The doxorubicin-selected lung cancer cell line H69AR is resistant to many chemotherapeutic agents. However, like most tumor samples from individuals with this disease, it does not overexpress P-glycoprotein, a transmembrane transport protein that is dependent on adenosine triphosphate (ATP) and is associated with multidrug resistance. Complementary DNA (cDNA) clones corresponding to messenger RNAs (mRNAs) overexpressed in H69AR cells were isolated. One cDNA hybridized to an mRNA of 7.8 to 8.2 kilobases that was 100- to 200-fold more expressed in H69AR cells relative to drug-sensitive parental H69 cells. Overexpression was associated with amplification of the cognate gene located on chromosome 16 at band p13.1. Reversion to drug sensitivity was associated with loss of gene amplification and a marked decrease in mRNA expression. The mRNA encodes a member of the ATP-binding cassette transmembrane transporter superfamily.

Summary Background Davunetide (AL-108, NAP) is an eightamino acid peptide that promotes microtubule stability and decreases tau phosphorylation in pre-clinical studies. Since PSP is tightly linked to tau pathology, davunetide could be an effective treatment for PSP.The goals of this study were to evaluate the efficacy and safety of davunetide in PSP. Methods A phase 2/3 double-blind, parallel group, clinical trial of davunetide 30 mg or placebo (randomized 1:1) administered intranasally twice daily for 52 weeks was conducted at 48centers. Participants met modifiedNNIPPS criteria for possible or probable PSP. Co-primary endpointswere the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England ADL(SEADL) scale at up to 52 weeks. Data from all individuals who received at least one dose of medication and had a post-baseline efficacy assessment were compared using a rank-based method.Secondary outcomes included the Clinical Global Impression of Change (CGIC) and the change in regional brain volumeon MRI. Clinicaltrials.gov identifier: NCT01110720. Findings 360 participants were screened, 313 were randomized and 243 (77.6%) completed the study. There were no group differences in PSPRS (mean difference: 0.49 [95% CI: −1.5, 2.5], p = 0.72) or SEADL (1% [−2, 4%], p = 0.76) change from baseline (CFB) and mean 52 week CFB PSPRS scores were similar between the davunetide (11.3 [9.8,12.8]) and placebo groups (10.9 [9.1, 13.0]). There wereno differences in any of the secondary or exploratory endpoints. There were 11deaths in the davunetide group and tenin the placebo group. There were more nasal adverse events in the davunetide group. Interpretation Davunetide is well tolerated but is not an effective treatment for PSP. Clinical trials of disease modifying therapy are feasible in PSP and should be pursued with other promising tau-directed therapies. Funding Allon Therapeutics

indicate that attitudes among the medical profession and patients are changing.There has been much discussion about clinical trials and informed consent,46 and, though we believe that informed consent is mandatory, we accept that a proportion of patients do not enter trials because they may dislike the idea of a random decision being made about treatment or because they refuse or request one part of the random option offered. A further group of patients are excluded because they do not fulfil the entry criteria for the trial, and this group may be larger than forecast at the time the trial was planned. These factors may be the reason why accrual to the Scottish breast conservation trial has been slower than anticipated. The planned total intake was 900 patients, and after four years 420 patients had been entered.In conclusion more than half of the patients thought initially to be suitable for conservation were excluded from our trials and one third of the remainder refused to take part. Those planning prospective clinical trials should therefore take into account the loss of patients through ineligibility and refusal when predicting the accrual rate and overall duration of any proposed trial and the possible effects of this selection on conclusions drawn from the results. Design-A study of all infants dying suddenly and unexpectedly and of two controls matched for age and date with each index case. The parents of control infants were interviewed within 72 hours of the index infant's death. Information was collected on bedding, sleeping position, heating, and recent signs of illness for index and control infants.Setting-A defined geographical area comprising most of the county of Avon and part of Somerset.Subjects-72 Infants who had died suddenly and unexpectedly (of whom 67 had died from the sudden infant death syndrome) and 144 control infants.Results-Compared with the control infants the infants who had died from the sudden infant death syndrome were more likely to have been sleeping prone (relative risk 8-8; 95% confidence interval 7.0 to 11-0; p<0-001), to have been more heavily wrapped (relative risk 1-14 per tog above 8 tog; 1-03 to 1-28; p<005), and to have had the heating on all night (relative risk 2-7; 1-4 to 5.2; p<0-01). These differences were less pronounced in the younger infants (less than 70 days) than the older ones. The risk of sudden unexpected death among infants older than 70 days, nursed prone, and with clothing and bedding of total thermal resistance greater than 10 tog was increased by factors of 15-1 (2.6 to 89.6) and 25-2 (3.7 to 169-0) respectively compared with the risk in

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New Zealand's high mortality rate from sudden infant death syndrome (SIDS) prompted the development of the New Zealand Cot Death Study. A report of the analysis of the data from the first year has been published. This report now gives the major identified risk factors from the full 3 year data set. In this case-control study there were 485 infants who died from SIDS in the post-neonatal age group, and 1800 control infants, who were a representative sample of all hospital births in the study region. Obstetric records were examined and parental interviews were completed in 97.5% and 86.9% of subjects, respectively. As expected many risk factors for SIDS were confirmed including: lower socio-economic status, unmarried mother, young mother, younger school-leaving age of mother, younger age of mother at first pregnancy, late attendance at antenatal clinic, non-attendance at antenatal classes, Maori, greater number of previous pregnancies, the further south the domicile, winter, low birthweight, short gestation, male infant and admission to a special care baby unit. In addition, however, we identified four risk factors that are potentially amenable to modification.(ABSTRACT TRUNCATED AT 250 WORDS)

A chronic disease management programme for COPD patients that incorporated a variety of interventions, including pulmonary rehabilitation and implemented by primary care, reduced admissions and hospital bed days. Key elements were patient participation and information sharing among healthcare providers.

The association between dummy use and sudden infant death syndrome (SIDS) was investigated in 485 deaths due to SIDS in the postneonatal age group and compared with 1800 control infants. Parental interviews were completed in 87% of subjects. The prevalence ofdummy use in New Zealand is low and varies within New Zealand. Dummy use in the two week period before death was less in cases of SIDS than in the last two weeks for controls (odds ratio (OR) 0 76, 95% confidence interval (CI) 0-57 to 1.02). Use of a dummy in the last sleep for cases of SIDS or in the nominated sleep for controls was significantly less in cases than controls (OR 0-44, 95% CI 0.26 to 0.73). The OR changed very little after controlling for a wide range of potential confounders.

A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis and biological activity of this new series of substituted 8,9-benzo[a]phenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein. Selected analogues were evaluated against the COR-L23 parental human non small cell lung carcinoma cell line and the COR-L23/R resistant cell line which overexpresses multidrug resistance protein. This series of novel angular benzophenazines were potent cytotoxic agents in these cell lines and may be able to circumvent multidrug resistance mechanisms which result in the lack of efficacy of many drugs in cancer chemotherapy. These compounds show dual inhibition of topoisomerase I and topoisomerase II and thus target two key enzymes responsible for the topology of DNA that are active at different points in the cell cycle. The introduction of chirality into the carboxamide side chain of these novel benzophenazine carboxamides has resulted in the discovery of a potent enantiospecific series of cytotoxic agents, exemplified by 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576 ((R)-4j' '). In vivo activity has been demonstrated for 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576, after intravenous administration to female mice, and this compound has been selected as a development candidate for further evaluation.