Reduced metal transferrin binding in neurological diseases

By employing G75 gel-filtration chromotography, it has been demonstrated that human plasma gallium speciation (and by implication, Al speciation) is bimodal. Normally, gallium was predominantly bound to a high molecular weight fraction which was presumably transferrin. Literature reviews and experimental work throughout this thesis provided evidence to support this idea. An aluminium-transferrin species was assumed to be relatively non-toxic and a protective function for this complex has been suggested. A second, low molecular weight species of gallium was observed and its identity has been suggested to be citrate. The results of this thesis support the concept citrate was a gallium binding ligand present in the plasma, but there was another species (tentatively identified as phosphate) which bound gallium to a much greater degree than did citrate in the majority of samples studied. The consequence of a low molecular weight species of aluminium is the possibility that this leads to a more rapid, uncontrolled deposition of the metal in the brain compared to a transferrin mediated mechanism. Plasma speciation studies in Alzheimer's disease, Parkinson's disease, Down's syndrome, and neonates has revealed an altered ratio of the two gallium species found in control subjects. In all groups there was an increase in the potentially more neurotoxic low molecular weight species. These observations have led to a suggested mechanism of accumulation of metals in the brain, which is known to occur in the first three groups. Possible pathogenic mechanisms are described. The results can also offer an explanation to the reported increased sensitivity to the toxic effects of aluminium in the neonate. Speciation studies on normal plasma has shown the balance between high and low molecular weight species of gallium to be influenced by many physiological factors. There appears to be a fine equilibrium between both species which can be altered without any great difficulty. Therefore, in the diseased groups studied, it is possible that there are subtle biochemical changes within the circulatory system to affect the equilibrium which results in an increased low molecular weight species of aluminium. Furthermore, it has been demonstrated that there is a group of normal controls with no clinical signs of Alzheimer's or Parkinson's disease which have reduced transferrin binding. This indicates there is a population of healthy people who are at risk to the development of either disease

Modelling variable glacier lapse rates using ERA-Interim reanalysis climatology: an evaluation at Vestari- Hagafellsjökull, Langjökull, Iceland

The near-surface air temperature lapse rate is an important tool for spatially distributing temperatures in snow- and ice-melt models, but is difficult to parameterize, as it is not simply correlated with boundary-layer meteorological variables, such as temperature itself. This contribution quantifies spring-autumn lapse rate variability over 5 years at Vestari-Hagafellsjökull, a southerly outlet of Langjökull in Iceland. It is observed that summer lapse rates (0.57 °C 100 m) are significantly lower than non-summer rates, and are also lower than the Saturated Adiabatic Lapse Rate (SALR), which is often adopted in melt models. This is consistent with reduced near-surface temperature sensitivity to free-atmosphere temperature change during the occurrence of melting. A Variable Lapse Rate (VLR) regression model is calibrated with standardized, 750 hPa temperature anomalies derived from ERA-Interim climatology, which is shown to be highly significantly correlated with near-surface temperatures. The modelled VLR overestimates cumulative June-September Positive Degree Days (PDDs) by 3% when used to extrapolate temperatures from 1100 to 500 m a.s.l. on the glacier, whereas the SALR overestimates cumulative PDDs by 14%. ERA-Interim data therefore appear to offer a good representation of free-atmosphere temperature variability over Vestari-Hagafellsjökull, and the modelling approach offers a simple means of improving lapse rate parameterizations in melt models. © 2012 Royal Meteorological Society

In situ permafrost thaw due to climate change drives holistic microbial community shifts with implications for methane cycling

Thawing permafrost is a potentially significant source of radiative forcing feedback due to increased emissions of methane, a biogenic greenhouse gas (GHG). This study investigated changes in the microbial community along a permafrost thaw gradient at Stordalen Mire, Sweden using 16S rRNA gene amplicon and metagenomic methods. In situ measurements of geochemical parameters, including CH4 and C isotopes, enabled linkage of community dynamics to significant shifts in C balance. The thaw gradient ranged from intact at a palsa (low productivity and GHG emissions), through partially thawed in a bog (high productivity, low GHG emissions) to a completely thawed fen (high productivity and GHG emissions). Microbial assemblages in both the palsa and fen were highly diverse (in both richness and evenness), consistent with climax communities. The microbial community in the bog had distinctly lower diversity, characteristic of ecosystem disturbance. The palsa community was dominated by Acidobacteria and Proteobacteria, as is typical of a range of soils including permafrost. Methanogens dominated both the bog and fen and were most abundant within the zone of water table fluctuation. Inferring methanogens’ production pathway from phylogeny showed a shift from mostly hydrogenotrophic methanogens in the bog towards acetotrophic methanogens in the fen. This corroborated porewater and flux emitted CH4 and CO2 carbon isotopic 13C signatures of CH4 and CO2. The fen, where the highest CH4 flux was recorded, was significantly richer in methanogenic archaea. A novel archaea, Candidatus Methanoflorens stordalenmirensis, was present at up to 70% relative abundance in the bog, enabling recovery of a population genome. The genome (and associated metaproteome) of ’M. stordalenmirensis’ indicates that hydrogenotrophic methane production is its main energy conservation pathway. ’Methanoflorens’ may be an indicator species of permafrost thaw, it is globally ubiquitous, and appears a major contributor to global methane production. Our results revealed a distinct difference in the microbial community structure and membership at each site, which can be directly associated with increasing methane emission and thaw state

Hydro-biogeochemical coupling beneath a large polythermal Arctic glacier: implications for subice sheet biogeochemistry

We analyze the interannual chemical and isotopic composition of runoff from a large, high Arctic valley glacier over a 5 year period, during which drainage evolved from a long-residence-time drainage system feeding an artesian subglacial upwelling (SGU) at the glacier terminus to a shorter-residence-time drainage system feeding an ice-marginal channel (IMC). Increased icemelt inputs to the SGU are thought to have triggered this evolution. This sequence of events provides a unique opportunity to identify coupling between subglacial hydrology and biogeochemical processes within drainage systems of differing residence time. The biogeochemistry of the SGU is consistent with prolonged contact between meltwaters and subglacial sediments, in which silicate dissolution is enhanced, anoxic processes (e.g., sulphate reduction) prevail, and microbially generated CO2 and sulphide oxidation drive mineral dissolution. Solute in the IMC was mainly derived from moraine pore waters which are added to the channel via extraglacial streams. These pore waters acquire solute predominantly via sulphide oxidation coupled to carbonate/silicate dissolution. We present the first evidence that microbially mediated processes may contribute a substantial proportion (80% in this case) of the total glacial solute flux, which includes coupling between microbial CO2-generation and silicate/carbonate dissolution. The latter suggests the presence of biofilms in subglacial/ice-marginal sediments, where local perturbation of the geochemical environment by release of protons, organic acids, and ligands stimulates mineral dissolution. These data enable inferences to be made regarding biogeochemical processes in longer-residence-time glacial systems, with implications for the future exploration of Antarctic subglacial lakes and other wet-based ice sheet environments

Transporting Clinical Research to Community Settings: Designing and Conducting a Multisite Trial of Brief Strategic Family Therapy

This paper describes the development and implementation of a trial of Brief Strategic Family Therapy (BSFT), an evidence-based drug intervention for adolescents, in eight community substance abuse treatment programs. Researchers and treatment programs collaborated closely to identify and overcome challenges, many of them related to achieving results that were both scientifically rigorous and applicable to the widest possible variety of adolescent substance abuse treatment programs. To meet these challenges, the collaborative team drew on lessons and practices from efficacy, effectiveness, and implementation research

Persistence of pharmacological treatment into adulthood, in UK primary care, for ADHD patients who started treatment in childhood or adolescence

Background ADHD guidelines in the UK suggest that children and adults who respond to pharmacological treatment should continue for as long as remains clinically effective, subject to regular review. To what extent patients persist with treatment from childhood and adolescence into adulthood is not clear. This study aims to describe, in UK primary care, the persistence of pharmacological treatment for patients with ADHD who started treatment aged 6–17 years and to estimate the percentage of patients who continued treatment from childhood and adolescence into adulthood. Methods The Health Improvement Network (THIN) database was used to identify patients with ADHD who received their first prescription for methylphenidate/ dexamfetamine/atomoxetine, aged 6–17 years. Patients were monitored until their ‘censored date’ (the earliest of the following dates: date the last prescription coded in the database ended, end of the study period (31st December 2008), date at which they transferred out of their practice, date of death, the last date the practice contributed data to the database). Persistence of treatment into adulthood was estimated using Kaplan Meier analysis. Results 610 patients had follow-up data into adulthood. 213 patients (93.4% male) started treatment between 6–12 years; median treatment duration 5.9 years. 131 (61.5%) stopped before 18 years, 82 (38.5%) were still on treatment age ≥18 years. 397 patients (86.4% male) started treatment between 13–17 years; median treatment duration was 1.6 years. 227 (57.2%) stopped before 18 years, 170 (42.8%) were still on treatment age ≥18 years. The number of females in both age categories was too small to formally test for differences between genders in persistence of treatment. Conclusion Persistence of treatment into adulthood is lower (~40%) compared with published rates of persistence of the condition (~65% when symptomatic definition of remission used). Due to the limited number of patients with data past 18 years, it is important that ongoing monitoring of prescribing into later adulthood is undertaken, particularly to observe the effects of recommendations in new guidelines

The “dirty dozen” of freshwater science: Detecting then reconciling hydrological data biases and errors

Sound water policy and management rests on sound hydrometeorological and ecological data. Conversely, unrepresentative, poorly collected or erroneously archived data introduces uncertainty regarding the magnitude, rate and direction of environmental change, in addition to undermining confidence in decision-making processes. Unfortunately, data biases and errors can enter the information flow at various stages, starting with site selection, instrumentation, sampling/ measurement procedures, post-processing and ending with archiving systems. Techniques such as visual inspection of raw data, graphical representation and comparison between sites, outlier and trend detection, and referral to metadata can all help uncover spurious data. Tell-tale signs of ambiguous and/or anomalous data are highlighted using 12 carefully chosen cases drawn mainly from hydrology (‘the dirty dozen’). These include evidence of changes in site or local conditions (due to land management, river regulation or urbanisation); modifications to instrumentation or inconsistent observer behaviour; mismatched or misrepresentative sampling in space and time; treatment of missing values, post-processing and data storage errors. As well as raising awareness of pitfalls, recommendations are provided for uncovering lapses in data quality after the information has been gathered. It is noted that error detection and attribution are more problematic for very large data sets, where observation networks are automated, or when various information sources have been combined. In these cases, more holistic indicators of data integrity are needed that reflect the overall information life-cycle and application(s) of the hydrological data

Adult adhd patients’ experiences of impairment, accessing services and treatment management: a qualitative study in England

Conference Theme: Beyond Diversity, Towards HarmonyThis journal supplement contain abstracts of the 20th European Congress of PsychiatryINTRODUCTION: There is limited understanding of the health and treatment-related experiences of adults with Attention Deficit Hyperactivity Disorder in England. AIMS: To explore the experiences of adults with ADHD regarding impairment, accessing diagnostic and treatment services, and to compare experiences between patients diagnosed during adulthood and childhood. METHODS: Semi-structured face-to-face interviews were conducted with 30 adults with ADHD, recruited across England. Half of the participants were diagnosed during childhood and the remainder during adulthood. Data was analysed using Thematic Analysis and data saturation was achieved. RESULTS: Getting a diagnosis and accessing ADHD services in adulthood was an 'uphill struggle', often due to negative and sceptical attitudes towards ADHD by healthcare professionals. Many patients struggled for years with misdiagnoses of depression and anxiety, and severe difficulties accessing care and treatment caused a downward spiral into functional impairment in some. Accumulated psychosocial burden was evident as living with undiagnosed ADHD had resulted in a chronic sense of failure and missed potential in many diagnosed from late adolescence onwards. Positive adjustment was facilitated by a younger age at diagnosis. Although medication was perceived as necessary in alleviating impairment, many deemed pharmacological treatment by itself as inadequate. Additional support, especially psychological therapies/psycho-education was strongly desired, yet few patients had access to non-pharmacological treatment. CONCLUSIONS: This study suggests that the unmet needs of adults with ADHD are substantial, particularly in those diagnosed from late adolescence onwards. The findings suggest there is a wide gap between policy and practice in England.postprintThe 20th European Congress of Psychiatry (EPA 2012), Prague, Czech Republic, 3-6 March 2012. In European Psychiatry, 2012, v. 27 suppl. 1, abstract no. P-87