'I can see this life for exactly what it is. I can now, anyway. We're walkin' a knife edge. One slip, one tiny slip an' we fall. An' there's a fuck of a long way to fall…even for us. An' we're kept ...there…on the knife edge…because they can tell yer which way t'go. Forward or down.' Fin's bright. Some would say gifted. But school isn't going well. While he is busy coping with his mum's depression and his younger brother's drug problem, he can feel his future slipping away. The few jobs that are available in North London are part-time or temporary, and Fin knows his future will be a life of unstable pay, minimal social security benefits, no pension and eroding health care. He is the uture of the emerging major class – living precarious lives at the mercy of the one percent: The Precariat. With his world collapsing slowly around him, Fin finds hope and attraction with the girl at the fried chicken drive-through window. But even she can't offer him a way out. Fin makes one final desperate bid to take control over the future – by giving his brother the chance to turn his life around…
Despite the well recognized protective effect of cruciferous vegetables against various cancers, including human colorectal cancers, little is known about how this effect is conferred. It is thought ...that some phytochemicals found only in these vegetables confer the protection. These compounds include the glucosinolates, of which indole-3-carbinol is one. They are known to induce carcinogen-metabolizing (phase II) enzymes, including the glutathione S-transferase (GST) family. Other effects in humans are not well documented. We wished to assess the effect of indole-3-carbinol on GST enzymes.
We carried out a placebo-controlled human volunteer study. All patients were given 400 mg daily of indole-3-carbinol for three months, followed by placebo. Serum samples were tested for the GSTM1 genotype by polymerase chain reaction. Serum GST levels were assessed using enzyme-linked immunosorbent assay and Western Blot methodologies.
Forty-nine volunteers completed the study. GSTM1 genotypes were obtained for all but two volunteers. A slightly greater proportion of volunteers were GSTM1-positive, in keeping with the general population. GST was detected in all patients. Total GST level was not affected by indole-3-carbinol dosing compared with placebo. Although not statistically significant, the GSTM1 genotype affected the serum GST level response to indole-3-carbinol.
Indole-3-carbinol does not alter total serum GST levels during prolonged dosing.
Maternal smoking can cause health complications in pregnancy. Particulate matter (PM
) metrics applied to second hand smoke (SHS) concentrations provide indoor air quality (IAQ) measurements and have ...been used to promote smoking behaviour change among parents of young children. Here, we present the qualitative results from a study designed to use IAQ measurements to help pregnant women who smoke to quit smoking.
We used IAQ measurements in two centres (Aberdeen and Coventry) using two interventions: 1. In Aberdeen, women made IAQ measurements in their homes following routine ultrasound scan; 2. In Coventry, IAQ measurements were added to a home-based Stop Smoking in Pregnancy Service. All women were invited to give a qualitative interview to explore acceptability and feasibility of IAQ measurements to help with smoking cessation. A case study approach using grounded theory was applied to develop a typology of pregnant women who smoke.
There were 39 women recruited (18 in Aberdeen and 21 in Coventry) and qualitative interviews were undertaken with nine of those women. Diverse accounts of smoking behaviours and experiences of participation were given. Many women reported changes to their smoking behaviours during pregnancy. Most women wanted to make further changes to their own behaviour, but could not commit or felt constrained by living with a partner or family members who smoked. Others could not envisage quitting. Using themes emerging from the interviews, we constructed a typology where women were classified as follows: 'champions for change'; 'keen, but not committed'; and 'can't quit, won't quit'. Three women reported quitting smoking alongside participation in our study.
Pregnant women who smoke remain hard to engage,. Although providing IAQ measurements does not obviously improve quit rates, it can support changes in smoking behaviour in/around the home for some individuals. Our typology might offer a useful assessment tool for midwives.
Mapping the Arabidopsis organelle proteome Dunkley, T.P.J; Hester, S; Shadforth, I.P ...
Proceedings of the National Academy of Sciences - PNAS,
04/2006, Letnik:
103, Številka:
17
Journal Article
Recenzirano
Odprti dostop
A challenging task in the study of the secretory pathway is the identification and localization of new proteins to increase our understanding of the functions of different organelles. Previous ...proteomic studies of the endomembrane system have been hindered by contaminating proteins, making it impossible to assign proteins to organelles. Here we have used the localization of organelle proteins by the isotope tagging technique in conjunction with isotope tags for relative and absolute quantitation and 2D liquid chromatography for the simultaneous assignment of proteins to multiple subcellular compartments. With this approach, the density gradient distributions of 689 proteins from Arabidopsis thaliana were determined, enabling confident and simultaneous localization of 527 proteins to the endoplasmic reticulum, Golgi apparatus, vacuolar membrane, plasma membrane, or mitochondria and plastids. This parallel analysis of endomembrane components has enabled protein steady-state distributions to be determined. Consequently, genuine organelle residents have been distinguished from contaminating proteins and proteins in transit through the secretory pathway.
Zircons from two paragneisses (from Mount Sones and Dallwitz Nunatak) and one orthogneiss (from Gage Ridge) in the Tula Mountains, Napier Complex (East Antarctica) were analyzed for U-Pb age, ...oxygen isotopes, REEs and by scanning ion imaging. A large number of zircons from all samples are reversely discordant. Mt Sones zircons show an age range from 3.0 Ga to 2.5 Ga and underwent high-grade metamorphism at both ~2.8 Ga and 2.5 Ga. Zircons from Dallwitz Nunatak record detrital ages between 3.5 Ga and 2.5 Ga. Zircons from Gage Ridge record multiple age groups, with concordant data between 3.6 Ga and 3.3 Ga and reversely discordant data that form a discrete ~3.8 Ga population. All of the grains show evidence of Pb mobility during metamorphism. Ion imaging of zircons reveals Y and U zonation, characteristic of magmatic zircon, together with a micro-scale patchy distribution of Pb and Pb that does not correspond to either growth zonation or crystal imperfections. Some of these patches yield ... ages >4 Ga, whereas others yield ages younger than the magmatic crystallization age. Reversely discordant data are the result of ancient Pb mobilization, which is independent of the degree of metamictisation, oxygen isotope and REE content of the zircons. This mobilization can result in spurious ages and was most likely caused by polymetamorphism under anhydrous conditions; that is two high-grade events; one poorly defined at ~2.8 Ga and the other ultra-high temperature (UHT) metamorphism at 2.5 Ga. (ProQuest: ... denotes formulae/symbols omitted.)
Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains ...a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and -independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand-driven nuclear translocation of AR and a downregulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation.
We conducted a trial in 103 patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) using imatinib 600 mg/day, with dose escalation to 800 mg/day for suboptimal response. The ...estimated cumulative incidences of complete cytogenetic response (CCR) by 12 and 24 months were 88% and 90%, and major molecular responses (MMRs) were 47% and 73%. In patients who maintained a daily average of 600 mg of imatinib for the first 6 months (n = 60), MMR rates by 12 and 24 months were 55% and 77% compared with 32% and 53% in patients averaging less than 600 mg (P = .037 and .016, respectively). Dose escalation was indicated for 17 patients before 12 months for failure to achieve, or maintain, major cytogenetic response at 6 months or CCR at 9 months but was only possible in 8 patients (47%). Dose escalation was indicated for 73 patients after 12 months because their BCR-ABL level remained more than 0.01% (international scale) and was possible in 45 of 73 (62%). Superior responses achieved in patients able to tolerate imatinib at 600 mg suggests that early dose intensity may be critical to optimize response in CP-CML. The trial was registered at www.ANZCTR.org.au as #ACTRN12607000614493.
The relationship between severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and the related syndrome SMEI-borderland (SMEB) with mutations in the sodium channel alpha 1 subunit gene SCN1A ...is well established. To explore the phenotypic variability associated with SCN1A mutations, 188 patients with a range of epileptic encephalopathies were examined for SCN1A sequence variations by denaturing high performance liquid chromatography and sequencing. All patients had seizure onset within the first 2 years of life. A higher proportion of mutations were identified in patients with SMEI (52/66; 79%) compared to patients with SMEB (25/36; 69%). By studying a broader spectrum of infantile epileptic encephalopathies, we identified mutations in other syndromes including cryptogenic generalized epilepsy (24%) and cryptogenic focal epilepsy (22%). Within the latter group, a distinctive subgroup designated as severe infantile multifocal epilepsy had SCN1A mutations in three of five cases. This phenotype is characterized by early onset multifocal seizures and later cognitive decline. Knowledge of an expanded spectrum of epileptic encephalopathies associated with SCN1A mutations allows earlier diagnostic confirmation for children with these devastating disorders.
Infantile spasms constitute a severe form of epileptic encephalopathy. In the International Collaborative Infantile Spasms Study (ICISS), we showed that combining vigabatrin with hormonal therapy was ...more effective than hormonal therapy alone at stopping spasms between days 14 and 42 of treatment. In this planned follow-up, we aimed to assess whether combination therapy was associated with improved developmental and epilepsy outcomes at 18 months of age.
In ICISS, a multicentre, open-label, randomised controlled trial, infants were enrolled from 102 hospitals (three in Australia, 11 in Germany, two in New Zealand, three in Switzerland, and 83 in the UK). Eligible infants had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) electroencephalogram (EEG) no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing epilepsy and developmental outcomes at 18 months were masked to treatment allocation. Minimum doses were oral prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without oral vigabatrin 100 mg/kg per day. The primary outcome at 18 months was development as assessed by the Vineland Adaptive Behaviour Scales (VABS) composite score. Secondary outcomes were the presence or absence of epileptic seizures or infantile spasms in the previous 28 days, as recorded by parents and carers, and the use of any anti-epileptic treatment (including ketogenic diet) in the previous 28 days. Analysis was by intention to treat. The trial is registered with the ISRCTN registry, number 54363174, and EudraCT, number 2006-000788-27.
Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (n=186) or hormonal therapy alone (n=191). 362 infants were assessed for developmental and epilepsy outcomes at 18 months, 181 in each treatment group. Mean VABS scores did not differ significantly between the combination therapy group and the hormonal therapy alone group (73·9 SE 1·3 vs 72·7 1·4, difference -1·2 95% CI -4·9 to 2·6, p=0·55). Presence of epilepsy at the assessment at age 18 months was similar in both treatment groups (54 30·0% of 180 infants who received combination therapy vs 52 29·2% of 178 who received hormonal therapy alone; difference 0·8% 95% CI -8·8 to 10·4, p=0·90). Presence of spasms was also similar in both treatment groups (27 15·0% of 180 infants on combination therapy vs 28 15·7% of 178 on hormonal therapy alone; difference 0·7% 95% CI -6·9 to 8·3, p=0·85). At the 18-month assessment, 158 (44·1%) of 358 infants were on some form of anti-epileptic treatment. Initial control of spasms between days 14 and 42 of treatment was associated with higher mean VABS scores at 18 months (79·1 SE 1·2 vs 63·2 1·1, difference 15·9 95% CI 12·4 to 19·5, p<0·001) and with higher likelihood of absence of seizures at 18 months (in 39 17·0% of 229 infants who achieved spasm cessation vs 67 51·9% of 129 who did not; difference 34·9% 24·8 to 45·0, p<0·001). Increasing lead-time to treatment was associated with lower VABS scores (analysis of variance: F4,354=6·38, p<0·001) and worse epilepsy outcomes (p=0·023).
Combination therapy did not result in improved developmental or epilepsy outcomes at 18 months. However, early clinical response to treatment was associated with improved developmental and epilepsy outcomes at 18 months. Longer lead-time to treatment was associated with poorer outcomes. Rapid diagnosis and effective treatment of infantile spasms could therefore improve outcomes.
The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, BRONNER-BENDER Stiftung/Gernsbach, University Children's Hospital Zurich.
Human plasma-derived factor VIII/von Willebrand factor complex concentrates are used to control bleeding in patients with von Willebrand disease (VWD) or haemophilia A (HA). The properties of these ...haemostatic factor concentrates vary widely, which can have significant clinical implications. This review provides an extensive overview of the molecular properties, in addition to pharmacokinetic, efficacy and safety data, and case studies of clinical experience of one such concentrate, Biostate. These data are discussed in the context of various therapeutic applications and compared with other factor concentrate products. Data are presented from data on file from the manufacturer; product information and published experimental and clinical pharmacokinetic, safety and efficacy study data; and example case studies of clinical experience. The data discussed herein demonstrate that Biostate has well-established efficacy profiles in the treatment of patients with VWD or HA, with the control of bleeding rated as 'excellent', 'good' or 'moderate' in >90% of patients. In an immune-tolerance induction setting, 73% of patients achieved a complete response following treatment with Biostate. Biostate was generally well tolerated in patients with HA or VWD, with infrequent minor adverse events reported and no reported cases of clinically relevant thrombosis.
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