Psychostimulants and delirium in patients receiving palliative care.

The use of psychostimulants to relieve opioid-induced drowsiness and symptoms of depression in medically ill patients has become increasingly established in North America. The role of psychostimulants in the care of patients receiving palliative care is beginning to be debated in the United Kingdom both in the hospice and hospital setting. Delirium has been well defined and reported as a significant problem in populations of patients receiving palliative care. Two case histories are presented to illustrate the potential benefit of psychostimulants in hypoactive delirium.

Preferential activation of nuclear factor of activated T cells c correlates with mouse strain susceptibility to allergic responses and interleukin-4 gene expression.

Dysregulated expression of the T helper 2 cytokine interleukin (IL)-4 is thought to play a fundamental role in the pathogenesis of allergic asthma. The molecular basis for dysregulated IL-4 production is not well understood. We analyzed in detail the molecular factors involved in regulating IL-4 transcription in a well-characterized mouse model. In this model, A/J mice developed allergen-induced IL-4 cytokine gene expression, airway inflammation, and hyperresponsiveness, whereas C3H/HeJ (C3H) mice did not. Here we report that isolated splenocytes from A/J and C3H mice stimulated ex vivo with concanavalin A reproduced the cytokine phenotype observed in the airway after antigen challenge. We hypothesized that differences in splenocyte IL-4 production involved either polymorphisms in regulatory IL-4 promoter regions, or the expression and activation of transcription factors necessary for promoter transactivation in a strain-dependent manner. To address these questions, we first sequenced ~ 700 base pairs containing well-characterized IL-4 promoter regulatory elements using genomic DNA obtained from C3H and A/J mice. Next, we used electrophoretic mobility shift assays with relevant IL-4 promoter sequences to screen nuclear extracts isolated from A/J and C3H splenocytes for functional transcriptional factor complexes. Here we show that susceptibility to antigen-induced airway hyperresponsiveness is not due to polymorphisms in the IL-4 promoter, but is associated with preferential expression of nuclear factor of activated T cells c in splenocyte nuclear extracts obtained from A/J mice. In conclusion, our data link dysregulated activation of a specific transcription factor with susceptibility to allergic airway inflammation.

Effective tamoxifen therapy of breast cancer involves both antiproliferative and pro-apoptotic changes.

Despite knowledge of oestrogen receptor status, it is not always possible to predict which breast cancers will respond to tamoxifen. We have previously reported that decreased expression of Bcl-2 and/or Ki-S1 were associated with tumour response to neo-adjuvant tamoxifen in 50 elderly women with oestrogen receptor (ER)-positive breast cancer. In this study, we confirm that the expression of Bcl-2 and Ki-S1 are surrogates for the frequency of apoptosis and mitosis respectively, within these untreated breast cancers, with an inverse relationship between Bcl-2 expression and the apoptotic index (P<0.05), and a positive relationship between Ki-S1 expression and the mitotic index (P<0.01). However, after 3 months' tamoxifen treatment these relationships were no longer apparent. Moreover, amongst the 27 tumours in which Bcl-2 expression was reduced during the 3 months' therapy, there was a significant correlation between the response to therapy and the increase in apoptosis (P<0.05), whereas in those tumours in which Bcl-2 did not fall with therapy, there was a significant correlation between response and the decrease in mitosis (P<0.05). These data suggest there are at least two mechanisms for effective tamoxifen therapy: increased apoptosis as a consequence of reduced Bcl-2 expression, and decreased proliferation.

The expression of Ki-S1 and BCL-2 and the response to primary tamoxifen therapy in elderly patients with breast cancer.

Ki-S1, a marker of proliferation, and bcl-2, the gene product of which is an antagonist of apoptosis, have been measured in 51 ER-positive primary breast cancers before and during tamoxifen treatment and then related to clinical response. Both markers were detected in the majority of tumours before treatment and, quantitatively, initial expression of Bcl-2 protein, but not Ki-S1, was significantly related to the percentage reduction in tumour volume as assessed by ultrasound. Staining for both markers was lower in post treatment samples than in those taken prior to treatments, but concordant decreases in staining indices were seen in only 11 of the 51 tumours. The results demonstrate, using clinical material, that the response to tamoxifen may involve changes in proliferation and/or susceptibility to cell-death.

Changes in expression of transforming growth factor beta mRNA isoforms in patients undergoing tamoxifen therapy.

Tumour was obtained from 37 patients with oestrogen receptor-positive breast cancer, before and during treatment with tamoxifen, and examined qualitatively and semi-qualitatively for mRNA of the three mammalian TGF-beta isoforms. Levels of TGF-beta isoforms were then correlated with tumour response to tamoxifen, as assessed by monthly ultrasound. A high incidence of expression by each isoform was found in tumour material taken both before and during treatment. Semiquantitative assessment of mRNA showed that in the majority of tumours, expression of TGF-beta s did not change markedly with treatment, i.e. beyond that which might have been caused by method reproducibility and tumour heterogeneity (variations of < 100% between pre- and post-treatment samples). In those displaying significant variation with treatment, expression of TGF-beta 1 and -beta 3 increased or decreased in equal numbers, whereas TGF-beta 2 expression tended to increase with treatment. Subdividing tumours by clinical response revealed no significant association between changes in expression of TGF-beta 1 and TGF-beta 3. There was, however, a significant correlation between changes in expression of TGF-beta 2 and response (P = 0.018). Thus, of 15 responding tumours displaying substantial changes, 11 showed an increase in TGF-beta 2 expression with treatment, whereas none of the non-responding tumours were associated with increased expression. While not providing evidence for a generalised increase in TGF-beta expression with tamoxifen treatment, the present study suggests that response to tamoxifen therapy may be associated with an increase in expression of specific TGF-beta isoforms in some, but not all, tumours.

Expression of transforming growth factor beta mRNA isoforms in human breast cancer.

Using an RNAse protection assay, expression of messenger RNA for isoforms of TGF-beta was determined in a series of breast cancers. Of 50 tumours, 45 (90%) expressed TGF-beta 1 mRNA, 39 (78%) expressed TGF-beta 2, and 47 (94%) expressed TGF-beta 3. Patterns of expression varied between different tumours: 37 (74%) cancers expressed all three TGF-beta isoforms, ten (20%) expressed only two isoforms and two expressed TGF-beta 1 alone. One sample showed no evidence of TGF-beta mRNA expression. Although most breast cancers expressed mRNA for at least one isoform of TGF-beta, there were differences in patterns of mRNA expression between individual tumours. The relatively small number of tumours examined precluded detailed analysis between expression and other clinical parameters, but a significant association was identified between one aspect of isoform expression and lymph node status, in that the majority of tumours expressing all three isoforms were associated with lymph node involvement, whereas tumours without one or more isoform were usually lymph node negative (P = 0.025 by Fisher's exact test).