Imaging features of myxoid soft-tissue tumours.

Myxoid soft-tissue tumours are mesenchymal neoplasms, which are characterised by the production of abundant extracellular myxoid matrix. Imaging plays an important role in the diagnosis of these tumours as well as treatment planning. The imaging features as well as the clinical course for these lesions are highly variable, depending on both the anatomical location of the tumour and the histopathological subtype. This article, illustrated by histopathologically proven cases from our tertiary referral soft-tissue sarcoma centre, reviews the spectrum of imaging findings and characteristic signs seen with different types of benign and malignant myxoid soft-tissue neoplasms.

Regulatory mechanisms of calcineurin phosphatase activity.

Calcineurin (protein phosphatase 3, Cn) is best known for its central position in Ca(2+)-dependent T-cell signaling. Interest in calcineurin has, however, conserved its momentum as new Ca(2+)-dependent pathways have been steadily surfacing in several other cell types, such as brain, heart, skin cells and beta pancreatic cells, and Cn appears to serve as a central controller of stress, immune response, and cellular proliferation and differentiation. Calcineurin is the principal target of the immunosuppressive drugs cyclosporin A (CsA) and tacrolimus (TRL). Therapy based on these immunosuppressants has markedly reduced the incidence of transplant rejection in allograft recipients. In addition, these drugs have proven very useful for patients suffering from chronic inflammatory skin conditions. Unfortunately, their application is somewhat limited by a broad spectrum of toxic side-effects, affecting several organ systems. This calls for enhancements in the design of this class of immunosuppressants. An intricate constellation of regulatory systems allows for precise modulation and adaptation of calcineurin activity in vivo. The last few years have been very fruitful in elucidating several long-standing issues regarding the binding patterns of substrates and inhibitors to Cn. This new knowledge may enable more precise manipulation of the Ca(2+)-calcineurin pathway in the near future, preferably targeted towards one specific substrate or cell system. In this review, we will discuss the factors and mechanisms underlying calcineurin activity regulation and their exploitation in recent approaches towards better immunosuppressants.

Peripheral T cell lymphoma: The Sheffield Lymphoma Group experience (1977-2001).

Peripheral T-cell lymphomas (PTCL) account for approximately 10% of all non-Hodgkin's lymphomas. The aim of this retrospective study was to analyse the presentation, management, outcome and significant prognostic factors in a large series of patients with PTCL. It includes 104 consecutive patients who presented to the Sheffield Lymphoma Group between 1977 and 2001. Clinical parameters were recorded for each subgroup. End points were response to treatment and survival. Survival analysis was used to assess the prognostic value of the variables. PTCL not otherwise specified contributed 52% of cases followed by anaplastic large cell lymphoma with 17% and angiocentric type with 13% of cases. The overall complete remission (CR) of the series was 59%. Stage at diagnosis affected response to treatment with 81% of cases in stage 1 and 2 achieving CR compared to 43% in stages 3 and 4 (p60 years (p<0.05), high grade histology (p<0.001), presence of B symptoms (p<0.005), nodal presentation (p<0.005) and advanced stage at diagnosis (p<0.001). Histological sub-type did not significantly correlate to outcome. In conclusion whilst a number of prognostic indicators can assist in determining the outcome in PTCL, these lymphomas are complex and often follow an unpredictable course. In order to make the best clinical decisions in individual cases, more clinical study is required.

Dry powder dosing in liquid vehicles: ocular tolerance and scintigraphic evaluation of a perfluorocarbon suspension.

The ocular tolerance and precorneal disposition of 99mTc-labelled sterile carbon-perfluorodecalin (PFD) and carbon-aqueous suspensions were examined in a cohort of healthy volunteers. Formulations were prepared in PFD or saline using charcoal particles, radiolabelled with [99mTc]diethylenetriaminepentaacetic acid (DTPA) under GMP conditions. Colloidal silicon dioxide was used as a suspending agent. Ocular tolerance was examined following the instillation of each formulation to the eyes of 12 volunteers. The precorneal distribution of both formulations in man was monitored using gamma scintigraphy. Dynamic and static data acquisitions were taken over a period of 150 min after dosing. Carbon particulates suspended in PFD did not show any irritation to the eye. Administration of PFD formulation in man produced a significant increase in ocular retention over a saline formulation (mean residence time (MRT)=157+/-42 and 0.29+/-0.08 min, respectively, P=0.0001). Distribution of the carbon in man followed the same pattern as in a previous reported study in animals. The carbon deposited uniformly along the lid margin in the case of the PFD vehicle, whereas it agglomerated following dosing in the saline vehicle and was ejected from the eye. The novel non-aqueous vehicle system is able to significantly improve the ocular retention of charcoal particles in man and provides a unique distribution of the particles in the eye, which suggests a potential for the PFD system for the treatment of periocular diseases.

Intragastric distribution of ion-exchange resins: a drug delivery system for the topical treatment of the gastric mucosa.

Previous studies by this group on freeze-dried oral dosage forms containing finely-divided ion-exchange resins revealed prolonged gastric residence and uniform distribution within the stomach. The present study was carried out to ascertain whether this was due to freeze-drying, properties of the radiolabelled ionic exchange resin, or the small dosing volume used. 99mTc-labelled cholestyramine resin was administered in two dosage forms, a freeze-dried tablet which dissolved in the oral cavity (orally dissolving tablet; ODT) and a 1.5 mL aqueous suspension. Two resin particle sizes (20-40 and 90-125 microns) were studied. Oesophageal transit and intragastric distribution and residence were followed by gamma scintigraphy. In a second study, in six subjects, gastric emptying of the water-soluble fraction of the ODT and 1.5 mL of water, was measured using 99mTc diethylenetriaminepentaacetic acid. Oesophageal transit of a water-soluble marker and resin in suspension was rapid, but the transit of the resin in the ODTs was significantly prolonged. Regardless of particle size or dosage form, the resin was evenly distributed throughout the stomach with 20-25% remaining for 5.5 h. In contrast, the water-soluble marker cleared from the stomach rapidly from both dosage forms. We suggest that oral dose forms containing finely-divided ion-exchange resins may form a useful system for topical treatment of the gastric mucosa, for example in targeting to Helicobacter pylori infection.

Phagocytic defects--monocytes/macrophages.

Mononuclear phagocytes originate from stem cells in the bone marrow which differentiate from monoblasts into promonocytes, then into circulating blood monocytes. Subsequently the monocytes can develop into macrophages and reside in a variety of tissues. Mononuclear phagocytes have cell surface receptors for a variety of substances (e.g., IgG, complement components, fibronectin, and sugars) and are capable of secreting a number of mediators (enzymes, complement components, coagulation components, and monokines). The tissue macrophages adapt to their environment and express unique differentiated functions that are related to various anatomic sites and organs (e.g., Kupffer cells, pulmonary alveolar macrophages, osteoclasts, microglia). Macrophages have the capacity to become "activated" by both specific and nonspecific immunologic stimuli and the "activated" macrophage has enhanced functional capabilities (e.g., tumoricidal, microbicidal, phagocytosis, secretion of mediators). Abnormal monocyte/macrophage function may be acquired or may be due to genetic or developmental disorders. Because of their central role in host defense (in inflammatory responses, in antigen presentation, and in immunoregulatory networks), monocyte/macrophage dysfunction may result in one or more pathophysiologic consequences: defects in monocyte maturation, deficiencies in the clearance of physiologic substrates in lysosomal diseases (e.g., Gaucher's disease, mucopolysaccharidoses, osteopetrosis, metachromatic leukodystrophy), decreased synthesis and secretion of mediators (complement component deficiencies), defects in microbicidal activity (chronic granulomatous disease) and defects which are acquired following infection and during chemotherapy (e.g., acquired immune deficiency syndrome).

The use of newspaper data in historical earthquake studies.

Studies of historical British earthquakes are an essential component of assessing seismic hazard in the U.K.; such studies rely heavily on macroseismic data obtained from printed newspapers. This paper discusses the ways in which newspapers have reported British earthquakes and the nature and limitations of the data that may be acquired from this source. Historical changes in the press as a source of macroseismic data are discussed. It is suggested that an understanding of the background and nature of newspaper data is an important component in the process of revaluating historical earthquakes from such data.

Susceptibility of Propionibacterium acnes to killing and degradation by human neutrophils and monocytes in vitro.

Propionibacterium acnes, the target of inflammation in acne, was tested for its sensitivity to the bactericidal and degradative functions of human polymorphonuclear leukocytes (PMN), monocytes, and their fractions. P. acnes strains were not killed by PMN under any conditions and were variably killed by monocytes in the presence of serum from acne patients. Control strains of Staphylococcus aureus and Micrococcus lysodeicticus were susceptible to both PMN and monocyte killing. P. acnes strains were also not killed by lysozyme, chymotrypsin, H2O2, human serum, PMN granule lysate, and PMN and monocyte cell lysates. The organism was sensitive to the bactericidal activity of myeloperoxidase in acid pH. In addition, P. acnes was shown to be relatively resistant to the degradative action of PMN and monocyte lysates, whereas M. lysodeicticus, S. aureus, and Staphylococcus epidermidis were all degraded to various degrees. The moieties that were liberated from P. acnes by PMN enzymes were predominantly low in molecular weight (1,000 to 25,000) and were consistent with cell wall fragments.

Resolution of pulmonary inflammation.

Mononuclear phagocytes are suggested to play a major orchestrating role in the resolution of inflammatory processes in the lung. Particular emphasis is placed on their participation in the progression from a lesion with neutrophils as the dominant infiltrating cell to one that contains macrophages, on the macrophage's role in removing neutrophils and cell debris, and on their promotion of repair mechanisms. It is suggested that monocytes must mature into macrophages before they are capable of active participation in the resolution of inflammation.

Production of growth factor activity for fibroblasts by human monocyte-derived macrophages.

Macrophages, derived from human monocytes by in vitro culture, released a growth factor for rabbit lung fibroblasts. The release of growth factor was increased following stimulation with both soluble (lipopolysaccharide and phorbol myristate acetate) and particulate (opsonized zymosan) substances. Production of the growth factor activity was dependent on the length of time the monocytes were in culture, the presence of serum during the period of monocyte maturation, and macrophage protein synthesis. The inability of serum-deprived monocytes to produce growth factor could be reversed by adding back serum. Eicosatetraynoic acid and dexamethasone but not indomethacin inhibited the production of growth factor suggesting that arachidonic acid metabolites other than prostaglandins may regulate growth factor production.

Functional and biochemical studies of multinucleated giant cells derived from the culture of human monocytes.

We compared phagocytic and metabolic activities of multinucleated giant cells (MGC) and macrophages derived from human monocytes after 9-14 d in culture. Phagocytosis of sheep erythrocytes (E) coated with IgG, of E coated with IgM and complement, and of Candida albicans was comparable in MGC and macrophages. The same percentage of ingested fungi was killed by MGC (24 +/- 4%) and macrophages (21 +/- 5%). Approximately 70% of MGC and macrophages exhibited superoxide-dependent reduction of nitroblue tetrazolium during stimulation. Ia antigen was present on approximately 75% of both cell types. Analysis of cell populations separated by nuclear fluorescence indicated that beta-glucosaminidase, acid phosphatase, and beta-glucuronidase activity per cell was higher in MGC, but specific activity of these enzymes was greater in macrophages. These results suggest that MGC have the capacity to function like macrophages in host defense against infection.

Human serum induces maturation of human monocytes in vitro. Changes in cytolytic activity, intracellular lysosomal enzymes, and nonspecific esterase activity.

The dependence of human monocyte maturation in vitro on autologous serum was examined. If autologous serum was present during the monocyte culture, cytolysis of K562 target cells increased, intracellular levels of three lysosomal enzymes increased, and the fluoride-inhibitable esterase staining of the monocytes changed into a fluoride-resistant esterase stain (characteristic of more mature extravascular mononuclear phagocytes). Monocytes cultured in the presence and in the absence of serum also assumed different shapes. All of these changes were dependent on the concentration of autologous serum present (0-10%) and the length of time the monocytes were in culture (0-7 days). Lack of development by monocytes cultured in the absence of serum was not due to a general loss of the ability of these cells to function, because phagocytosis of antibody-coated erythrocytes was not lost following 7 days in culture in the absence of serum.

Contact with specific surfaces stimulates the production of the second component of complement (C2) in human peripheral blood monocytes via a lymphocyte factor.

Whole mononuclear cells plated on surfaces coated with the polymer, poly (2-hydroxyethyl methacrylate) (poly-HEMA) produced significantly less C2 when compared to production by cells on tissue culture plastic dishes. The reduction in C2 production was dependent on the amount of poly-HEMA used to coat the dishes and was not due to nonspecific damage of the cells or effects of the poly-HEMA on the hemolytic activity of C2. T and B lymphocytes, but not monocytes, plated on tissue culture plastic produced a soluble factor that increased the production of C2 in freshly adherent monocytes. Lymphocytes plated on the poly-HEMA surface did not produce this soluble factor, which was termed surface-dependent factor (SDF). Whole mononuclear cells plated on poly-HEMA were able to respond to SDF by increasing C2 production by the same percentage as cells on the tissue culture plastic. This suggested that the primary basis for the decreased production of C2 by monocytes in the whole mononuclear cells plated on the poly-HEMA was decreased production of SDF by the lymphocytes. The effect of the poly-HEMA surface on C2 production was probably related to a generalized alteration in maturation of monocytes into macrophages, for SDF had the same type of effect on beta-glucosaminidase levels in monocytes as seen with C2, except that the magnitude of the effect was less. These studies suggest that interaction of lymphocytes with surfaces may modulate the function of the lymphocytes. In addition, interaction of lymphocytes with surfaces and the production of SDF in vivo may be responsible for enhancing maturation of monocytes in tissues.

Protein synthesis-dependent and protein synthesis-independent secretion of lysosomal hydrolases from rabbit and human macrophages.

Rabbit alveolar macrophages and human monocyte-derived macrophages released lysosomal enzymes in response to a variety of stimuli. The release of these enzyme appeared to be under the control of at least two distinct mechanisms. The first involved a rapid release of preformed granule constituents in response to a phagocytic load. This release reaction was concentration- and time-dependent, was not affected by the protein synthesis inhibitors cycloheximide and puromycin, and resulted in a concomitant loss in intracellular enzyme levels. The second mechanism involved a prolonged secretion in response to lower concentration of stimuli, which increased with time, and was inhibited by cycloheximide and puromycin. The secretion did not result in the loss of intracellular enzyme stores; rather an induction of enzyme was seen following such stimulation, which resulted in increases in the total concentration within the cultures. This protein synthesis-dependent secretion of acid hydrolases from human macrophages varied for each lysosomal hydrolase and each stimulus. beta-Glucosaminidase synthesis and secretion was induced by low-dose opsonized zymosan, by latex particles, and by formaldehyde-treated SRBC. However, only the last mentioned stimulus caused release of acid phosphates although all three particles induced synthesis of the enzyme. None of the stimuli at these concentrations (10:1 particle to cell ratio) caused the release of beta-glucoronidase, although the enzyme was releasable if higher stimulus concentrations were used. In addition the enzyme was not inducible under these conditions. It is concluded that each of the acid hydrolases studied may be under different control in the human macrophage and that the cells may respond in a qualitatively different way to different types of phagocytosable stimuli.