Selective toxicity of a new lipophilic antifolate, BW301U, for methotrexate-resistant cells with reduced drug uptake

Three methotrexate (MTX)-resistant cell lines and their MTX-sensitive counterparts have been used to examine 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methyl-pyrido[2,3-d]pyrimidine (BW301U), a novel lipophilic antifolate, and compare its cytotoxicity with MTX and metoprine. Collateral sensitivity for both BW301U and metoprine was observed in CCRF-CEM/MTX R-cells, where MTX resistance appeared to be primarily due to a deficiency in drug uptake. This was particularly pronounced with BW301U which proved to be as effective in killing CCRF-CEM/MTX R as was MTX with the parental CCRF-CEM cell line. This effect was not seen in other cell lines, L5178Y/MTX or L1210/MTX R, where resistance to MTX was correlated with either an overproduction of 5,6,7,8-tetrahydrofolate:nicotinamide adenine dinucleotide phosphate oxidoreductase EC 1.5.1.3 (DHFR) or with combined uptake defect and increased DHFR levels, respectively. In each case, however, BW301U and metoprine, especially at high concentrations, were more effective than MTX in treating MTX-resistant cells.     

The effect of atracurium or fazadinium on intra-ocular pressure. A comparative study during induction of general anaesthesia

The effect of atracurium 0.6 mg/kg (group A; n = 11) and fazadinium 1 mg/kg (group F; n = 11) on intraocular pressure (IOP) was investigated in 22 patients during induction of anaesthesia with thiopentone 4 mg/kg and fentanyl 0.015 mg/kg. IOP was significantly reduced (p less than 0.01) in all patients following induction of anaesthesia. Intubation produced a rise in IOP in all patients but this was not statistically significant and remained below pre-induction values. The changes were similar in each group. Both of these neuromuscular blockers appear suitable relaxants to use for intraocular surgery.     

The use of vaginal specula in improving infection control

Sarah Tattersall reports on an initiative to encourage GP practices to comply with best practice in infection control by providing evidence on the advantages of purchasing single-use vaginal specula.     

Respiratory cooling and thermoregulatory coupling in reptiles

Comparative physiological research on reptiles has focused primarily on the understanding of mechanisms of the control of breathing as they relate to respiratory gases or temperature itself. Comparatively less research has been done on the possible link between breathing and thermoregulation. Reptiles possess remarkable thermoregulatory capabilities, making use of behavioural and physiological mechanisms to regulate body temperature. The presence of thermal panting and gaping in numerous reptiles, coupled with the existence of head-body temperature differences, suggests that head temperature may be the primary regulated variable rather than body temperature. This review examines the preponderance of head and body temperature differences in reptiles, the occurrence of breathing patterns that possess putative thermoregulatory roles, and the propensity for head and brain temperature to be controlled by reptiles, particularly at higher temperatures. The available evidence suggests that these thermoregulatory breathing patterns are indeed present, though primarily in arid-dwelling reptiles. More importantly, however, it appears that the respiratory mechanisms that have the capacity to cool evolved initially in reptiles, perhaps as regulatory mechanisms for preventing overheating of the brain. Examining the control of these breathing patterns and their efficacy at regulating head or brain temperature may shed light on the evolution of thermoregulatory mechanisms in other vertebrates, namely the endothermic mammals and birds.     

Effects of hexosamines and omega-3/omega-6 fatty acids on pH regulation by interleukin 1-treated isolated bovine articular chondrocytes

Previous work has shown that interleukin 1 (IL-1) increases the activity of acid extruders in articular chondrocytes, while the H⁺-adenosine triphosphatase (ATPase) inhibitor bafilomycin can prevent aggrecanase-mediated cartilage degradation. The H⁺ transport induced by IL-1 may therefore be required for proteinase activity. In the present study, the effects of hexosamines and fish oils on H⁺-ATPase activity have been characterised for isolated bovine articular chondrocytes. Cells isolated in the presence of IL-1 were acidified, and the fraction of acid extrusion mediated by Na⁺–H⁺ exchange and an H⁺-ATPase were determined using specific inhibitors. Exposure to IL-1 significantly enhanced both components of acid extrusion. Co-incubation with glucosamine or mannosamine attenuated the H⁺-ATPase fraction of efflux. The addition of glucosamine at 9 h after exposure to IL-1—when H⁺-ATPase activation is already apparent—was also able to abolish H⁺-ATPase activity, implying that hexosamines do not exert effects at the level of protein synthesis. Co-incubation with the glucose transport inhibitor phloretin elicited similar effects to the hexosamines, suggesting that modulation of adenosine triphosphate levels may underlie their effects on H⁺-ATPase function. The omega-3 fish oil linolenic acid but not the omega-6 fish oil linoleic acid reduced H⁺-ATPase activity to levels seen in IL-1-untreated cells, although total efflux remained elevated, as a result of an enhanced H⁺ leak. These observations support a model whereby IL-1 stimulates an H⁺-ATPase-dependent system, possibly involved in aggrecanase activation, which appears to be one of the target mechanisms interrupted by dietary supplements reported to have symptom-modifying effects on osteoarthritis.     

Implementing patient question-prompt lists into routine cancer care

Objective

To examine the feasibility and acceptability of routine provision of patient question prompt lists (QPLs) to promote patient participation and patient-clinician communication in medical consultations.

Methods

Four cancer centres across NSW, Australia (two rural, two urban) were invited to participate, involving distribution of QPLs to patients seeing a medical or radiation oncologist, or palliative care clinician. Patients rated their satisfaction after their next consultation. Cancer specialists provided their views at the end of the study.

Results

Sixty-four percent (389/606) of patients attending consultations received a QPL. Of patients offered a QPL (426), 91% accepted. Of 139 patients surveyed post-consultation, 89% reported reading the QPL and, of these, 44% referred to the QPL during the consultation at least once. All of 10 cancer specialists providing their views post-implementation reported that QPL implementation in routine practice was feasible and did not strain resources.

Conclusions

Cancer patients and cancer specialists showed support for routine dissemination of the QPL.

Practice implications

For successful implementation of evidence-based tools we recommend promotion by local clinical champions, negotiation with clinic staff about dissemination methods, raised patient awareness through on-site project facilitators, media, consumer and support groups, and availability of resources in hard copy and via online sources.