Prospective gene expression analysis accurately subtypes acute leukaemia in children and establishes a commonality between hyperdiploidy and t(12;21) in acute lymphoblastic leukaemia

We have prospectively analysed and correlated the gene expression profiles of children presenting with acute leukaemia to the Royal London and Great Ormond Street Hospitals with morphological diagnosis, immunophenotype and karyotype. Total RNA extracted from freshly sorted blast cells was obtained from 84 lymphoblastic [acute lymphoblastic leukaemia (ALL)], 20 myeloid [acute myeloid leukaemia (AML)] and three unclassified acute leukaemias and hybridised to the high density Affymetrix U133A oligonucleotide array. Analysis of variance and significance analysis of microarrays was used to identify discriminatory genes. A novel 50-gene set accurately identified all patients with ALL and AML and predicted for a diagnosis of AML in three patients with unclassified acute leukaemia. A unique gene set was derived for each of eight subtypes of acute leukaemia within our data set. A common profile for children with ALL with an ETV6-RUNX1 fusion, amplification or deletion of ETV6, amplification of RUNX1 or hyperdiploidy with an additional chromosome 21 was identified. This suggests that these rearrangements share a commonality in biological pathways that maintains the leukaemic state. The gene TERF2 was most highly expressed in this group of patients. Our analyses demonstrate that not only is microarray analysis the single most effective tool for the diagnosis of acute leukaemias of childhood but it has the ability to identify unique biological pathways. To further evaluate its prognostic value it needs to be incorporated into the routine diagnostic analysis for large-scale clinical trials in childhood acute leukaemias.     

Medication adherence and fracture risk among patients on bisphosphonate therapy in a large United States health plan

The association between bisphosphonate adherence in the first 12 months after therapy initiation and subsequent fracture risk was examined. Patients were identified from a large, commercially-insured population with integrated pharmacy and medical claims. Eligible patients were aged ≥45 years, were new to osteoporosis therapy (no osteoporosis medication claims in prior year) with first (index) bisphosphonate claim between 1/1/2005 and 4/30/2008, and had continuous insurance coverage for ≥12 months pre- and post-index. Patients with fracture claims ≤12-months post-index were excluded. Adherence was assessed using the medication possession ratio (MPR) over 12-months post-index (i.e., sum of days' supply dispensed divided by 365 days). Patients with a MPR>0.8 were considered adherent. The follow-up period to assess incident fracture began at month 13. The analysis included 33,558 new bisphosphonate users with mean age (SD) 59.5 (9.3) years; 94.0% were female. Median MPR at 12 months was 0.61 for alendronate and risedronate; 0.58 for ibandronate. Proportionally more nonfracture patients (39.3%) had a MPR>0.8 compared with fracture patients (34.9%, p<0.001). In multivariate modeling of bisphosphonate users' experience, those with a MPR>0.8 had a 14% lower risk of subsequent fracture than those with MPR<0.5, after controlling for demographics, insurance type, select comorbidities, and other potential confounders (p=0.0459). In a large, commercially-insured population, suboptimal adherence with bisphosphonate treatment was associated with increased fracture risk even after controlling for potential confounders.     

Occupational aspects of epilepsy in the civil service.

Eighty five civil servants with epilepsy who were referred to the Civil Service Occupational Health Service over an 18 month period formed the study population. The reasons for these referrals and their outcomes have been analysed. The main reasons for referral were prolonged or frequent sickness absence, unsatisfactory work performance, epilepsy starting during employment, the discovery of undisclosed epilepsy, and for advice on working conditions. In 30 the outcome was medical retirement, although in only 15 was this due to epilepsy alone. Of the other 15, medical retirement was necessary in four because of the combination of epilepsy with another medical disorder, and in 11 because of a coincidental condition unrelated to their epilepsy. Only six out of 15 referred on account of epilepsy related sickness absence, and none of the 14 referrals due to epilepsy related unsatisfactory work performance resulted in early retirement. This reflected the invaluable role that the occupational physicians had in recognising where problems were due to poor control of the epilepsy or to the side effects of the antiepileptic medication and in arranging through general practitioners or hospital doctors for appropriate adjustment of the drug regimen. Nine of the 22 subjects who developed epilepsy during employment, however, were retired on medical grounds.     

Metabolic fate of the new anti-ulcer drug enprostil in animals. 3rd communication: tissue accumulation after consecutive oral administration of [3H]-enprostil in rats

Accumulation characteristics of radioactivity in organs and tissues were investigated after oral administration of [3H]-enprostil ((+/-)-11a,15a-dihydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranorp r osta-4,5,13(t)- trienoic acid methyl ester, TA-84135) to male rats once a day (20 micrograms/kg/d) for 1, 7 or 14 days. [3H]-Enprostil was found to be partially metabolized in vivo to volatile tritium (3H2O). The ratios of volatile tritium to total radioactivity in plasma increased with repeated administration of [3H]-enprostil and the levels of volatile tritium were almost equilibrated within 7 days of drug administration. The formation rate of volatile tritium was estimated to be 1-2% of the single dose. The blood levels of non-volatile radioactivity at 1 h after each daily dosing were nearly constant. The levels at 24 h, however, increased with repeated dosing. The levels of non-volatile radioactivity in most tissues at 1 h after the multiple administration (7 and 14 times) were higher than those after the single dose. At 24 h, levels were noticeable after multiple dosing even in the tissues in which levels below the detection limit were found after the single dose. From the comparison of the multiple-dose groups, the levels in most tissues attained steady state within 7 times dosing. The daily excretions of radioactivity in the urine, feces and expired air were constant throughout the period of consecutive administration. The total recovery of administered dose was 92%, which was similar to that achieved in the single-dosing group. As described above, the retention of non-volatile radioactivity was observed in most tissues.(ABSTRACT TRUNCATED AT 250 WORDS)