence in translocating bipolar cells. This suggests that nucleokinesis is a distinct step in whole-cell translocation of bipolar cells on biological substrata and that pseudopodia can be used as nuclear transport organs. In contrast, adenocarcinoma cells cultured on artificial substrata and in the absence of AMF display a fibroblast-like motility pattern with the nucleus centrally located within the migrating cell.

From the Big Bang to sustainable societies.

A series of events in the history of cosmos has created the prerequisites for life on Earth. With respect to matter, the earth is a closed system. However, it receives light from the sun and emits infrared radiation into space. The difference in thermodynamic potential between these two flows has provided the physical conditions for self-organization. The transformation of lifeless matter into modern life forms, with their high degree of order and complexity, has occurred in the context of the earth's natural cycles, including the water cycle and the biochemical cycles between plants and animals. Primary production units, the cells of green plants, can use the thermodynamic potential of the energy balance in a very direct way, i.e. in photosynthesis. Plant cells are unique in their ability to synthesize more structure than is broken down elsewhere in the biosphere. The perpetuation of this process requires the recycling of wastes. However, modern industrial societies are obsessed with the supply side, ignoring the principle of matter's conservation and neglecting to plan for the entire material flow. As a result there has been an accumulation of both visible and invisible garbage (pollution), which disturbs the biosphere and reduces stocks of natural resources. Furthermore, due to complexity and delay mechanisms, we usually cannot predict time parameters for the resulting socio-economic consequences or the development of disease. To continue along this path of folly is not compatible with the maintenance of wealth, nor with the health of humans or the biosphere. Rather than address the millions of environmental problems one at a time, we need to approach them at the systemic level. It is essential to convert to human life-styles and forms of societal organization that are based on cyclic processes compatible with the earth's natural cycles. The challenge to the developed countries is not only to decrease their own emissions of pollutants but to develop the cyclic technology and life styles needed by the entire human community.

Treatment of myelodysplastic syndromes with retinoic acid and 1 alpha-hydroxy-vitamin D3 in combination with low-dose ara-C is not superior to ara-C alone. Results from a randomized study. The Scandinavian Myelodysplasia Group (SMG).

63 evaluable patients with myelodysplastic syndromes (MDS) and 15 with acute myelogenous leukemia (AML) were randomized between low-dose ara-C (arm A) and low dose ara-C in combination with 13-cis-retinoic acid (13-CRA) and 1 alpha-hydroxy-vitamin D3 (1 alpha D3) (arm B). 69 patients were evaluable and 18 (26.1%) responded to therapy. The addition of 13-CRA and 1 alpha D3 had no positive influence on survival of the patients, remission rates or duration of remissions. 12/27 patients in arm A and 6/29 patients in arm B progressed from MDS to AML during the course of the study (p = 0.0527). Arm B gave significantly more side-effects than arm A (p = 0.005). Therapeutic effects of 13-CRA and 1 alpha D3 on MDS is not supported by this study. However, an inhibiting effect on AML development in some MDS subgroups cannot be excluded.

Serum-dependent growth patterns of two, newly established human mesothelioma cell lines.

Two cell lines with different in vitro growth patterns were established from the pleural fluid of a patient with malignant epithelial pleural mesothelioma. The cell line established in RPMI 1640 supplemented with human AB serum had an epithelial morphology, while the cell line established in fetal calf serum-supplemented medium had a fibroblast-like morphology. Exposure of the fibroblast-like cell line to human AB serum-containing medium resulted in a nearly complete transformation of the morphology to the epithelial-like phenotype, and the epithelial-like cell line changed its phenotype to fibroblast-like upon exposure to fetal calf serum-supplemented medium. Both cell lines formed colonies in soft agarose and secreted hyaluronic acid into the culture medium. In both cell lines all the metaphases studied lacked chromosomes 5 and 9, demonstrating the same clonal origin. However, one marker and a missing chromosome 11 were found only in the fibroblast-like cell line. We conclude that human AB serum supplement can be used for the establishment of human tumor cell lines, and that the choice of serum can affect the in vitro morphology of the established mesothelioma cell lines. The mechanisms behind the different growth patterns seem to be a selective stimulation of different subpopulations of malignant cells as well as induction of changes in the morphology of individual cells.

Alpha-interferon receptors in malignant B-cells from patients with chronic lymphocytic leukemia: relation to induction of 2'-5'-oligoadenylate synthetase and blast transformation.

alpha-Interferon (IFN-alpha) induces blast transformation of malignant B-cells from approximately 65% of chronic lymphocytic leukemia patients. We have shown previously that induction of blast transformation correlates with induction of 2'-5'-oligoadenylate synthetase. In this paper we address the question of whether low responsiveness to IFN-alpha is associated with a reduced expression of the IFN receptor. IFN-alpha receptor expression was studied by the binding of radioiodinated IFN-alpha to peripheral blood malignant B-cells from 20 chronic lymphocytic leukemia patients and to blood cells from 5 healthy donors. Chronic lymphocytic leukemia cells from all 20 patients displayed high affinity IFN-alpha receptors [mean Kd, 62 +/- 9 (SE) pM] ranging between 110 and 850 binding sites/cell [mean, 416 +/- 51]. Nonmalignant mononuclear blood cells showed similar binding data (411 +/- 105 binding sites/cell; Kd 66 +/- 20 pM). Receptor expression did not correlate with the degree of blast transformation or with induction of 2'-5'-oligoadenylate synthetase. We conclude that the deficiency of IFN sensitivity is localized somewhere between signal transduction from the receptor and induction of 2'-5'-oligoadenylate synthetase.

Induction of proliferation and blast transformation by interferon in human malignant and non-malignant lymph node B cells.

The influence of interferon (IFN) on cellular proliferation, blast transformation, and differentiation was studied in lymph node cells from 17 patients with B-cell lymphomas, one patient with T-cell lymphoma, and eight patients with enlarged, non-malignant lymph nodes. The effects of IFN on lymph node cells were compared with effects on mononuclear blood cells from chronic lymphocytic leukemia (CLL) patients and healthy donors. Natural IFN-alpha (nIFN-alpha) induced a proliferative response in cells from seven of 17 of the B-cell lymphomas, in two of eight of the non-malignant lymph nodes, and in lymphoid blood cells from two of 32 CLL patients. With few exceptions, the proliferating cells were B cells and the data suggest that IFN acts directly on the B cells. Proliferation was not induced with IFN in cells from the T-cell lymphoma or in mononuclear blood cells from 13 healthy donors. nIFN-alpha induced blast transformation in cells from ten of 14 of the B-cell lymphomas and in four of seven of the non-malignant lymph nodes. Also beta- and gamma-IFN were shown to induce proliferation and blast transformation in lymph node cells from some patients. No major effect on the expression of various differentiation markers could be observed following culture in the presence of nIFN-alpha. We conclude that IFNs can induce proliferation and blast transformation in malignant and non-malignant B cells from lymph nodes.

Management of non-Hodgkin lymphoma in adults in Scandinavia, United Kingdom, and The Netherlands. Report from the European School of Oncology intercity meeting at Huddinge Hospital, 3rd June, 1988.

Current treatment strategies in northern Europe of non-Hodgkin lymphoma are presented. High-grade malignant lymphomas have been treated with doxorubicin-containing polychemotherapy in various modes. The advantage of six-drug regimens over CHOP-like therapy is as yet not proven. Patients with the ability to tolerate the calculated dose have good prognosis. High-dose therapy and bone marrow transplantation should be considered in poor-risk patients with lymphoblastic lymphomas in first remission, patients with all high-grade histologies in partial remission after first-line therapy and patients with relapse that are still responsive to therapy. Preliminary results from autologous bone marrow transplantation in follicular lymphoma are also encouraging. Chlorambucil induces multiple remissions in follicular lymphoma, with a median duration of the 1st, 2nd and 3rd remission being the same. The watch and wait strategy seems justified initially in most asymptomatic generalized low-grade malignant lymphomas. Systemic therapy is required in aggressive stage II-IV lymphomas. A meticulous investigation is needed for stage I patients before giving local treatment only. Immune phenotyping is of great value for diagnosis and staging. Liver, but not bone marrow involvement seems to be an adverse prognostic factor. Follicular lymphoma is an example of a dynamic tumour with gradual cellular changes associated with new and more malignant clinical signs.

Effects of retinoic acid, 1,25-dihydroxyvitamin D3, cytosine arabinoside and alpha-interferon on bone marrow cells from patients with myelodysplastic syndromes.

Bone marrow cells from 15 patients with myelodysplastic syndromes and 2 with acute myeloid leukemia were incubated in vitro with all-trans-retinoic acid (RA), 1,25-dihydroxy vitamin D3 (D3), cytosine arabinoside (ara-C) and alpha-interferon (IFN). 3H-thymidine incorporation (3H-TdR), differentiation and clonal growth were studied. D3 was found to be the most effective inducer of differentiation and differentiation was correlated with a decreased 3H-TdR. Differentiation with one of the inducers was significantly correlated to differentiation with any of the other inducers. Patterns of differentiation and spontaneous and D3-induced 3H-TdR were used to divide the patients into 3 different groups. In the first group, 5 patients with extremely low spontaneous 3H-TdR and differentiation in combination with a slightly increased 3H-TdR after induction differed from all other patients by a higher percentage of bone marrow blast and a more pronounced pancytopenia. The two other groups had a high spontaneous 3H-TdR but differed with respect to the D3-induced differentiation which was absent in one group (n = 6) and present in the other (n = 5). The two groups showed no difference in the clinical features.

Clonal analysis of the response of HL-60 cells to retinoic acid and vitamin D in the presence or absence of leukocyte-conditioned medium.

The capacity of retinoic acid (RA) and vitamin D to induce differentiation of HL-60 cells in an agar gel system that permits a high cloning efficiency was studied in the presence or absence of leukocyte-conditioned medium (LCM). Vitamin D was about 10 times more effective in inducing differentiation than RA. LCM significantly increased the differentiation-inductive capacity of both vitamins, although LCM did not have an effect of its own. During the first days of culture, the number of cells per clone increased with either vitamin or LCM alone as compared to control cultures. This suggests that cellular proliferation may be important in the initial phase of the differentiation induction. No synergy in this respect was found between RA and vitamin D in the presence or absence of LCM. Thus it is doubtful whether RA and vitamin D have a true synergistic effect on individual HL-60 cell differentiation as previously described in liquid cultures. Furthermore, the findings suggest that the process of differentiation induction regarding the growing cells in agar gel involves an all-or-none process. The data may also help elucide the observed relationship between the in vitro production of colony stimulating activity and favorable prognosis of AML.

Therapeutic effects of low-dose cytosine arabinoside, alpha-interferon, 1 alpha-hydroxyvitamin D3 and retinoic acid in acute leukemia and myelodysplastic syndromes.

62 evaluable patients with myelodysplastic syndromes (MDS) or acute leukemia were treated with different combinations of low dose ara-C, alpha-interferon (IFN), 1 alpha-hydroxyvitamin D3 (vit D3) and retinoic acid. The aim was to study the efficacy and toxicity of each combination. The overall rate was 44%. Of these, 50% responded favorably to the combination of IFN, vit D3 and retinoic acid (IDR), which was comparable to the response rate of 43% for low-dose ara-C. The results of the IDR treatment may be explained by additive or synergistic effects between the separate drugs in the combination. Ara-C and IDR treatment was generally well-tolerated but interferon gave more side effects than any other drug used in the study. Evaluation of the full combination of ara-C, IFN, vit D3 and retinoic acid was not possible because of toxicity. Marrow hypoplasia was infrequent (5/27 patients) in cases responding favorably to treatment. Complete remissions were not longer than partial remissions or significant responses.