The addition of arsenic trioxide to low-dose Ara-C in older patients with AML does not improve outcome

Most patients with acute myeloid leukaemia (AML) are older, with many unsuitable for conventional chemotherapy. Low-dose Ara-C (LDAC) is superior to best supportive care but is still inadequate. The combination of arsenic trioxide (ATO) and LDAC showed promise in an unrandomised study. We report a randomised trial of LDAC versus LDAC + ATO. Patients with AML according to WHO criteria or myelodysplastic syndrome with > 10% blasts, considered as unfit for conventional chemotherapy, were randomised between subcutaneous Ara-C (20mg b.d. for 10 days) and the same LDAC schedule with ATO (0.25 mg/kg) on days 1-5, 9 and 11, for at least four courses every 4 to 6 weeks. Overall 166 patients were entered; the trial was terminated on the advice of the DMC, as the projected benefit was not observed. Overall 14% of patients achieved complete remission (CR) and 7% CRi. Median survival was 5.5 months and 19 months for responders (CR: not reached; CRi: 14 months; non-responders: 4 months). There were no differences in response or survival between the arms. Grade 3/4 cardiac and liver toxicity, and supportive care requirements were greater in the ATO arm. This randomised comparison demonstrates that adding ATO to LDAC provides no benefit for older patients with AML. Leukemia (2011) 25, 1122-1127; doi:10.1038/leu.2011.59; published online 8 April 2011

The incidences of trisomy 8, trisomy 9 and D20S108 deletion in polycythaemia vera: an analysis of blood granulocytes using interphase fluorescence in situ hybridization:an analysis of blood granulocytes using interphase fluorescence in situ hybridization

We have used interphase fluorescence in situ hybridization (IFISH) to detect trisomy 8, trisomy 9 and 20q deletion in circulating granulocytes from patients with polycythaemia vera (PV). Out of 64 PV patients, 15 (23%) exhibited an abnormality. Two patients had trisomy 9, three had trisomy 8 and 10 patients had hemizygous deletion of D20S108 (a locus in the 20q common deleted region). Aberrant nuclei ranged from 10% to 80% in these 15 cases. There was no correlation between the presence of a marker and sex, age, interval between presentation and IFISH analysis, neutrophil or platelet count or therapy. Conventional marrow cytogenetic karyotype results were available in 23 cases and there was concurrence between these and blood IFISH in 16 cases (13 normal and three with 20q/D20S108 deletion by both methods). Three patients with D20S108 deletion by IFISH were normal by previous marrow cytogenetic testing and four cases with 20q deletion by previous marrow cytogenetics had normal blood granulocytes according to IFISH. Thus, we confirm that trisomies 8 and 9 and deletion of 20q are diagnostically useful markers of PV. IFISH analysis of blood granulocytes is a practical method for detecting these markers, but as an adjunct to, not as a substitute for, conventional marrow cytogenetics.

Erythrocytosis due to a mutation in the erythropoietin receptor gene

Familial erythrocytosis, associated with high haemoglobin levels and low serum erythropoietin (Epo), has been shown to co-segregate with a sequence repeat polymorphism at the 5' region of the erythropoietin receptor (EpoR) in a large Finnish family. We have investigated the cause of erythrocytosis in an English boy. Sequencing of the cytoplasmic region of the EpoR detected a de novo transition mutation of G to A at nucleotide 6002. This mutation resulted in the formation of a stop codon at amino acid 439 with the loss of 70 amino acids from the carboxy terminus. The mutation (G6002A) has arisen independently in a Finnish family and de novo in this English boy. Patients with unexplained erythrocytosis and low serum Epo levels should be investigated for EpoR mutations.

Managing Island Life:Social, Economic and Political Dimensions of Formality and Informality in Island Life

"Managing Island Life: Social, Economic and Political Dimensions of Formality and Informality in Island Life" is a significant and timely contribution to the study of islands and island life. Wide-ranging in terms of both geographical and theoretical sweep, contributions consider the conceptualisation of the island as well as social, economic and political dimensions of island life and living. Showcasing the current state of island research, contributors cover diverse areas of island life such as: informal economies in the West Indies; the effects of natural convservation policies in the Highlands and Islands of Scotland; the role of internet sites in British Isles heritage tourism, and the impact of multicultural policies in the Indian Ocean. This volume will appeal to undergraduate social scientists as well as professional anthropologists, sociologists and geographers, policy makers and islands and regional specialists.

Laterite as a disinfectant.

A groundwater programme monitoring flow and quality of a potable water spring in a slum district in Kampala, Uganda revealed that although latrines acted as the principal means of organic waste disposal for the 1000 plus people living in the spring’s catchment, levels of faecal indicator bacteria (TVC 45 Deg C) in spring discharge remained at or below detection during the dry season, despite the presence of high levels of chloride (45mg/l-56mg/l) and nitrate (23mg/l – 30mg/l NO3-N), indicating sewage impacts. A programme of column and batch testing of laterite underlying the area provided a means of investigating the soil’s attenuation capacity under more controlled conditions.
X-ray diffraction analyses revealed the laterite to be dominated by quartz and kaolinite with minor (<5% by volume) quantities of haematite. Batch studies revealed that over 99% of bacteriophage adsorbed to haematite in less than 5 minutes. By contrast batch tests on haematite-free soil samples from the Blue Hills in Australia showed that although they had comparable dominant mineralogy and iron coverage on their surfaces (determined from Energy dispersive X-ray fluorescence) they had negligible ability to adsorb H40/1.
Based on the results of the batch studies using natural soils, a programme of batch studies, undertaken using pure haematite showed the mineral to have an extremely high capacity to adsorb bacteriophage, and suggested that it was responsible for the levels of attenuation observed.
The results of column studies were in keeping with the findings of batch experiments. Injection of 20 pore volumes of 300 pfu/mL of the bacteriophage H40/1 into a 20mm diameter glass column packed with sand sized (Ø>500µm) laterite revealed that the column could irreversibly remove over 2.5 log10 bacteriophage over its 10cm length.
Importance:
Mineralogical and batch test data provide convincing evidence to show that laterite can potentially act as an inexpensive means of removing micro organisms from water. The material, particularly in nodular form, displays considerable potential to act as an alternative filter material to conventional quartz filter sands.

Prophylactic ranitidine treatment in critically ill children - a population pharmacokinetic study

Aims: To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. Methods: Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. Results: A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (-12.618; P <0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1lh for total clearance and 285l for volume of distribution, both allometrically modelled for a 70kg adult. Final estimates for absorption rate constant and bioavailability were 1.31h and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. Conclusions: Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary.

Donepezil and memantine for moderate-to-severe Alzheimer's disease

Background: Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. Methods: We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS.
Results: Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P = 0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone.
Conclusions: In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035).

'Sliabh in Irish place-names' in Nomina 32 (2009)

This article deals with one of the most common elements in names of Irish hills and mountains. The grammar, phonology, etymology, semantic range and chronology of the element are examined. Sliabh is particularly complex in terms of its semantic range, which includes the following senses: 1) a mountain or hill (standing alone or forming part of a range); 2) a range of hills or mountains; 3) an moor or area of upland. The word is present in the earliest attested stages of the Irish language, and there is some evidence for all three meanings in Old Irish, though senses 1 and 2 are best attested. It is suggested that the view advanced by MacBain and Thurneysen that sliabh is etymologically related to Eng. slope and that this reflects its original meaning is open to some doubt in view of the lack of evidence for this sense in early Irish and the lack of clear cognates in other branches of Celtic and Indo-European languages.

Prognostic and therapeutic relevance of c-FLIP in acute myeloid leukaemia

Chemoresistance is a major contributor to the aggressiveness of AML and is often due to insufficient apoptosis. The CFLAR gene is expressed as long and short splice forms encoding the anti-apoptotic proteins c-FLIP(L) and c-FLIP(S) (CFLAR(L) and CFLAR(S) , respectively) that play important roles in drug resistance. In univariate analyses of CFLAR mRNA expression in adult AML patients, those individuals with higher than median mRNA expression of the long splice form CFLAR(L) (but not the short splice form) had significantly lower 3 year overall survival (P = 0·04) compared to those with low expression. In cell line studies, simultaneous down-regulation of c-FLIP(L) and c-FLIP(S) proteins using siRNA induced apoptosis in U937 and NB-4 AML cells, but not K562 or OCI-AML3 cells. However, dual c-FLIP(L/S) downregulation sensitized all four cell lines to apoptosis induced by recombinant tumour necrosis factor-related apoptosis-inducing ligand (rTRAIL). Moreover, specific downregulation of c-FLIP(L) was found to recapitulate the phenotypic effects of dual c-FLIP(L/S) downregulation. The histone deacetylase (HDAC)1/2/3/6 inhibitor Vorinostat was found to potently down-regulate c-FLIP(L) expression by transcriptional and post-transcriptional mechanisms and to sensitize AML cells to rTRAIL. Further analyses using more selective HDAC inhibitors revealed that HDAC6 inhibition was not required for c-FLIP(L) down-regulation. These results suggest that c-FLIP(L) may have clinical relevance both as a prognostic biomarker and potential therapeutic target for HDAC inhibitors in AML although this requires further study.