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Biomedical subjects

N Williams

Publications and source records attributed to N Williams.

At least 307 records · Page 17Linked to original sources
PubMed1990

Recombinant interleukin 6 stimulates immature murine megakaryocytes.

Human recombinant interleukin 6 (IL-6) was found to stimulate the growth of immature mouse megakaryocytes maximally at 2 ng/ml, leading to significant increases in the number of large megakaryocytes readily detectable by light microscopy. IL-6 did not stimulate megakaryocyte progenitor cells to form colonies of megakaryocytes, but potentiated megakaryocyte colony formation when added in the presence of interleukin 3. The stimulation could be neutralized by an anti-IL-6 serum. The data indicate that IL-6 is a potent differentiation stimulus of megakaryocyte development in cell culture.

Animals↗
PubMed1990

The level of differentiation of megakaryocyte progenitors and the subsequent modulation of megakaryocyte antigens on developing colony cells.

Human megakaryocyte development was studied in cell culture by first determining the differentiation stage of the clonable progenitor cell population and then analyzing the kinetics of expression of two megakaryocyte antigens using an immunoalkaline phosphatase system. Studies on the expression of two antigens present on megakaryocytes but not detectable on platelets (Mk-A, Mk-B) revealed that Mk-A antigen was found on megakaryocytes in colonies of less than six to eight cells at early times of cell culture. By contrast, Mk-B antigen was detected only in large megakaryocytes starting day 7 of culture and observed primarily in colonies of greater than eight cells. These studies show that human megakaryocyte progenitors are among the more mature of the precursor classes and link the antigen A bearing megakaryocytes to the developmental sequence as the immediate progeny of the precursor population with limited mitotic capacity. Amplification of antigen B expression is late in the developmental process, being detected by this method on only large megakaryocytes in well-formed colonies after 7-9 days of culture.

Agar↗
PubMed1989

A placebo-controlled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn's disease.

We randomly assigned 71 patients with active chronic Crohn's disease who were resistant to or intolerant of corticosteroids to treatment with oral cyclosporine (5 to 7.5 mg per kilogram of body weight per day) or placebo for three months. Disease activity was assessed on a clinical grading scale without knowledge of the treatment given. At the end of the treatment period, 22 of the 37 cyclosporine-treated patients (59 percent) had improvement, as compared with 11 of the 34 placebo-treated patients (32 percent) (P = 0.032). During cyclosporine treatment, there was significant improvement in plasma orosomucoid levels (P = 0.0025) and the Crohn's Disease Activity Index (P = 0.00012). The effect of treatment became evident after two weeks. In the subsequent three months, during which the patients were gradually withdrawn from treatment, the improvement continued in 14 of the 37 patients (38 percent) in the cyclosporine group and in 5 of the 34 (15 percent) in the placebo group (P = 0.034). No serious adverse events were observed. We conclude that cyclosporine has a beneficial therapeutic effect in patients with active chronic Crohn's disease and resistance to or intolerance of corticosteroids.

Administration, Oral↗
PubMed1989

Topical delivery of liposomally encapsulated interferon evaluated in a cutaneous herpes guinea pig model.

The topical delivery of liposomally encapsulated interferon was evaluated in the cutaneous herpes simplex virus guinea pig model. Application of liposomally entrapped interferon caused a reduction of lesion scores, whereas application of interferon formulated as a solution or as an emulsion was ineffective. The method of liposomal preparation rather than the lipid composition of the bilayers appeared to be the most important factor for reducing lesion scores. Only liposomes prepared by the dehydration-rehydration method were effective. This finding implied that the dehydration and subsequent rehydration of the liposomes facilitate partitioning of the interferon into liposomal bilayers, where the drug is positioned for transfer into the lipid compartment of the stratum corneum. Liposomes do not appear to function as permeation enhancers but seem to provide the needed physicochemical environment for transfer of interferon into the skin.

Administration, Topical↗
PubMed1989

A new measure of health status for clinical trials in inflammatory bowel disease.

We have developed a measure of subjective health status (quality of life) for patients with inflammatory bowel disease (IBD). Ninety-seven patients with IBD described problems they had experienced as a result of the disease; the 32 most frequent and important items were included in the Inflammatory Bowel Disease Questionnaire (IBDQ). Sixty-one IBD patients were evaluated twice. One month separated the evaluations, at which disease activity indices, the IBDQ, and a number of other questionnaires were administered. Reproducibility studies in 19 stable patients showed improvement in scores, but also a small within-person standard deviation. Responsiveness studies revealed large changes in scores in patients who had improved or deteriorated and suggested that the IBDQ was more responsive than a general health status measure. Responsiveness appeared greater in patients with ulcerative colitis than in those with Crohn's disease. Predicted and observed correlations between changes in IBDQ score and changes in other measures were similar. We conclude that although further testing is required, particularly in examining the relation between changes in the IBDQ and changes in the activity of Crohn's disease, the IBDQ shows promise as a measure of health status for clinical trials in IBD.

Attitude to Health↗
PubMed1989

Multiple levels of regulation of megakaryocytopoiesis.

A working hypothesis for the regulation of megakaryocytopoiesis is described on the basis of current data. The hypothesis proposes that in vivo megakaryocytes are generated by 1) the expansion of clonable progenitor cells into immature megakaryocytes by locally produced (and regulated) interleukin-3 (IL-3) and 2) the development and maturation of immature megakaryocytes by a dual system; by a lineage specific mechanism involving thrombopoietic stimuli in the steady state and thrombocytopenic conditions, and by a lineage nonspecific mechanism via IL-3 in damaged or reconstituting marrow. The hypothesis predicts that if IL-3 is a significant in vivo regulator of megakaryocyte formation and development, receptor for IL-3 should be present on megakaryocytes and may be vestigially on platelets. Small but significant levels of 125I IL-3 were found to bind to platelets from normal mice. The level of binding on platelets was found to be enhanced sevenfold from mice that had received high levels of irradiation followed by bone marrow transplantation. This contrasted with a twofold increase in the level of binding to platelets from mice made acutely thrombocytopenic with antiplatelet serum. The data suggest that IL-3 may be involved in the in vivo regulation of murine megakaryocytopoiesis and may be a significant factor in rebound thrombopoiesis following bone marrow damage.

Animals↗
PubMed1989

In vivo effects of interleukin-1 alpha on regenerating mouse bone marrow myeloid colony-forming cells after treatment with 5-fluorouracil.

Injection of a single dose of recombinant human interleukin-1 alpha (r-hu-IL-1 alpha) into mice 24 hr after 5-fluorouracil (FU) treatment resulted in an increased rate of recovery of three types of colony-forming cells (CFCs) in the bone marrow. Myeloid progenitors with high proliferative potential (responsive to CSF-1 + IL-3 + IL-1 alpha), low proliferative potential (responsive to CSF-1), megakaryocyte progenitors, and total nucleated cells per femur increased up to 5-fold, 7-fold, 3-fold, and 3-fold, respectively, in a dose related fashion compared with the control FU treated marrows. The kinetics of FU kill and recovery of these CFCs are shown.

Animals↗
PubMed1989

The roles of factors from lung in murine megakaryocytopoiesis.

The roles of factors from mouse lung in stimulating murine megakaryocytopoiesis were examined. Conditioned medium from normal mice was found to contain interleukin 3 (IL-3) activity in addition to granulocyte-macrophage colony-stimulating factor (GM-CSF) and megakaryocyte potentiator (Mk-potentiator). The Mk-potentiator activity of mouse lung-conditioned medium (MLCM) was found to be immunologically distinct from IL-3. Biochemical separation of MLCM showed Mk-potentiator activity with an activity profile distinct from IL-3 and GM-CSF. When titrated, Mk-potentiator was the major activity enhancing megakaryocyte colony formation in MLCM. By contrast, at high concentrations of MLCM, all factors were present and may play a role in megakaryocyte colony growth and development.

Animals↗
PubMed1988

Quality of life in patients with inflammatory bowel disease.

To investigate the effect of inflammatory bowel disease (IBD) on the quality of life, we interviewed 43 patients with ulcerative colitis (UC) and 54 with Crohn's disease. Patients identified frequent and important problems in five areas. Primary bowel symptoms, systemic symptoms, and altered emotional function were common; functional and social impairment were less frequent. Systemic symptoms such as fatigue were more prevalent in patients with Crohn's disease. Apart from primary bowel complaints, patients seldom volunteered other facets of quality of life impairment; this was particularly true for impairment of emotional function. We conclude that despite troublesome intestinal and systemic symptoms, most patients with IBD avoid major disruption in work and personal lives. Physicians must inquire specifically about emotional problems relating to IBD; in particular, fear of surgery is important to address. Psychosocial interventions should be targeted to those patients with problems in this area.

Adult↗
PubMed1988

Concentration-effect relationships with carbamazepine and its epoxide on psychomotor and cognitive function in epileptic patients.

A battery of psychometric tests was administered to 85 patients with epilepsy, of whom 26 were untreated, 40 received carbamazepine monotherapy and 19 took carbamazepine with another anticonvulsant. Carbamazepine alone had little effect on performance, but carbamazepine polypharmacy produced significant impairment. Increasing concentrations of carbamazepine (four tests) and its active metabolite, carbamazepine 10,11 epoxide (seven tests), correlated with decreasing performance in the monotherapy patients.

Adult↗
PubMed1988

Primary tumours of the small intestine in Jamaica.

A review of 60 patients with primary small bowel tumours seen at the University Hospital, Jamaica, during the 15 year period 1971-1985, revealed that adenocarcinoma was the commonest tumour (27%), followed by smooth muscle tumour (23%), and carcinoids (11%). There were 32 malignant and 28 benign tumours. The mean age at presentation was 56 years, with a range of 4 to 85 years. The most common clinical presentation was intestinal obstruction, followed by pain, weight loss, abdominal mass and intussusception. In the majority of patients the diagnosis was not made preoperatively, and 80% with adenocarcinoma had lymph node metastases. Increased awareness of the diagnosis in symptomatic patients may result in improved survival.

Adenocarcinoma↗
PubMed1987

Mitochondrial ATP synthase: dramatic Mg2+-induced alterations in the structure and function of the F1-ATPase moiety.

The ATPase activity of the F1 moiety of rat liver ATP synthase is inactivated when incubated prior to assay at 25 degrees C in the presence of MgCl2. The concentration of MgCl2 (130 microM) required to induce half-maximal inactivation is over 30 times higher than the apparent Km (MgCl2) during catalysis. Moreover, the relative efficacy of divalent cations in inducing inactivation during prior incubation follows an order significantly different from that promoting catalysis. Inactivation of F1-ATPase activity by Mg2+ is accompanied by the dramatic dissociation from the F1 complex of alpha subunits and part of the gamma-subunit population. The latter form a precipitate while the beta, delta, and epsilon subunits, and the remaining part of the gamma-subunit population, remain soluble. Dissociation is not a sudden "all or none" event but parallels loss of ATPase activity until alpha subunits have almost completely dissociated together with about 50% of the gamma-subunit population. Mg2+-induced loss of F1-ATPase activity cannot be prevented by including either the hydrolytic substrates ATP, GTP, or ITP in the incubation medium or the product ADP. Ethylenediaminetetraacetic acid, mercaptoethanol, and dithiothreitol are also ineffective in preventing loss of ATPase activity. Significantly, KPi at high concentration (greater than or equal to 200 mM) is effective in partially protecting F1 against inactivation. However, the most effective means of preventing Mg2+-induced inactivation of F1-ATPase activity is to rebind F1 to its F0 moiety in F1-depleted particles. When bound to F0, F1 is protected completely against divalent cation induced inactivation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Ligand binding studies of the F1 moiety of rat liver ATP synthase: implications about the enzyme's structure and mechanism.

F1-ATPase of rat liver was examined for its capacity to interact with both metal ions and nucleotides and for the effect of covalent ATPase inhibitors on these interactions. As isolated, rat liver F1 contains about 2 mol of Mg2+/mol of F1, 1 mol of which can be removed or exchanged. The remaining mole of Mg2+ per mole of F1 remains very tightly associated with F1 and is recovered in the alpha gamma fraction after cold denaturation. Rat liver F1 also contains as isolated a nearly equivalent amount of nucleotide (approximately 1.7 mol/mol of F1) which is readily removed by incubation at room temperature followed by column centrifugation. The "2 Mg2+ enzyme" binds almost 3 mol of 5'-adenylyl imidodiphosphate (AMP-PNP)/mol of F1 in the presence or absence of added divalent cation. When divalent cation is present as Co2+, an equivalent activator to Mg2+ in the ATPase reaction, 1 mol of F1 binds 3 mol of both AMP-PNP and Co2+. under these conditions, the very tight Mg2+ site remains loaded, the exchangeable Mg2+ site is replaced with AMP-PNPCo, and two additional AMP-PNPCo sites are filled. At this point, ADP can be loaded onto the enzyme as a fourth nucleotide at a site separate and distinct from the AMP-PNP sites. Significantly, rat liver F1 contains only a single readily detectable ADP binding site in the presence or absence of divalent cation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1987

Haemopoietic growth factors stimulating murine megakaryocytopoiesis: interleukin-3 is immunologically distinct from megakaryocyte-potentiator.

The biological and immunological properties of stimulators of in vitro murine megakaryocytopoiesis were studied using a heterologous anti-interleukin 3 (IL-3) serum. All megakaryocyte colony development was inhibited with the antiserum using three sources of IL-3, including WEHI-3 cell conditioned medium (WEHI-3CM), pokeweed mitogen-spleen conditioned medium (PWM-SCM) and recombinant IL-3. The data indicate that IL-3 is an absolute requirement for murine megakaryocyte colony development in this system. By comparison the antiserum abolished all myeloid colony growth stimulated by WEHI-3CM, but not PWM-SCM. The in vitro development of single megakaryocytes stimulated by a second putative growth factor, megakaryocyte-potentiator, was not inhibited by the antibody. The antiserum precipitated a 26 kd molecular weight protein from a radioiodinated sample of IL-3. No crossreactivity by the antiserum with other colony-stimulating factors (CSF) including CSF-1 and granulocyte-macrophage CSF was observed. The data indicates that IL-3 and megakaryocyte-potentiator are immunologically unrelated and provides further support that the two factors are separate molecules.

Acetylcholinesterase↗
PubMed1987

Effects of auranofin and other antirheumatic drugs on human myelopoiesis in vitro.

Leukopenia is one of the more serious side effects of auranofin (AF) therapy for rheumatoid arthritis. AF and its deacetylated form inhibited the development of macrophage and granulocytic colonies from progenitor cells in human bone marrow even at concentrations less than or equal to 10(-9)M. The disease suppressive activity of AF could result in part from the reduction of cell numbers in arthritic lesions and our findings provide a mechanism for this possibility. In contrast, other slow acting antirheumatic drugs, sulfasalazine, chloroquine and hydroxychloroquine, show partial inhibition of colony development but at concentrations of the order of 10(-5)M.

Anti-Inflammatory Agents↗