Clinical application of [18F]FDG PET/CT in follicular lymphoma.

The objective of the present paper was to review the clinical application of [18F]FDG PET/CT in follicular lymphoma (FL). Once it was clear that, despite it is characterized as indolent, this type of lymphoma usually shows a high [18F]FDG avidity, PET/CT became more important and it's now considered the standard technique in staging, re-staging and response evaluation. Many studies have shown its impact on the management of patients (as it can change the stage in a significant proportion of cases and lead to treatment modifications), its superiority over CT (mainly because it's able to distinguish fibrosis in residual masses from viable tumor) and its prognostic value. The latter was initially associated only to the degree of metabolic response, which has proved to be a strong and independent predictive factor in terms of disease-free survival (DFS) and overall survival (OS). Thus, a negative PET/CT scan could be considered a guarantee in high-tumor-burden follicular lymphoma patients. However, semiquantitative parameters such as metabolic tumor volume or total lesion glycolysis, may also provide useful information and help us to identify patients with poor prognosis, guiding a risk-adjusted management and follow-up.

Effects of furocoumarins from Cachrys trifida on some macrophage functions.

Phytochemical and biological studies aimed at the discovery and development of novel antiinflammatory agents from natural sources have been conducted in our laboratory for a number of years. In this communication, three naturally occurring furocoumarins (imperatorin, isoimperatorin and prantschimgin) were evaluated as potential inhibitors of some macrophage functions involved in the inflammatory process. These furocoumarins have been tested in two experimental systems: ionophore-stimulated mouse peritoneal macrophages serve as a source of cyclooxygenase-1 and 5-lipoxygenase, and mouse peritoneal macrophages stimulated with E. coli lipopolysaccharide are the means of testing for anti-cyclooxygenase-2 and nitric-oxidesynthase activity. All above-mentioned furocoumarins showed significant effect on 5-lipoxygenase (leukotriene C4) with IC50 values of < 15 microM. Imperatorin and isoimperatorin exhibited strong-to-medium inhibition on cyclooxygenase-1- and cyclooxygenase-2-catalysed prostaglandin E2 release, with inhibition percentages similar to those of the reference drugs, indometacin and nimesulide, respectively. Of the three furocoumarins, only imperatorin caused a significant reduction of nitric oxide generation. Imperatorin and isoimperatorin can be classified as dual inhibitors, since it was evident that both cyclooxygenase and lipoxygenase pathways of arachidonate metabolism were inhibited by these compounds. However, selective inhibition of the 5-lipoxygenase pathway is suggested to be the primary target of action of prantschimgin.

Experimental reproduction of winter dysentery in lactating cows using BCV -- comparison with BCV infection in milk-fed calves.

Infection models were developed for adult cows and for young calves using the same strain of bovine coronavirus (BCV), which for the first time allows experimental reproduction of winter dysentery (WD) in seronegative lactating cows. The cattle were infected through direct contact with an experimentally inoculated calf. All experimental cattle shed faecal BCV with development of diarrhoea, being profusely watery with small amounts of blood in the most severely affected animals, including both cows and calves. The cows, in contrast to the calves, showed depressed general condition and appetite leading to a marked decrease in milk yield. Further age-associated differences were a shorter incubation period in the two youngest calves, but with milder fever and milder decrease in white blood cell counts. These findings shed light on the apparent epidemiological differences between WD and calf BCV diarrhoea suggesting that, (1) the same strains of BCV cause natural outbreaks of calf diarrhoea and WD, (2) seronegative cows are more severely affected by the infection than seronegative conventionally reared calves, and (3) unaffected general condition in diarrhoeic calves may lead to underestimation of the occurrence of calf diarrhoea in WD outbreaks. In response to infection, all cattle produced early interferon type 1 in serum and, except for one calf, in nasal secretions. A finding not previously reported is the detection of interferon type 1 responses in bovine milk. All cattle developed high IgM antibody responses and long-lasting IgA antibody responses both systemically and locally. The serum IgM antibody responses came earlier in most of the calves than in the cows. Prolonged IgM antibody responses were detected in serum and milk, while those in nasal secretions were much shorter. BCV-specific IgA was present in nasal secretions from all cattle throughout the 6 months follow-up. The IgA antibody response in serum was detected up to 17 months post-infection and the duration showed an age-related variation indicating a more prominent IgA memory in the adult cattle and in the older calves than in the younger ones. BCV-specific IgG was detected in all cattle during the experimental period of up to 22 months. In conclusion, WD was reproduced in seronegative lactating cows. The cows showed a more severe general diseases than seronegative calves infected concurrently. Very long-lasting IgA antibody responses were detected both systemically and locally.

Effects of six diterpenes on macrophage eicosanoid biosynthesis.

Six diterpenes (three clerodanes, two abietanes and one rosane) were tested for interactions with the cyclooxygenase and 5-lipoxygenase pathways of arachidonate metabolism and for effects of nitric oxide production. Two abietane diterpenes, aethiopinone and 11,12-dihydroxy-6-oxo-8,11,13-abietatriene and the rosane lagascatriol showed a remarkable effect on COX-1 pathway of PGE2 release in calcium ionophore A23187-stimulated peritoneal macrophages. Only the two latter diterpenes showed inhibition on COX-2 pathway of PGE2 release in E. coli LPS-stimulated peritoneal macrophages. In addition, all compounds assayed were inhibitors of LTC4 release with IC50 < or = 10 microM. Clerodane diterpenes were inactive in COX assay. None of the diterpenes assayed, except 11,12-dihydroxy-6-oxo-8,11,13-abietatriene, affected NO production. The results obtained suggest that the cellular mechanisms of action of some of these substances may involve inhibition of cyclooxygenase/lipoxygenase pathways and nitric oxide production.

In vitro anti-inflammatory activity of iridoids and triterpenoid compounds isolated from Phillyrea latifolia L.

Two iridoids, oleuropeoside and ligustroside, and two triterpenoid compounds, oleanolic acid and ursolic acid, have been isolated from the leaves of Phillyrea latifolia L. (Oleaceae). These compounds were tested for interactions with the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways of arachidonate metabolism in calcium ionophore-stimulated mouse peritoneal macrophages and human platelets, and for their effect on cell viability. Structure-activity relationships obtained for in vitro screening results were discussed. These compounds are capable of exerting inhibitory actions on enzymes of the arachidonate cascade. All compounds assayed showed a significant effect on prostaglandin E2 (PGE2)-release, with inhibition percentages similar to the reference drug indomethacin (IC50 = 0.95 microM). The IC50 values of the active compounds are: oleuropeoside 47 microM, ligustroside 48.53 microM, oleanolic acid 23.51 microM and ursolic acid 60.91 microM. In the leukotriene C4 (LTC4)-assay, only oleanolic acid showed a significant effect (IC50 = 16.79 microM). We also investigated the action of compounds on thromboxane B2 (TXB2)-release induced by calcium ionophore in human platelets. Of all the tested compounds, only ligustroside (IC50 = 122.63 microM) and ursolic acid (IC50 = 50.21 microM) showed a significant effect, although with less potency than the reference drug ibuprofen (IC50 = 1.27 microM). Thus, our compounds possess an array of potentially beneficial anti-inflammatory properties which may, alongside other constituents, contribute to the claimed therapeutic properties of the plant from which they are derived.

Capture ELISA systems for the detection of bovine coronavirus-specific IgA and IgM antibodies in milk and serum.

Isotype-capture ELISAs for BCV-specific IgA and IgM were developed and tested on milk and serum samples from Swedish cattle. The capture ELISAs showed higher sensitivity than indirect ELISAs for detection of BCV-specific IgA and IgM. In the capture ELISAs the agreement between detection in milk and serum samples was 94% for IgA and 86% for IgM. The correlation between log(10) titres in milk and serum was r=0.82 (P<0.001) for IgA and 0.84 (P<0.001) for IgM. Milk seemed a better target than serum for diagnosing specific IgA at low levels. There was no variation in the isotype-specific BCV antibody titres between healthy quarters of the same udder, but subclinical mastitis was associated with higher levels of IgA antibodies and weak false IgM positive reactions in undiluted milk. Bovine IgA and IgM antibodies in milk and serum showed high stability towards freezing and thawing and storage at room temperature. The antibody responses to BCV were followed in milk and serum from six dairy cows and in serum from four calves for a period of 1 year after an outbreak of winter dysentery (WD). In this outbreak some animals became reinfected with BCV. The IgA and IgM capture ELISAs differentiated between primarily BCV infected and reinfected animals. In the primarily infected cattle, IgM antibodies were first detected in milk and serum four to nine days after the first WD symptoms observed, and were subsequently detected for at least 2-3 weeks. IgM was also detected in the reinfected cows, but mostly at lower levels and for a shorter period of time than in the primarily infected animals. In milk, however, the IgM response of the reinfected cows was detected for a longer period of time than in serum. Six months after the outbreak, IgA was still detected in both serum and milk of all six cows and also in serum of one calf. The reinfected cows showed higher and more long-lasting peak levels of IgA in milk and serum than the primarily infected cows, indicating boosting of the IgA response.

Inhibition of prostaglandin E2 and leukotriene C4 in mouse peritoneal macrophages and thromboxane B2 production in human platelets by flavonoids from Stachys chrysantha and Stachys candida.

Seven flavonoids of Stachys chrysantha and Stachys candida have been isolated. The structures of the compounds were elucidated by spectroscopic methods, particularly highfield NMR spectroscopy. The effects of the methanol extracts of these two endemic Greek Stachys sp. and their main flavonoids were examined on arachidonic acid (AA) metabolism in the cellular system (mouse peritoneal macrophages and human platelets). Their cytotoxicity on cells was also investigated. Most samples assayed did not exhibit any significant effect on prostaglandin E2 (PGE2)-release from calcium ionophore-stimulated mouse peritoneal macrophages. Only chrysoeriol-7-O-beta-(3''-E-p-coumaroyl)-glucopyranoside, at the highest non-cytotoxic dose (50 microM), inhibited the release of PGE2, but this effect is not statistically significant. The release of leukotriene C4 (LTC4) by mouse peritoneal macrophages stimulated with calcium ionophore was inhibited by a crude extract of S. chrysantha, with an IC50 value of 34.3 microg/ml. Xanthomicrol (IC50 = 29.2 microM) and chrysoeriol-7-O-beta-D-(3''-E-p-coumaroyl)-glucopyranoside (IC50 = 11.1 microM) also inhibited the release of LTC4, although it showed less potency than the reference compound nordihydroguaiaretic acid (NDGA) (IC50 = 2 microM). However, most samples assayed showed a significant effect on thromboxane B2 (TXB2)-release from calcium ionophore-stimulated human platelets, with inhibition percentages slightly lower than the reference drug ibuprofen (IC50 = 7 microM). The IC50 values are: crude extract of S. candida 23.3 microg/ml; crude extract of S. chrysantha 23.1 microg/ml; xanthomicrol 28.8 microM; calcycopterin 2.66 microM and chrysoeriol-7-O-beta-D-(3''-E-p-coumaroyl)-glucopyranoside 8.8 microM. Our results indicate that the selective inhibition of TX-synthase enzyme may be the primary target of action of most of these samples, and one of the mechanisms through which thus exert their antiinflammatory effects.

Effects of compounds extracted from Tanacetum microphyllum on arachidonic acid metabolism in cellular systems.

In the present study, the effects of compounds extracted from Tanacetum microphyllum, four flavonoids and one sesquiterpene lactone, on arachidonic acid metabolism in cellular systems were examined. In the PGE2- and LTC4-release assay, most compounds did not exhibit any significant effect. Only hydroxyachillin, and the flavonoids centaureidin and 5,3'-dihydroxy-4'-methoxy-7-methoxycarbonylflavonol showed a significant effect, although with less potency than the reference drugs, indomethacin and NDGA. However, all compounds inhibited the release of TXB2 from ionophore-stimulated human platelets. The action is more marked with the flavonoids santin and ermanin.

Effects of compounds extracted from Santolina oblongifolia on TXB(2) release in human platelets.

A group of compounds isolated from the medicinal plant, Santolina oblongifolia, have been investigated for their effects on the release of platelet cyclo-oxygenase metabolite thromboxane A(2) (measured as thromboxane B(2)) from ionophore-stimulated human platelets. These compounds, which are dual inhibitors of cyclo-oxygenase (prostaglandin E(2)) and lipoxygenase (leukotriene C(4)) activity in vitro, are: apigenin, luteolin, quercetin, herniarin, scopoletin, scopolin and aesculetin. All compounds assayed presented a dose-related response to thromboxane B(2) release, with the percentages of inhibition being slightly lower than the reference drug, ibuprofen. Inhibition was more evident with the flavonoids. Our data support the inhibition of arachidonic acid metabolism as one of the mechanisms for which flavonoids and coumarins from S. oblongifolia exert their anti-inflammatory effect.

Adjuvant-carrageenan-induced inflammation in mice.

1. A study was conducted to evaluate the optimum conditions for the induction of adjuvant-carrageenan-induced inflammation (ACII) in Swiss and DBA/1 mice. 2. ACII was induced in mice under experimental conditions similar to those known to be effective in rats. Mice were immunized by subdermal injection of Freund's complete adjuvant (CFA), followed by a subplantar inoculation of carrageenan at different times. 3. The diversities of the responses on ACII between both strains of mice and rats were observed. Data obtained indicate that DBA/1 mice showed an increase in hindpaw and ankle joint swelling, which was more evident on day 21 after carrageenan injection, independently of the time of application of this phlogistic agent. At this time, the histopathological changes were similar to those seen in rats, and were characterized by epidermal hyperplasia, with leukocyte infiltration and granuloma formation. 4. We found that DBA/1 mice, instead of rats, can be used for the evaluation of anti-inflammatory drug activity. However, it is advisable also to consult the histological data to establish whether the synovial changes revert.

Organ-preserving management of rhabdomyosarcoma of the prostate and bladder in children.

Between November 1978 and July 1991, ten children between one and eight years of age with Group III pelvic rhabdomyosarcoma (IRS classification) and considered inoperable at diagnosis were treated primarily with intensive poly-chemotherapy. Complementary radiotherapy and conservative surgery were added as needed. Eight of the ten survive free of disease with functioning bladders for periods ranging from 5.7-18.4 years.

Isolation of two flavonoids from Tanacetum microphyllum as PMA-induced ear edema inhibitors.

The CH2Cl2 extract of Tanacetum microphyllum exhibited antiinflammatory activity on PMA-mouse ear model. Two antiinflammatory flavonoids, 5,7-dihydroxy-3,6,4'-trimethoxyflavone (santin) (1) and 5,7-dihydroxy-3,4'-dimethoxyflavone (ermanin) (2), were isolated.