A prospective, randomized, open label, phase iii clinical trial of novottf-100a vs best standard of care chemotherapy in patients with recurrent glioblastoma

BACKGROUND: Glioblastoma, the most common adult primary malignant brain tumor, confers poor prognosis (median survival of 15 months) notwithstanding aggressive treatment. Combination chemotherapy including carmustine (BCNU) or temozolomide (TMZ) with the MGMT inhibitor O6-benzylguanine (O6BG) has been used, but has been associated with dose-limiting hematopoietic toxicity. OBJECTIVE: To assess safety and efficacy of a retroviral vector encoding the O6BG-resistant MGMTP140K gene for transduction and autologous transplantation of hematopoietic stem cells (HSCs) in MGMT unmethylated, newly diagnosed glioblastoma patients in an attempt to chemoprotect bone marrowduring combination O6BG/TMZ therapy. METHODS: Three patients have been enrolled in the first cohort. Patients underwent standard radiation therapy without TMZ followed by G-CSF mobilization, apheresis, and conditioning with 600 mg/m2 BCNU prior to infusion of gene-modified cells. Posttransplant, patients were treated with 28-day cycles of single doseTMZ (472 mg/m2) with 48-hour intravenous O6BG (120 mg/m2 bolus, then 30 mg/m2/d). RESULTS: The BCNU dose was nonmyeloablative with ANC ,500/mL for ≤3 d and nadir thrombocytopenia of 28,000/mL. Gene marking in pre-infusion colony forming units (CFUs) was 70.6%, 79.0%, and 74.0% in Patients 1, 2, and 3, respectively, by CFU-PCR. Following engraftment, gene marking in white blood cells and sorted granulocytes ranged between 0.37-0.84 and 0.33-0.83 provirus copies, respectively, by real-time PCR. Posttransplant gene marking in CFUs from CD34-selected cells ranged from 28.5% to 47.4%. Patients have received 4, 3, and 2 cycles of O6BG/TMZ, respectively, with evidence for selection of gene-modified cells. One patient has received a single dose-escalated cycle at 590 mg/m2 TMZ. No additional extra-hematopoietic toxicity has been observed thus far and all three patients exhibit stable disease at 7-8 months since diagnosis CONCLUSIONS: We believe that these data demonstrate the feasibility of achieving significant engraftment of MGMTP140K-modified cells with a well-tolerated dose of BCNU. Further follow-up will determine whether this approach will allow for further dose escalation of TMZ and improved survival.

Gemcitabine, oxaliplatin and 5-FU in advanced bile duct and gallbladder carcinoma: two parallel, multicentre phase-II trials.

BACKGROUND: Gemcitabine, oxaliplatin and 5-fluorouracil (5-FU) are active in biliary tract cancer and have a potentially synergistic mode of action and non-overlapping toxicity. The objective of these trials was to determine response, survival and toxicity separately in patients with bile duct cancer (BDC) and gallbladder cancer (GBC) treated with gemcitabine/oxaliplatin/5-FU chemotherapy. METHODS: Eligible patients with histologically proven, advanced or metastatic BDC (n=37) or GBC (n=35) were treated with gemcitabine (900 mg m(-2) over 30 min), oxaliplatin (65 mg m(-2)) and 5-FU (1500 mg m(-2) over 24 h) on days 1 and 8 of a 21-day cycle. Tumour response was the primary outcome measure. RESULTS: Response rates were 19% (95% CI: 6-32%) and 23% (95% CI: 9-37%) for BDC and GBC, respectively. Median survivals were 10.0 months (95% CI: 8.6-12.4) and 9.9 months (95% CI: 7.5-12.2) for BDC and GBC, respectively, and 1- and 2-year survival rates were 40 and 23% in BDC and 34 and 6% in GBC (intention-to-treat analysis). Major grade III and IV adverse events were neutropenia, thrombocytopenia, elevated bilirubin and anorexia. CONCLUSION: Triple-drug chemotherapy achieves comparable results for response and survival to previously reported regimens, but with more toxicity.

Adult consequences of late adolescent alcohol consumption: a systematic review of cohort studies.

Alcohol is responsible for a significant portion of the global burden of disease. There is widespread concern reported in the media and other sources about drinking trends among young people, particularly heavy episodic or “binge” drinking. Prominent among policy responses, in the UK and elsewhere, have been attempts to manage antisocial behaviour related to intoxication in public spaces. Much less attention has been given to the longer term effects of excessive drinking in adolescence on later adult health and well-being. Some studies suggest that individuals “mature out” of late adolescent drinking behaviour, whilst others identify enduring effects on drinking and broader health and social outcomes in adulthood. If adolescent drinking does not cause later difficulties in adulthood then intervention approaches aimed at addressing the acute consequences of alcohol, such as unintentional injuries and anti-social behaviour, may be the most appropriate solution. If causal relationships do exist, however, this approach will not address the cumulative harms produced by alcohol, unless such intervention successfully modifies the long-term relationship with alcohol, which seems unlikely. To address this issue a systematic review of cohort studies was conducted, as this approach provides the strongest observational study design to evaluate evidence for causal inference.This resource was contributed by The National Documentation Centre on Drug Use.

The impact of vascular burden on late-life depression.

Small vessel pathology and microvascular lesions are no longer considered as minor players in the fields of cognitive impairment and mood regulation. Although frequently found in cognitively intact elders, both neuroimaging and neuropathological data revealed the negative impact on cognitive performances of their presence within neocortical association areas, thalamus and basal ganglia. Unlike cognition, the relationship between these lesions and mood dysregulation is still a matter of intense debate. Early studies focusing on the role of macroinfarct location in the occurrence of post-stroke depression (PSD) led to conflicting data. Later on, the concept of vascular depression proposed a deleterious effect of subcortical lacunes and deep white matter demyelination on mood regulation in elders who experienced the first depressive episode. More recently, the chronic accumulation of lacunes in thalamus, basal ganglia and deep white matter has been considered as a strong correlate of PSD. We provide here a critical overview of neuroimaging and neuropathological sets of evidence regarding the affective repercussions of vascular burden in the aging brain and discuss their conceptual and methodological limitations. Based on these observations, we propose that the accumulation of small vascular and microvascular lesions constitutes a common neuropathological platform for both cognitive decline and depressive episodes in old age.

Asthme a début tardif [Late-onset asthma].

Late-onset asthma is a common disease, with characteristics that differentiate it from childhood asthma persisting in adults, including a heterogeneity of underlying mechanism, a correlation with occupational exposure and the tendency to chronicize. Inadequate perception of the disease importance and difficulties in diagnosis, due to the association to COPD, the broad differential diagnosis spectrum and an atypical clinical manifestation, make this disease entity underdiagnosed and under-treated, with consequences for morbidity and mortality. The treatment of adults with asthma follows the usual guidelines, but must take into account an occasional poor therapeutic response and the risk of side effects in polymorbid patients.

On the origin of the ultradeep East Barents Sea basin

Very large subsidence, with up to 20 km thick sediment layers, is observed in the East Barents Sea basin. Subsidence started in early Paleozoic, accelerated in Permo-Triassic times, finished during the middle Cretaceous, and was followed by moderate uplift in Cenozoic times. The observed gravity signal suggests that the East Barents Sea is at present in isostatic balance and indicates that a mass excess is required in the lithosphere to produce the observed large subsidence. Several origins have been proposed for the mass excess. We use 1-D thermokinematic modeling and 2-D isostatic density models of continental lithosphere to evaluate these competing hypotheses. The crustal density in 2-D thermokinematic models resulting from pressure-, temperature-, and composition-dependent phase change models is computed along transects crossing the East Barents Sea. The results indicate the following. (1) Extension can only explain the observed subsidence provided that a 10 km thick serpentinized mantle lens beneath the basin center is present. We conclude that this is unlikely given that this highly serpentinized layer should be formed below a sedimentary basin with more than 10 km of sediments and crust at least 10 km thick. (2) Phase changes in a compositionally homogeneous crust do not provide enough mass excess to explain the present-day basin geometry. (3) Phase change induced densification of a preexisting lower crustal gabbroic body, interpreted as a mafic magmatic underplate, can explain the basin geometry and observed gravity anomalies. The following model is proposed for the formation of the East Barents Sea basin: (1) Devonian rifting and extension related magmatism resulted in moderate thinning of the crust and a mafic underplate below the central basin area explaining initial late Paleozoic subsidence. (2) East-west shortening during the Permian and Triassic resulted in densification of the previously emplaced mafic underplated body and enhanced subsidence dramatically, explaining the present-day deep basin geometry.

An international, randomized, double-blind, placebo-controlled, phase III trial of pregabalin monotherapy in treatment of patients with fibromyalgia.

OBJECTIVE: To evaluate the efficacy and safety of pregabalin monotherapy versus placebo for symptomatic pain relief and improvement of patient global assessment in patients with fibromyalgia (FM) enrolled from countries outside the United States. METHODS: This international, multicenter, double-blind, placebo-controlled trial randomly assigned 747 patients with FM to placebo or 300, 450, or 600 mg/day pregabalin twice daily for 14 weeks. Primary efficacy measures were endpoint mean pain scores and Patient Global Impression of Change (PGIC). Secondary outcomes included assessments of sleep and function. RESULTS: Patients in the 450 mg/day pregabalin group showed significant improvements versus placebo in endpoint mean pain score (-0.56; p = 0.0132), PGIC (73% improved vs 56% placebo; p = 0.0017), and function [Fibromyalgia Impact Questionnaire (FIQ) total score -5.85; p = 0.0012]. PGIC was also significant for 600 mg/day pregabalin (69% improved; p = 0.0227). Results for these endpoints were nonsignificant for pregabalin at 300 mg/day and for pain and FIQ score at 600 mg/day. Early onset of pain relief was seen, with separation from placebo detected by Week 1 in all pregabalin groups. All pregabalin doses demonstrated superiority to placebo on the Medical Outcomes Study-Sleep Scale Sleep Disturbance subscale and the Sleep Quality diary. Dizziness and somnolence were the most frequently reported adverse events. CONCLUSION: Pregabalin demonstrated modest efficacy in pain, global assessment, and function in FM at 450 mg/day, and improved sleep across all dose levels, but it did not provide consistent evidence of benefit at 300 and 600 mg/day in this study. Pregabalin was generally well tolerated for the treatment of FM. (Clinical trial registry NCT00333866).

Tethyan margins in space and time

Rifting processes, leading to sea-floor spreading, are characterized by a sequence of events: transtensive phase of extension with syn-rift volcanism; simple shear extension accompanied by lithospheric thinning and asthenospheric up-welling and thermal uplift of the rift shoulder and asymmetric volcanism. The simple shear model of extension leads to an asymmetric model of passive margin: a lower plate tilted block margin and an upper plate flexural, ramp-like margin- Both will be affected by thermal contraction and subsidence, starting soon after sea-floor spreading. Based on these actualistic models Tethyan margins are classified as one type or the other. Their evolution from the first transtensional phase of extension to the passive margin stage are analyzed. Four main rifting events are recognized in the Tethyan realm: an episode of lower Paleozoic events leading to the formation of the Paleotethys; a Late Paleozoic event leading to the opening of the Permotethys and East Mediterranean basin: an early Mesozoic event leading to the opening of the Pindos Neotethys and a Jurassic event related to the opening of the Alpine/Atlantic Neotethys. Type margins are given as example of each rifting event: -Northern Iran (Alborz) as a type area for the Late Ordovician to Silurian rifting of Paleotethys. -Northern India and Oman for the Late Carboniferous to early Permian rifting of Permotethys. -The East Mediterranean (Levant, Tunisia) as a Late Carboniferous rifting event. -The Neotethyan rifting phases are separated in two types: an eastern Pindos system found in Turkey and Greece is genetically linked to the Permotethys with a sea-floor spreading delayed until middle Triassic: a western Alpine system directly linked to the opening of the central Atlantic is characterized by a Late Triassic transtensive phase, an early to Middle Liassic break-away phase and. following sea-floor spreading, a thermal subsidence phase starting in Dogger. Problems related to the closure of the Paleozoic oceanic domains are reviewed. A Late Permian, early Triassic phase of `'docking'' between an European accretionary prism (Chios) and a Paleotethyan margin is supported by recent findings in the Mediterranean area. Back-arc rifting within the European active margin led to the formation of marginal seas during Permian and Triassic times and will contribute to the closure of the Paleozoic oceans.

ICT Skills Action Plan 2014-2018

In January 2012, in a direct response to specific skills shortages for people with high-level ICT skills, the Department of Education and Skills published a joint Government–industry ICT Action Plan aimed at building the supply of high-level ICT graduates. One of the key measures in the Plan was the roll-out, from March 2012, of more than 800 places on intensive NFQ level 8 higher diploma ICT skills conversion programmes by higher education providers in partnership with industry. In recognition of the ICT and software development skills shortages that continue to exist, a second phase of the ICT Skills Programme was rolled-out in late 2012, with the Higher Education Authority requesting proposals from higher education providers for a further round of specialist programmes aimed at addressing identified ICT and software development skills gaps. From spring 2013, a number of higher education providers are again offering a number of Level 8 Conversion Programmes, in collaboration with industry partners, which will provide graduates from other skills areas with the opportunity to up-skill or re-skill through a 1 year full-time HDip Conversion Programme in core computing/programming, software and data analysis.

Schizodeme analysis of Trypanosoma cruzi Colombian strain clones isolated from the acute phase of murine infection

Colombian strain of Trypanosoma cruzi, biodeme Type III (T. cruzi I), has been cloned by micromanipulation at two phases of the acute infection: early (10 days ) and advanced (30 days). Twelve clones were obtained therefrom. Characterization by their biological and biochemical behavior showed an identity among the several clones and their parental strain, albeit with different degrees of virulence. Molecular characterization of the kinetoplast DNA (kDNA) after amplification by polymerase chain reaction revealed identical profiles of the bands from the kDNA minicircle by the analysis of restriction fragment lenght polymorphism for the isolated clones, their parental strain, and to the clones isolated at two different phases of the infection. Results suggest the predominance of a "principal clone", in the composition of the Colombian strain, responsible for the biological and biochemical behavior. However, no relationship was detected between the molecular profile of kDNA and the degree of virulence presented by the several clones.

Clinical forms of Trypanosoma cruzi infected individuals in the chronic phase of Chagas disease in Puebla, Mexico

In Mexico, despite the relatively high seroprevalence of Trypanosoma cruzi infection in humans in some areas, reported morbidity of Chagas disease is not clear. We determined clinical stage in 71 individuals seropositive to T. cruzi in the state of Puebla, Mexico, an area endemic for Chagas disease with a reported seroprevalence of 7.7%. Diagnosis of Chagas disease was made by two standardized serological tests (ELISA, IHA). Individuals were stratified according to clinical studies. All patients were submitted to EKG, barium swallow, and barium enema. Groups were identified as indeterminate form (IF) asymptomatic individuals without evidence of abnormalities (n = 34 cases); those with gastrointestinal alterations (12 patients) including symptoms of abnormal relaxation of the lower esophageal sphincter and absent peristalsis in the esophageal body, grade I megaesophagus, and/or megacolon; patients with clinical manifestations and documented changes of chronic Chagas heart disease who were subdivided as follows: mild (8 patients) - mild electrocardiographic changes of ventricular repolarization, sinus bradychardia); moderate (6 patients) - left bundle branch block, right bundle branch block associated with left anterior fascicular block); severe (8 patients) - signs of cardiomegaly, dilated cardiomyopathy); and the associated form (3 cases) that included presence of both cardiomyopathy and megaesophagus. These data highlight the importance of accurate evaluation of the prevalence and clinical course of Chagas disease in endemic and non-endemic areas of Mexico.