Summary Background Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with ...oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. Methods 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2–3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. Results After a median follow-up of 55·7 months (range 0–89·7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0·76 (95% CI 0·66–0·88, p=0·0001) in favour of exemestane, absolute benefit 3·3% (95% CI 1·6–4·9) by end of treatment (ie, 2·5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0·85 (95% CI 0·71–1·02, p=0·08), 0·83 (0·69–1·00, p=0·05) when 122 patients with oestrogen-receptor-negative disease were excluded. Conclusions Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2–3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.
Aluminium phosphide poisoning Bogle, R G; Theron, P; Brooks, P ...
Emergency medicine journal : EMJ,
01/2006, Letnik:
23, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We describe a lethal poisoning in a healthy woman caused by deliberate ingestion of aluminium phosphide (AlP), a pesticide used to kill rodents and insects. Toxicity of AlP and review of cases ...reported to the National Poisons Information Service (London) 1997–2003 are discussed.
Pomegranate juice is growing in popularity in the UK. We report a potential interaction between pomegranate juice and warfarin. Laboratory studies have shown that pomegranate juice inhibits ...cytochrome P450 enzymes involved in warfarin metabolism. As with previous reports of interactions between food and warfarin, this case does not definitively prove the association between pomegranate juice consumption and increased warfarin bioactivity but highlights the importance of taking a complete drug, food and juice history when assessing patients with unstable anticoagulation.
Transport of L-arginine and nitrite production were examined in the murine macrophage cell line J774. Bacterial lipopolysaccharide (LPS) induced a dose- and time-dependent stimulation of nitrite ...production, which was further increased in the presence of interferon-gamma. Nitrite synthesis was absolutely dependent on extracellular L-arginine and inhibited in the presence of L-lysine or L-ornithine. In unactivated J774 cells L-arginine transport was saturable, with an apparent Km of 0.14 +/- 0.04 mM and Vmax. of 15 +/- 2 nmol/h per 10(6) cells. LPS (1 microgram/ml) induced a time-dependent stimulation of L-arginine transport, and after 24 h the Vmax. increased to 34 +/- 2 nmol/h per 10(6) cells. These findings indicate that activation of J774 cells with LPS produces an increase in both L-arginine transport and nitrite synthesis. The elevated rate of L-arginine transport in activated J774 cells may provide a mechanism for sustained substrate supply during enhanced utilization of L-arginine for the generation of NO.
This study attempted to enhance the efficacy of peripheral nerve regeneration using our previously tested poly(
l-lactic acid) (PLLA) conduits by incorporating them with allogeneic Schwann cells ...(SCs). The SCs were harvested, cultured to obtain confluent monolayers and two concentrations (1×10
4 and 1×10
6
SC/ml) were combined with a collagen matrix (Vitrogen) and injected into the PLLA conduits. The conduits were then implanted into a 12
mm right sciatic nerve defect in rats. Three control groups were used: isografts, PLLA conduits filled with collagen alone and empty silicone tubes. The sciatic functional index (SFI) was calculated monthly through four months. At the end of second and fourth months, the gastrocnemius muscle was harvested and weighed for comparison and the graft/conduit and distal nerve were harvested for histomorphologic analysis. The mean SFI demonstrated no group differences from isograft control. By four months, there was no significant difference in gastrocnemius muscle weight between the experimental groups compared to isograft controls. At four months, the distal nerve demonstrated a statistically lower number of axons/mm
2 for the high and low SC density groups and collagen control. The nerve fiber density was significantly lower in all of the groups compared to isograft controls by four months. The development of a “bioactive” nerve conduit using tissue engineering to replace autogenous nerve grafts offers a potential approach to improved patient care. Although equivalent nerve regeneration to autografts was not achieved, this study provides promising results for further investigation.
The effects of bradykinin and ATP on L-arginine transport and nitric oxide (NO) production were studied in porcine aortic endothelial cells cultured and perfused on microcarriers and deprived of ...L-arginine for 24 h. Stimulation of cells with bradykinin (100 nM) or ATP (100 microM) resulted in a rapid increase in L-arginine uptake and NO release. In the presence of nitro-L-arginine (100 microM), an inhibitor of NO synthase, the stimulatory effect of bradykinin on L-arginine uptake was partially inhibited while NO release was completely abolished. Nitro-L-arginine alone was not an inhibitor of basal L-arginine transport, suggesting that its inhibitory action was not directly on the L-arginine transporter but a result of the inhibition of NO generation. These data indicate that during agonist-stimulated NO production there is a concomitant increase in the transport of L-arginine into endothelial cells providing a mechanism for the continual generation of NO.
1. We have investigated whether changes in extracellular ion composition and substrate deprivation modulate basal and/or bradykinin-stimulated
L-arginine transport and release of nitric oxide (NO) ...and prostacyclin (PGI2) in porcine aortic endothelial cells cultured
and superfused on microcarriers. 2. Saturable L-arginine transport (Km = 0.14 +/- 0.03 mM; Vmax = 2.08 +/- 0.54 nmol min-1
(5 x 10(6) cells)-1) was pH insensitive and unaffected following removal of extracellular Na+ or Ca2+. 3. Cationic arginine
analogues, including L-lysine and L-ornithine, inhibited L-arginine transport, whilst 2-methylaminoisobutyric acid, beta-2-amino-bicyclo2,2.1-heptane-2-carboxylic
acid, L-phenylalanine, 6-diazo-5-oxo-norleucine, L-glutamine, L-cysteine and L-glutamate were poor inhibitors. 4. Deprivation
of L-arginine (30 min to 24 h) reduced intracellular free L-arginine levels from 0.87 +/- 0.07 to 0.40 +/- 0.05 mM (P < 0.05)
and resulted in a 40% stimulation of L-arginine, L-lysine and L-ornithine transport. 5. L-arginine and NG-monomethyl-L-arginine
(L-NMMA), but not N omega-nitro-L-arginine methyl ester (L-NAME), trans-stimulated efflux of L-3Harginine. 6. Depolarization
of endothelial cells with 70 mM K+ reduced L-arginine influx and prevented the stimulation of transport by 100 nM bradykinin,
but agonist-induced release of NO and PGI2 was still detectable. 7. Basal rates of L-arginine transport and NO release were
unaffected during superfusion of cells with a nominally Ca(2+)-free solution. Bradykinin-stimulated L-arginine transport was
insensitive to removal of Ca2+, whereas agonist-induced NO release was abolished. 8. Although bradykinin-stimulated NO release
does not appear to be coupled directly to the transient increase in L-arginine transport, elevated rates of L-arginine influx
via system y+ in response to agonist-induced membrane hyperpolarization or substrate deprivation provide a mechanism for enhanced
L-arginine supply to sustain NO generation.
Sensitizing the insensitive Ashrafian, H; Bogle, R G
Clinical nephrology,
06/2004, Letnik:
61, Številka:
6
Journal Article
Recenzirano
Lithium is still the treatment of choice in bipolar affective disorder. The patient presented here represents an example of the possible severity of metabolic defects resulting from lithium use. In ...this case, it caused severe intractable nephrogenic diabetes insipidus (NDI). Our case report draws attention to 2 important messages. The first is the complexity in treating psychiatric patients that is often not borne out in the medical literature. The second is the role and power of pharmacological augmentation. While the role of these agents has been appreciated for some time, the use of carbamazepine and of drug combinations is not as well recognized. We emphasize the clinical features of NDI, lithium's metabolic sequelae and furthermore collate the most up-to-date account of the signalling effects conferred by these agents in a summary diagram.
Propofol, an intravenous anaesthetic agent, causes marked vasodilatation in vivo. In the present study the effects of propofol on the release of nitric oxide (NO) from vascular endothelial cells was ...determined in vitro. Application of propofol to co‐cultures of porcine aortic endothelial and smooth muscle cells resulted in a rapid increase in cyclic GMP formation. This increase was significantly inhibited following pretreatment of the cells with either NG‐nitro‐l‐arginine (l‐NOARG) or in the presence of haemoglobin. When applied to smooth muscle cells alone, propofol did not result in an increase in cyclic GMP levels. These results demonstrate that propofol stimulates the production and release of NO from cultured endothelial cells and suggest that the vasodilatation and hypotension observed when propofol is given in vivo may be due to NO release.
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