Stimulation of spinal 5-HT(2A/2C) receptors potentiates the capsaicin-induced in vivo release of substance P-like immunoreactivity in the rat dorsal horn

Stimulation of spinal serotonin (5-HT)_2A/2C receptors has previously been reported to lead to either a pro-nociceptive or an anti-nociceptive response. Behavioral data have indicated that the pro-nociceptive effect is related to the release of substance P (SP). The aim of this in vivo microdialysis study was to investigate if stimulation of spinal 5-HT_2A/2C receptors by the selective agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) induces spontaneous or capsaicin-evoked increase in the release of SP-like immunoreactivity (SP-LI) in the rat dorsal horn. A dose of capsaicin (25 μM in the perfusion medium administered for 30 min), which did not lead to a significant release of SP-LI on its own, induced a significant increase of greater than 4-fold of the SP-LI level following spinal application of 50 nmol DOI. Higher (500 nmol) or lower (5 nmol) doses of DOI failed to induce a similar effect. In rats with a peripheral inflammation, induced by carrageenan, capsaicin (25 μM) induced a non-significant increase of SP-LI. A significant 8-fold increase of the SP-LI level was detected following administration of 50 nmol DOI in combination with capsaicin. The effect of DOI, which was completely prevented by co-administration of the 5-HT_2A receptor antagonist ketanserin in control animals without peripheral inflammation, was only partly blocked in animals with carrageenan induced peripheral inflammation. In conclusion, stimulation of 5-HT_2A/2C receptors facilitates the capsaicin-evoked release of SP-LI in the dorsal horn in both animals with and without carrageenan-induced unilateral inflammation. The observation that the highest dose of DOI failed to induce SP-LI release may be due to an inhibitory postsynaptic action at this dose.     

Periapical inflammation affecting coronally-inoculated dog teeth with root fillings augmented by white MTA orifice plugs

Placement of orifice plugs has been suggested to augment the seal of conventional root canal fillings. This study assessed in vivo the efficacy of white mineral trioxide aggregate (MTA) plugs in preventing periapical inflammation subsequent to coronal inoculation of root-filled teeth. The two-rooted mandibular premolars of six beagle dogs were conventionally prepared and filled with gutta-percha and sealer. A white MTA orifice plug was placed into one canal in each tooth. Pulp chambers were inoculated with plaque except for 12 teeth (negative control), and restored. Radiographs were taken at regular intervals. At 10 months, dogs were killed and jaw blocks processed for histology. None of the roots revealed radiographic or histologic evidence of severe inflammation. Mild inflammation was observed in 17% and 39% of the roots with and without an orifice plug, respectively (McNemar, p > 0.05). Without development of severe inflammation, the seal augmentation efficacy of MTA orifice plugs could not be determined.     

Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed.

PURPOSE: We conducted a retrospective analysis to evaluate the safety and efficacy of Campath-1H, an anti-CD52 humanized monoclonal antibody, in previously treated T-prolymphocytic leukemia (T-PLL) patients in a compassionate-use program. PATIENTS AND METHODS: Seventy-six patients with T-PLL (including four chemotherapy-naive patients) received 3, 10, and 30 mg of Campath-1H on sequential days, followed by 30 mg three times weekly, as 2-hour intravenous infusions, for 4 to 12 weeks. RESULTS: Median patient age was 60 years (range, 35 to 84). Spleen liver, lymph node, and skin involvement were present in 64%, 40%, 54%, and 18% of patients, respectively. All tested patients had CD2, CD7, CD4, and/or CD8 positivity, whereas CD5 and CD3 were positive in 98% and 96% of tested patients, respectively. The objective response rate was 51% (95% confidence interval [CI], 40% to 63%), with a 39.5% complete response (CR) rate (95% CI, 28% to 51%). The median duration of CR was 8.7 months (range, 0.13+ to 44.4), and median time to progression was 4.5 months (range, 0.1 to 45.4) compared with 2.3 months (range, 0.2 to 28.1) after first-line chemotherapy. The median overall survival was 7.5 months (14.8 months for CR patients). The most common Campath-1H-related adverse events were acute reactions during or immediately after infusions. Fifteen infectious episodes occurred during treatment in 10 patients (13%), leading to treatment discontinuation in three. Eight patients experienced possibly related, late-onset infections. Severe thrombocytopenia and/or neutropenia occurred in six patients (8%), leading to treatment discontinuation in four. Two treatment-related deaths occurred. CONCLUSION: Campath-1H is an active drug in T-PLL patients for whom first-line therapy has failed. It has a favorable risk/benefit ratio and should be prospectively investigated in chemotherapy-naive patients.     

The cyclosporin PSC 833 increases survival and delays engraftment of human multidrug-resistant leukemia cells in xenotransplanted NOD-SCID mice.

Circumvention of chemoresistance in cancer may involve several modulator drugs with high affinity for the multidrug transporter P-glycoprotein (Pgp), which is expressed in a number of multi-resistant malignancies. Pgp acts as a membrane efflux pump with broad substrate specificity including antineoplastic drugs and endogenous substances such as certain cytokines and sphingolipids. Therefore, the consequence of Pgp blockade could be far more complex than intracellular drug retention. In the present study exposure of the Pgp inhibitor, PSC 833 (1200 ng/ml), to Pgp expressing KG1a/200 human leukemia cells provoked cell cycle arrest and apoptosis in vitro. This finding was put to test in vivo using a xenotransplant model of KG1a/200 human cells intravenously inoculated into non-obese diabetic severe combined immunodeficient (NOD-SCID) mice. The animals were randomly allocated to receive treatment with PSC 833 (n = 32) or placebo (n = 24). PSC 833 (30 mg/kg) was subcutaneously injected six or 12 times separated by 48-96 h. The overall mean whole blood concentration of PSC 833 was 1191 +/- 60 ng/ml (s.e.m.) at 20 h after administration. Tumor engraftment was significantly reduced in the treatment group (P = 0.037), which also had prolonged survival compared to control animals (P = 0.0016). This is the first study that demonstrates antileukemic effects of a Pgp inhibitor as single agent therapy in vivo, and the present data raise the possibility of alternative exploitation of modulators in cancer chemotherapy.     

In vitro antitumour activity of cis- and trans-5-fluoro-5,6-dihydro-6-alkoxy-uracils; effects on thymidylate synthesis.

A class of new 5-fluorouracil (FU) analogues, the 5-fluoro-5,6-dihydro-6- alkoxy-uracils was synthesised with a modification at the 6-position of the pyrimidine ring. At this position the analogues have a hydroxy or alkoxy group of different chain lengths either in the cis- or trans-configuration. The antiproliferative effect of these compounds was tested on five cell lines of different origin. Generally, the analogues with a cis-configuration had a higher activity than those with a trans-configuration. The growth inhibitory effect of the compounds decreased with increasing alkoxy chain length, but the compound with a hydroxy group had the lowest growth inhibitory effect. One analogue, cis-5-F-5,6-dihydro-6-methoxy-uracil had a higher antiproliferative effect than FU in one of the cell lines. Effects on thymidylate synthase (TS), the possible target of these analogues, were evaluated by thymidine rescue of growth inhibition and incorporation of tritiated deoxyuridine (3H-UdR) into DNA. In solid tumour cell lines addition of TdR reversed the antiproliferative effect. Inhibition of TS in intact cells was determined by measuring 3H-UdR incorporation in two cell lines. The effect of cis-5-F-5,6-dihydro-6-methoxy-uracil on incorporation of 3H-UdR was 2- to 5-fold stronger than that of FU in both cell lines. All other compounds produced a higher 3H-UdR incorporation than FU both at equimolar and equi-toxic concentration. Concluding from these results we regard cis-5-F-5,6-dihydro-6-methoxy-uracil as the most promising FU analogue of this series, because of its higher antiproliferative activity than FU and marked inhibition of TS in intact cells.     

Studies on the tissue-disposition and fate of N-[14C]ethyl-N-nitrosourea in mice.

The tissue-disposition and fate of N-[14C]ethyl-N-nitrosourea has been studied in mice. A large part of the injected N-[14C]ethyl-N-nitrosourea radioactivity was found to be exhaled as 14CO2. Whole-body autoradiography showed evenly distributed radioactivity in most tissues shortly after the administration of N-[14C]ethyl-N-nitrosourea which probably is due to the homogeneously distributed substance and the non-enzymatically formed ethyl-carbonium ions which have reacted with the tissues. The blood-brain barrier seemed to have a capacity to partially prevent the uptake of the substance in the central nervous system. A high radioactivity was observed in the liver, which may imply that N-[14C]ethyl-N-nitrosourea is enzymatically decomposed in this tissue. An observed labelling of kidneys may be connected with urinary excretion of radioactivity. The radioactivity in the liver and kidney decreased at later survival intervals and a distribution pattern appeared, which was characterized by a labelling of tissues with a high protein or steroid synthesis and of fat containing tissues. The distribution pattern corresponded to the one seen after the administration of [14C]acetaldehyde and is probably due to normal biosynthetic incorporation of radioactivity in the 2-carbon pool. Pretreatments with pyrazole, nialamide and diethyldithiocarbamate caused a marked inhibition of the exhalation of 14CO2 and of the incorporation of radioactivity in the liver. This effect may be directed towards the decomposition of N-[14C]ethyl-N-nitrosourea itself, but an effect on the metabolism of formed 2-carbon fragments is also possible. The incorporation of radioactivity in other tissues was not influenced by the pretreatments.     

C-peptide, IGF-I, sex-steroid hormones and adiposity: a cross-sectional study in healthy women within the European Prospective Investigation into Cancer and Nutrition (EPIC)

Objectives: The risk of some cancers is positively associated with body weight, which may influence circulating levels of sex-steroid hormones, insulin and IGF-I. Interrelationships between these hormones and the associations with adiposity were evaluated in healthy women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC).Methods: A cross-sectional analysis was performed on anthropometric and hormonal data from 743 pre- and 1217 postmenopausal women. Body mass index (BMI) and waist circumference were used as indicators of adiposity. C-peptide, Insulin Growth Factor (IGF)-I, Insulin Growth Factor binding protein (IGFBP)-3, androgens, estrogens and sex hormone binding globulin (SHBG) were measured by immunoassays; free sex steroid concentrations were calculated.Results: BMI and waist circumference were positively correlated with estrogens in postmenopausal women and with C-peptide, free testosterone and inversely with SHBG in all women. C-peptide and IGF-I were inversely correlated with SHBG, and positively with free sex steroids in postmenopausal women. IGF-I was positively associated with postmenopausal estrogens and androgen concentrations in all women.Conclusions: Sex-steroid concentrations appear to be regulated along several axes. Adiposity correlated directly with estrogens in postmenopausal women and with insulin, resulting in lower SHBG and increased levels of free sex steroids. Independent of adiposity and insulin, IGF-I was associated with decreased SHBG levels, and increased concentrations of androgens and postmenopausal estrogens.     

Online interaction. Effects of storytelling in an internet breast cancer support group

The internet provides new ways of forming social relationships among people with breast cancer and is increasingly used for this purpose. This qualitative study, using ethnographic case-study method, aimed to explore how support groups on the internet can break the social isolation that follows cancer and chronic pain, by analysing the storytelling emerging on the Scandinavian Breast Cancer Mailing list. Using participant observation and face-to-face or online interviews of participants, we investigated the motivations of 15 women who chose the internet to counteract social isolation after breast cancer. The results showed that the women were empowered by the exchanges of knowledge and experience within the support group. The internet was considered a means for finding ways of living with breast cancer. Our study suggests that internet support groups have important potential for the rehabilitation of cancer patients.