Hematopoiesis occurs in close association with a complex network of cells loosely termed the hematopoietic microenvironment. Analysis of the mechanisms of microenvironmental regulation of hematopoiesis has been hindered by the complexity of the microenvironment as well as the heterogeneity of hematopoietic stem cells and early progenitor cells. We have established immortalized primate bone marrow-derived stromal cell lines to facilitate analysis of the interactions of hematopoietic cells with the microenvironment in a large animal species. One such line, PU-34, was found to produce a variety of growth factors, including an activity that stimulates the proliferation of an interleukin 6-dependent murine plasmacytoma cell line. A cDNA encoding the plasmacytoma stimulatory activity was isolated through functional expression cloning in mammalian cells. The nucleotide sequence contained a single long reading frame of 597 nucleotides encoding a predicted 199-amino acid polypeptide. The amino acid sequence of this cytokine, designated interleukin 11 (IL-11), did not display significant similarity with any other sequence in the GenBank data base. Preliminary biological characterization indicates that in addition to stimulating plasmacytoma proliferation, IL-11 stimulates the T-cell-dependent development of immunoglobulin-producing B cells and synergizes with IL-3 in supporting murine megakaryocyte colony formation. These properties implicate IL-11 as an additional multifunctional regulator in the hematopoietic microenvironment.

Background-Life stress contributes to symptom onset and exacerbation in the majority of patients with irritable bowel syndrome (IBS) and functional dyspepsia (FD); research evidence is conflicting, however, as to the strength of these effects. Aims-To test prospectively the relation of chronic life stress threat to subsequent symptom intensity over time. Patients-One hundred and seventeen consecutive outpatients satisfying the modified Rome criteria for IBS (66% with one or more concurrent FD syndromes) participated. Methods-The life stress and symptom intensity measures were determined from interview data collected independently at entry, and at six and 16 months; these measures assessed the potency of chronic life stress threat during the prior six months or more, and the severity and frequency of IBS and FD symptoms during the following two weeks. Results-Chronic life stress threat was a powerful predictor of subsequent symptom intensity, explaining 97% of the variance on this measure over 16 months. No patient exposed to even one chronic highly threatening stressor improved clinically (by 50%) over the 16 months; all patients who improved did so in the absence of such a stressor. Conclusion-The level of chronic life stress threat predicts the clinical outcome in most patients with IBS/FD. (Gut 1998;43:256-261) Keywords: irritable bowel syndrome; chronic life stress threat; symptom intensityIn irritable bowel (IBS) and functional dyspepsia (FD) syndromes, major life stress situations precede onset and/or exacerbation of symptoms, 1-3 and early observations suggest that symptoms either disappear or improve following resolution of major life stress problems. 4 Furthermore, an impressive and sustained improvement in symptoms occurs following the acquisition of more eVective stress management skills.5-7 In a recent study of patients with functional gastrointestinal disorders (FGID), 8 we showed a significant correspondence between the intensity of chronic life stress threat and the severity and extent of aVective, gastrointestinal, and extraintestinal symptomatology, particularly in patients with IBS-FD syndromes. Despite these observations, the extent to which life stress contributes to the course of IBS and/or FD symptoms remains uncertain. 10To extend our previous cross sectional findings, our aim was to examine, in patients with IBS, group and individual patterns of change in life stress and symptom intensity over time. Specifically we aimed to determine within subject: (1) covariance of life stress and subsequent symptom intensity over three time frames; (2) time lag relations (with and without relevant covariates); (3) the role of personality, age, sex, and emotional distress in the above; (4) the life stress predictors of any improvement or lack of improvement in symptom intensity over time; and (5) the life stress predictors of clinical (50% or more) improvement or no clinical improvement in symptom intensity over time. We hypothesised that: (1) life stress and subsequent symptom intensity will...

Leukaemia inhibitory factor (LIF) is a cytokine that induces macrophage differentiation of the murine M1 myeloid leukaemia cell line. We have isolated a cDNA clone encoding a novel human haemopoietic growth factor, human interleukin for DA cells (HILDA) that supports the proliferation of the murine interleukin-3-dependent leukaemic cell line, DA-la (refs 3-5). HILDA proved to be identical to LIF. The demonstration that the differentiation factor LIF will also serve as a growth factor for at least one myeloid leukaemic cell line provides further evidence that the distinction between growth-promoting and differentiation-inducing activities are largely determined by the target cell type.

Anabasum is a synthetic analog of Δ8‐tetrahydrocannabinol (THC)‐11‐oic acid that in preclinical models of experimental inflammation exerts potent anti‐inflammatory actions with minimal central nervous system (CNS) cannabimimetic activity. Here we used a novel model of acute inflammation driven by i.d. UV‐killed E. coli in healthy humans and found that anabasum (5 mg) exerted a potent anti‐inflammatory effect equivalent to that of prednisolone in terms of inhibiting neutrophil infiltration, the hallmark of acute inflammation. These effects arose from the inhibition of the neutrophil chemoattractant LTB4, while the inhibition of antiphagocytic prostanoids (PGE2, TxB2, and PGF2α) resulted in enhanced clearance of inflammatory stimulus from the injected site. Anabasum at the higher dose of 20 mg possessed the additional properties of triggering the biosynthesis of specialized pro‐resolving lipid mediators including LXA4, LXB4, RvD1, and RvD3. Collectively, we demonstrate for the first time a striking anti‐inflammatory and pro‐resolution effects of a synthetic analog of THC in healthy humans.

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People with cancer and major depression report a wide variety of problems that include, but go beyond concerns about, both cancer and depression. The large number of problems related to concerns about other people's well-being and difficulties in interpersonal relationships, stresses the importance of these topics to patients and should be given more weight in the assessment and management of depressed cancer patients.

There is increasing national and international interest in overprescribing and polypharmacy, and the burden that the inappropriate use of multiple medicines can place on individual patients and on society as a whole. This paper explores the challenges faced by prescribers and pharmacists wishing to reduce polypharmacy, including the uncertainties about the risks and benefits of continuing or stopping individual drugs. We discuss the factors influencing us to prescribe—which may lead to overprescribing—including the increasing number of guidelines, perceived patient pressure and advertising. We offer a critical appraisal of the tools currently available to clinicians and pharmacists aiming to rationalise medicines, and finally a systems‐wide approach to improving overprescribing and problematic polypharmacy.

There is an increasing awareness that polypharmacy – the use of multiple medicines by one individual – may bring harm as well as benefit. This has been termed ‘problematic polypharmacy’ and is associated with increased risk of admission to hospital, decreased quality of life and psychological harm. This article addresses the factors that may be contributing to the global rise of polypharmacy (the whys), the problems it can cause (the so whats), and some opportunities and strategies for improving and avoiding problematic polypharmacy in the future (the what nexts).