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1.  Patients’ practices and experiences of using nebuliser therapy in the management of COPD at home 
BMJ Open Respiratory Research  2015;2(1):e000076.
Background and aim
How patients use their nebulisers at home is vital to ensure effective treatment and optimal health outcomes for patients with chronic obstructive pulmonary disease (COPD). The aim of the study was to identify the practicalities and problems associated with nebuliser use by patients with COPD at home, which may impact on the safety and effectiveness of therapy.
Design and setting
A cross-sectional descriptive study in which participants were recruited from two levels of care: primary care, involving 38 GP practices in North West London, and intermediate care with a major acute hospital.
In-depth interviews were conducted with a representative sample of 50 patients with COPD using nebulisers in their home, recruited from general practice populations and at hospital discharge. A checklist was used to record activities and patients demonstrated use of their nebuliser. Qualitative procedures were employed to identify the range of problems experienced with nebuliser use.
A wide range of practical issues was identified at all stages: problems prior to nebulisation: setting up equipment, lack of instructions, manual dexterity and time required. Problems during medication administration: inhalation technique, duration of nebulisation and understanding how to achieve optimal efficacy. Problems post-administration: inadequate cleaning of nebuliser components, access to accessories and use of damaged parts or self-repairs. Other problems included noise, weight and non-portability of equipment.
Patients with COPD using nebulisers at home experienced problems with all aspects, many of which may be anticipated to compromise clinical outcomes. Healthcare providers should be aware of these problems to effectively support patients with COPD with the use of their nebulisers at home.
PMCID: PMC4360584  PMID: 25806114
Nebuliser therapy
2.  Carbon Dioxide Emissions as Affected by Alternative Long-Term Irrigation and Tillage Management Practices in the Lower Mississippi River Valley 
The Scientific World Journal  2014;2014:626732.
Ensuring the sustainability of cultivated soils is an ever-increasing priority for producers in the Lower Mississippi River Valley (LMRV). As groundwater sources become depleted and environmental regulations become more strict, producers will look to alternative management practices that will ensure the sustainability and cost-effectiveness of their production systems. This study was conducted to assess the long-term (>7 years) effects of irrigation (i.e., irrigated and dryland production) and tillage (conventional and no-tillage) on estimated carbon dioxide (CO2) emissions from soil respiration during two soybean (Glycine max L.) growing seasons from a wheat- (Triticum aestivum L.-) soybean, double-cropped production system in the LMRV region of eastern Arkansas. Soil surface CO2 fluxes were measured approximately every two weeks during two soybean growing seasons. Estimated season-long CO2 emissions were unaffected by irrigation in 2011 (P > 0.05); however, during the unusually dry 2012 growing season, season-long CO2 emissions were 87.6% greater (P = 0.044) under irrigated (21.9 Mg CO2 ha−1) than under dryland management (11.7 Mg CO2 ha−1). Contrary to what was expected, there was no interactive effect of irrigation and tillage on estimated season-long CO2 emissions. Understanding how long-term agricultural management practices affect soil respiration can help improve policies for soil and environmental sustainability.
PMCID: PMC4211165  PMID: 25371912
3.  Direct and indirect influences of arbuscular mycorrhizal fungi on phosphorus uptake by two root hemiparasitic Pedicularis species: do the fungal partners matter at low colonization levels? 
Annals of Botany  2013;112(6):1089-1098.
Background and Aims
Because most parasitic plants do not form mycorrhizal associations, the nutritional roles of arbuscular mycorrhizal (AM) fungi in them have hardly been tested. Some facultative root hemiparasitic Pedicularis species form AM associations and hence are ideal for testing both direct and indirect effects of AM fungi on their nutrient acquisition. The aim of this study was to test the influence of AM inoculation on phosphorus (P) uptake by Pedicularis rex and P. tricolor.
32P labelling was used in compartmented pots to assess the contribution of the AM pathway and the influence of AM inoculation on P uptake from a host plant into the root hemiparasites. Laboratory isolates of fungal species (Glomus mosseae and G. intraradices) and the host species (Hordeum vulgare ‘Fleet’) to which the two Pedicularis species showed obvious responses in haustorium formation and growth in previous studies were used.
Key Results
The AM colonization of both Pedicularis spp. was low (<15 % root length) and only a very small proportion of total plant P (<1 %) was delivered from the soil via the AM fungus. In a separate experiment, inoculation with AM fungi strongly interfered with P acquisition by both Pedicularis species from their host barley, almost certainly because the numbers of haustoria formed by the parasite were significantly reduced in AM plants.
Roles of AM fungi in nutrient acquisition by root parasitic plants were quantitatively demonstrated for the first time. Evidence was obtained for a novel mechanism of preventing root parasitic plants from overexploiting host resources through AM fungal-induced suppression of the absorptive structures in the parasites.
PMCID: PMC3783241  PMID: 23946322
Arbuscular mycorrhizal fungi; Glomus; Hordeum vulgare; barley; Orobanchaceae; Pedicularis rex; P. tricolor; phosphorus uptake; root hemiparasitic plant
4.  Nutrient requirements differ in two Pedicularis species in the absence of a host plant: implication for driving forces in the evolution of host preference of root hemiparasitic plants 
Annals of Botany  2013;112(6):1099-1106.
Background and Aims
Facultative root hemiparasitic plants generally have a wide host range, but in most cases show an obvious host preference. The reasons for the marked difference in growth performance of hemiparasites when attached to different hosts are not fully understood. In this study, the hypothesis was tested that hemiparasites showing a preference for different hosts have different nutrient requirements.
Two facultative root hemiparasitic Pedicularis species (P. rex and P. tricolor) with a different host dependency and preference were used to test their responses to inorganic solutes. The effects of nitrogen, phosphorus and potassium on growth of the hemiparasitic plants not attached to a host were determined, using an orthogonal design in pot cultivation under greenhouse conditions. Variables including biomass, shoot nutrient concentration, root:shoot (R:S) ratios and the number of haustoria were measured.
Key Results
As in autotrophic plants, nutrient deficiency reduced dry weight (DW) and nutrient concentrations in the root hemiparasites. Nitrogen and phosphorus significantly influenced growth of both Pedicularis species, while potassium availability influenced only shoot DW of P. rex. Nitrogen had far more effect on growth of P. rex than on P. tricolor, while phosphorus deficiency caused more marked growth depression in P. tricolor than in P. rex. Pedicularis rex grew faster than P. tricolor in a range of nutrient supplies. Different patterns of biomass allocation between the two Pedicularis species were observed. While P. rex invested more into roots (particularly fine rootlets) than P. tricolor, the number of haustoria produced by P. rex was relatively much lower than that produced by P. tricolor, which had a much smaller root system.
The two Pedicularis species differ in nutrient requirements and biomass allocation. Distinct interspecific traits in growth and nutrient requirements can be driving forces for the differential interactions between hemiparasites and their hosts.
PMCID: PMC3783243  PMID: 23946321
Inorganic solute; root hemiparasitic plant; Orobanchaceae; Pedicularis; pot cultivation; nitrogen; phosphorus; potassium
5.  Scaffolding Proteins: Not Such Innocent Bystanders 
Current biology : CB  2013;23(12):R515-R517.
Sequential transfer of information from one enzyme to the next within the confines of a protein kinase scaffold enhances signal transduction. Though frequently considered to be inert organizational elements, two recent reports implicate kinase-scaffolding proteins as active participants in signal relay.
PMCID: PMC3924780  PMID: 23787043
6.  Intrinsic disorder within an AKAP-protein kinase A complex guides local substrate phosphorylation 
eLife  2013;2:e01319.
Anchoring proteins sequester kinases with their substrates to locally disseminate intracellular signals and avert indiscriminate transmission of these responses throughout the cell. Mechanistic understanding of this process is hampered by limited structural information on these macromolecular complexes. A-kinase anchoring proteins (AKAPs) spatially constrain phosphorylation by cAMP-dependent protein kinases (PKA). Electron microscopy and three-dimensional reconstructions of type-II PKA-AKAP18γ complexes reveal hetero-pentameric assemblies that adopt a range of flexible tripartite configurations. Intrinsically disordered regions within each PKA regulatory subunit impart the molecular plasticity that affords an ∼16 nanometer radius of motion to the associated catalytic subunits. Manipulating flexibility within the PKA holoenzyme augmented basal and cAMP responsive phosphorylation of AKAP-associated substrates. Cell-based analyses suggest that the catalytic subunit remains within type-II PKA-AKAP18γ complexes upon cAMP elevation. We propose that the dynamic movement of kinase sub-structures, in concert with the static AKAP-regulatory subunit interface, generates a solid-state signaling microenvironment for substrate phosphorylation.
eLife digest
It was once thought that proteins needed to have structures that were both ordered and stable, but this view was changed by the discovery that certain proteins contain regions that are disordered and flexible. In some cases these regions of intrinsic disorder help the protein to function by linking more stable regions that are active. However, in other proteins the disordered regions are themselves biologically active and can, for example, function as enzymes.
Protein kinase A is a family of enzymes that contains both ordered and disordered regions, with the ordered sections being involved in phosphorylation, a chemical process that is widely used for communication within cells. However, in order to initiate phosphorylation, these kinases must be anchored to a rigid substrate nearby, so a second group of proteins called AKAPs–which is short for A-kinase anchoring proteins–hold the kinases in place by binding to their disordered regions. These AKAPs also help the kinases to dock with other molecules involved in phosphorylation.
A full structural picture of how the kinases induce phosphorylation has yet to be obtained, partly because it is extremely difficult to determine the structure of the disordered regions within the kinases. Moreover, the AKAPs are also disordered, which makes it difficult to work out how the kinases are held in position.
Smith, Reichow et al. have used electron microscopy to reveal that the disordered region has two important roles: it determines how far away from the anchoring protein that the active region of the kinase can operate, and it influences how efficiently the kinase can bind to its target molecule in order to induce phosphorylation. Future challenges include investigating how the inherent flexibility of AKAP complexes contribute to the efficient phosphorylation of physiological targets.
PMCID: PMC3814001  PMID: 24192038
A-kinase anchoring protein (AKAP); cAMP signaling; single particle reconstruction; cAMP-dependent kinase (PKA); electron microscopy; intrinsic disorder; None
8.  Inoculation with arbuscular mycorrhizal fungi suppresses initiation of haustoria in the root hemiparasite Pedicularis tricolor 
Annals of Botany  2012;109(6):1075-1080.
Background and Aims
Plant parasitism and arbuscular mycorrhizal (AM) associations have many parallels and share a number of regulatory pathways. Despite a rapid increase in investigations addressing the roles of AM fungi in regulating interactions between parasitic plants and their hosts, few studies have tested the effect of AM fungi on the initiation and differentiation of haustoria, the parasite-specific structures exclusively responsible for host attachment and nutrient transfer. In this study, we tested the influence of AM fungi on haustorium formation in a root hemiparasitic plant.
Using a facultative root hemiparasitic species (Pedicularis tricolor) with the potential to form AM associations, the effects of inoculation were tested with two AM fungal species, Glomus mosseae and Glomus intraradices, on haustorium initiation in P. tricolor grown alone or with Hordeum vulgare ‘Fleet’ (barley) as the host plant. This study consisted of two greenhouse pot experiments.
Key Results
Both AM fungal species dramatically suppressed intraspecific haustorium initiation in P. tricolor at a very low colonization level. The suppression over-rode inductive effects of the parasite's host plant on haustoria production and caused significant growth depression of P. tricolor.
AM fungi had strong and direct suppressive effects on haustorium formation in the root hemiparasite. The significant role of AM fungi in haustorium initiation of parasitic plants was demonstrated for the first time. This study provides new clues for the regulation of haustorium formation and a route to development of new biocontrol strategies in management of parasitic weeds.
PMCID: PMC3336945  PMID: 22362663
Root hemiparasite; Pedicularis tricolor; Orobanchaceae; arbuscular mycorrhizal fungi; initiation of haustoria; Hordeum vulgare ‘Fleet’; Glomus mosseae; Glomus intraradices
9.  Folic acid administration reduces neointimal thickening, augments neo-vasa vasorum formation and reduces oxidative stress in saphenous vein grafts from pigs used as a model of diabetes 
Diabetologia  2010;53(5):980-988.
There is evidence that plasma homocysteine augments vein graft failure and that it augments both micro- and macro-angiopathy in patients with diabetes mellitus. It is therefore suggested that homocysteine may augment vein graft thickening, a major cause of vein graft failure, in diabetic patients, as well as impairing adaptive growth of a new vasa vasorum, possibly through overproduction of superoxide. In order to test these proposals, the effect of folic acid administration, which lowers plasma homocysteine, on vein graft thickening and microvessel density was studied in pigs used as a model of diabetes.
Non-ketotic hyperglycaemia was induced in Landrace pigs by intravenous injection of streptozotocin, and folic acid was fed daily for 1 month. Vein grafts were excised and the thickness of the neointima and media and microvessel density were assessed by planimetry and superoxide formation.
Plasma total homocysteine was significantly reduced by folic acid in both control and diabetic pigs, whereas glucose was unchanged. Compared with controls, diabetic pigs showed increased neointimal thickness and superoxide formation and decreased adventitial microvessel density. Folic acid reduced neointimal thickness and superoxide formation and augmented microvessel density in diabetic but not in control pigs.
Folic acid administration reduces neointimal thickening, augments vasa vasorum neoformation and reduces oxidative stress in saphenous vein grafts from diabetic pigs. Folic acid may therefore be particularly effective in reducing vein graft failure in diabetic patients.
PMCID: PMC3596781  PMID: 20182861
Folic acid; Neointima; Oxidative stress; Type 2 diabetes; Vein graft
10.  Unraveling the Influence of Arbuscular Mycorrhizal Colonization on Arsenic Tolerance in Medicago: Glomus mosseae is More Effective than G. intraradices, Associated with Lower Expression of Root Epidermal Pi Transporter Genes 
We used medic (Medicago truncatula) to investigate effects of inoculation with two arbuscular mycorrhizal (AM) fungi and application of arsenate (AsV) and phosphate (Pi) on mechanisms underlying increased tolerance (in terms of growth) of AM plants to AsV. We tested the hypotheses that (1) inoculation with AM fungi results in down-regulation of MtPht1;1 and MtPht1;2 genes (encoding high-affinity Pi and AsV uptake systems in the direct root epidermal pathway) and up-regulation of the AM-induced MtPht1;4 (responsible for transfer of Pi from the arbuscular interface to cortical cells), and (2) these changes are involved in decreased As uptake relative to P uptake and hence increased As tolerance. We also measured expression of MtMT4, a Pi starvation-inducible gene, other genes encoding Pi uptake systems (MtPht 1;5 and MtPht1;6) and arsenate reductase (MtACR) and phytochelatin synthase (MtPCS), to gain insights into broader aspects of P transfers in AM plants and possible detoxification mechanisms. Medic responded slightly to AM colonization in terms of growth in the absence of As, but positively in terms of P uptake. Both growth and P responses in AM plants were positive when As was applied, indicating As tolerance relative to non-mycorrhizal (NM) plants. All AM plants showed high expression of MtPT4 and those inoculated with Glomus mosseae showed higher selectivity against As (shown by P/As molar ratios) and much lower expression of MtPht1;1 (and to some extent MtPht1;2) than Glomus intraradices-inoculated or NM plants. Results are consistent with increased P/As selectivity in AM plants (particularly those inoculated with G. mosseae) as a consequence of high P uptake but little or no As uptake via the AM pathway. However, the extent to which selectivity is dependent on down-regulation of direct Pi and AsV uptake through epidermal cells is still not clear. Marked up-regulation of a PCS gene and an ACR gene in AM plants may also be involved and requires further investigation.
PMCID: PMC3325761  PMID: 22509169
arsenate; Medicago truncatula; arbuscular mycorrhizal fungi; Glomus intraradices; Glomus mosseae; phosphate; Pi transporter
11.  Discovery of cellular substrates for protein kinase A using a peptide array screening protocol 
Biochemical Journal  2011;438(1):103-110.
Post-translational modification of proteins is a universal form of cellular regulation. Phosphorylation on serine, threonine, tyrosine or histidine residues by protein kinases is the most widespread and versatile form of covalent modification. Resultant changes in activity, localization or stability of phosphoproteins drives cellular events. MS and bioinformatic analyses estimate that ~30 % of intracellular proteins are phosphorylated at any given time. Multiple approaches have been developed to systematically define targets of protein kinases; however, it is likely that we have yet to catalogue the full complement of the phosphoproteome. The amino acids that surround a phosphoacceptor site are substrate determinants for protein kinases. For example, basophilic enzymes such as PKA (protein kinase A), protein kinase C and calmodulin-dependent kinases recognize basic side chains preceding the target serine or threonine residues. In the present paper we describe a strategy using peptide arrays and motif-specific antibodies to identify and characterize previously unrecognized substrate sequences for protein kinase A. We found that the protein kinases PKD (protein kinase D) and MARK3 [MAP (microtubule-associated protein)-regulating kinase 3] can both be phosphorylated by PKA. Furthermore, we show that the adapter protein RIL [a product of PDLIM4 (PDZ and LIM domain protein 4)] is a PKA substrate that is phosphorylated on Ser119 inside cells and that this mode of regulation may control its ability to affect cell growth.
PMCID: PMC3292260  PMID: 21644927
kinase; peptide array; phosphoproteome; protein kinase A (PKA)
12.  AKAP18 contains a phosphoesterase domain which binds AMP 
Journal of molecular biology  2007;375(5):1329-1343.
Protein kinase A anchoring proteins (AKAPs), defined by their capacity to target the cAMP-dependent protein kinase to distinct sub-cellular locations, function as molecular scaffolds mediating the assembly of multi-component complexes to integrate and organise multiple signalling events. Despite their central importance in regulating cellular processes, little is known regarding their diverse structures and molecular mechanisms. Here, using bioinformatics and X-ray crystallography, we define a central domain of AKAP18δ (AKAP18CD) as a member of the 2H phosphoesterase family. The domain features two conserved His-x-Thr motifs positioned at the base of a groove located between two lobes related by pseudo two-fold symmetry. Nucleotide co-crystallisation screening revealed that this groove binds specifically to 5’AMP/CMP, with the affinity constant for AMP in the physiological concentration range. This is the first example of an AKAP capable of binding a small molecule. Our data generate two functional hypotheses for the AKAP18 central domain. It may act as a phosphoesterase, although we did not identify a substrate, or as an AMP sensor with the potential to couple intracellular AMP levels to PKA signalling events.
PMCID: PMC3188456  PMID: 18082768
AKAP; PKA; scaffold; AMP; phosphoesterase
13.  AKAP-Lbc mobilizes a cardiac hypertrophy signaling pathway 
Molecular cell  2008;32(2):169-179.
Elevated catecholamines in the heart evoke transcriptional activation of the Myocyte Enhancer Factor (MEF) pathway to induce a cellular response known as pathological myocardial hypertrophy. We have discovered that the A-Kinase Anchoring Protein AKAP-Lbc is up-regulated in hypertrophic cardiomyocytes. It coordinates activation and movement of signaling proteins that initiate MEF2-mediated transcriptional reprogramming events. Live-cell imaging, fluorescent kinase activity reporters and RNA interference techniques show that AKAP-Lbc couples activation of protein kinase D (PKD) with the phosphorylation-dependent nuclear export of the class II histone deacetylase HDAC5. These studies uncover a role for AKAP-Lbc in which increased expression of the anchoring protein selectively amplifies a signaling pathway that drives cardiac myocytes towards a pathophysiological outcome.
PMCID: PMC3169907  PMID: 18951085
15.  Plugging PKA into ERK scaffolds 
Cell Cycle  2011;10(5):731-732.
Cancers often arise in part through derangements in protein kinase signaling. A striking example of this is the finding that approximately 30% of human tumors have mutations in Ras or B-Raf, leading to aberrant ERK kinase activation. Kinase signaling networks are often organized by scaffolding and anchoring proteins that help shape the dynamics of signal processing. AKAP-Lbc associates with the ERK scaffold protein KSR-1 to organize a growth factor and cAMP responsive signaling network. AKAP-Lbc also directs PKA phosphorylation of KSR-1 on a critical residue to ensure maximal signaling efficiency.
PMCID: PMC3322337  PMID: 21311231
16.  AKAP-Lbc enhances cyclic AMP control of the ERK1/2 cascade 
Nature cell biology  2010;12(12):1242-1249.
Mitogen-activated protein kinase (MAPK) cascades propagate a variety of cellular activities1. Processive relay of signals through RAF–MEK–ERK modulates cell growth and proliferation2,3. Signalling through this ERK cascade is frequently amplified in cancers, and drugs such as sorafenib (which is prescribed to treat renal and hepatic carcinomas) and PLX4720 (which targets melanomas) inhibit RAF kinases4,5. Natural factors that influence ERK1/2 signalling include the second messenger cyclic AMP6,7. However, the mechanisms underlying this cascade have been difficult to elucidate. We demonstrate that the A-kinase-anchoring protein AKAP-Lbc and the scaffolding protein kinase suppressor of Ras (KSR-1) form the core of a signalling network that efficiently relay signals from RAF, through MEK, and on to ERK1/2. AKAP-Lbc functions as an enhancer of ERK signalling by securing RAF in the vicinity of MEK1 and synchronizing protein kinase A (PKA)-mediated phosphorylation of Ser 838 on KSR-1. This offers mechanistic insight into cAMP-responsive control of ERK signalling events.
PMCID: PMC3042953  PMID: 21102438
17.  Young people's experiences of managing asthma and diabetes at school 
Archives of Disease in Childhood  2007;92(12):1077-1081.
To examine the experiences and concerns of young people and their parents regarding the management of medication for asthma or diabetes whilst at school.
Face‐to‐face semi‐structured interviews were conducted with 69 young people aged 8–15 years (43 with asthma and 26 with diabetes) and their parents (138 interviews in total) in their own homes. Respondents were recruited through randomly selected general practice surgeries in contrasting areas in South East England. Interviews were audio‐recorded, transcribed verbatim and analysed using established qualitative analytical procedures.
Young people with asthma and diabetes discussed difficulties regarding access to and use of their medicines at school which may jeopardise optimal condition management. School medicines policies could be a further hindrance. Young people endeavour to find ways to accommodate their medication and condition related needs whilst at school, in an attempt to limit the impact of their condition upon school activities such as sport, school trips and relationships with peers. Parents expressed concern regarding the awareness and levels of support available to their sons/daughters, in particular if a crisis should develop.
In order to ensure optimal care, there is a need for the development of protocols tailored to the needs of young people with different conditions. These should preferably be devised in partnership between the young person, their parents and the school to ensure that the flexibility and support required for optimal management are offered.
PMCID: PMC2066080  PMID: 17855440
18.  Factors Associated With Exacerbation of Heart Failure Include Treatment Adherence and Health Literacy Skills 
We determined the factors associated with exacerbation of heart failure, using a cohort (n = 192) nested within a randomized trial at a university-affiliated ambulatory practice. Factors associated with emergency or hospital care included left ventricular ejection fraction, hematocrit and serum sodium levels, refill adherence, and the ability to read a prescription label. Refill adherence of <40% was associated with a threefold higher incidence of hospitalization for heart failure than a refill adherence of ≥80% (P = 0.002). In multivariable analysis, prescription label reading skills were associated with a lower incidence of heart failure–specific emergency care (incidence rate ratio, 0.76; 95% confidence interval (CI), 0.19–0.69), and participants with adequate health literacy had a lower risk of hospitalization for heart failure (incidence rate ratio, 0.34; 95% CI, 0.15–0.76). We conclude that inadequate treatment adherence and health literacy skills are key factors in the exacerbation of heart failure. These findings emphasize the need for careful instruction of patients about their medications.
PMCID: PMC2855238  PMID: 19262464
19.  Rapid screening for major depression in post‐myocardial infarction patients: an investigation using Beck Depression Inventory II items 
Heart  2006;92(11):1656-1660.
To determine the ability of three questions from the Beck Depression Inventory II (BDI‐II) to detect major depressive disorder (MDD) in a cohort of patients hospitalised for acute myocardial infarction (MI).
Prospective observational study.
Coronary care unit and cardiac step‐down unit of an urban academic medical centre.
131 post‐MI patients within 72 h of symptom onset.
Patients were administered the BDI‐II and participated in a structured diagnostic interview for MDD. Three individual BDI‐II items (regarding sadness, loss of interest and loss of pleasure) were examined individually and in two‐question combinations to determine their ability to screen for MDD.
Main outcome measures
Sensitivity, specificity, negative and positive predictive values and proportion of patients with MDD correctly identified.
The individual items and two‐question combinations had good sensitivity (76–94%), specificity (70–88%) and negative predictive values (97–99%). Item 1 (sadness) performed the best of the individual items (48% with a positive response to the item had MDD; 3% with a negative response had MDD; over 80% of patients with MDD were correctly identified). A combination of questions about sadness and loss of interest performed best among the two‐question combinations (37% with positive response had MDD v 1% with a negative response; 94% of patients with MDD were identified).
One to two questions regarding sadness and loss of interest serve as simple and effective screening tools for post‐MI depression.
PMCID: PMC1861254  PMID: 16644855
20.  The genome of the simian and human malaria parasite Plasmodium knowlesi 
Nature  2008;455(7214):799-803.
Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the ‘kra’ monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia1,2. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated3, and it has a close phylogenetic relationship to Plasmodium vivax​4, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood cell preference, absence of a dormant liver stage or ‘hypnozoite’ in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone5) nuclear genome sequence. This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome4 and other sequenced Plasmodium genomes6-8. In contrast to other Plasmodium genomes, putative variant antigen families are dispersed throughout the genome and are associated with intrachromosomal telomere repeats. One of these families, the KIRs9, contains sequences that collectively match over one-half of the host CD99 extracellular domain, which may represent an unusual form of molecular mimicry.
PMCID: PMC2656934  PMID: 18843368
21.  Region-dependent attenuation of μ opioid receptor-mediated G-protein activation in mouse CNS as a function of morphine tolerance 
British Journal of Pharmacology  2007;151(8):1324-1333.
Background and purpose:
Chronic morphine administration produces tolerance in vivo and attenuation of μ opioid receptor (MOR)-mediated G-protein activation measured in vitro, but the relationship between these adaptations is not clear. The present study examined MOR-mediated G-protein activation in the CNS of mice with different levels of morphine tolerance.
Experimental approach:
Mice were implanted with morphine pellets, with or without supplemental morphine injections, to induce differing levels of tolerance as determined by a range of MOR-mediated behaviours. MOR function was measured using agonist-stimulated [35S]guanylyl-5′-O-(γ-thio)-triphosphate ([35S]GTPγS) and receptor binding throughout the CNS.
Key results:
Morphine pellet implantation produced 6-12-fold tolerance in antinociceptive assays, hypothermia and Straub tail, as measured by the ratio of morphine ED50 values between morphine-treated and control groups. Pellet implantation plus supplemental injections produced 25-50-fold tolerance in these tests. In morphine pellet-implanted mice, MOR-stimulated [35S]GTPγS binding was significantly reduced only in the nucleus tractus solitarius (NTS) and spinal cord dorsal horn in tissue sections from morphine pellet-implanted mice. In contrast, MOR-stimulated [35S]GTPγS binding was significantly decreased in most regions examined in morphine pellet+morphine injected mice, including nucleus accumbens, caudate-putamen, periaqueductal gray, parabrachial nucleus, NTS and spinal cord.
Conclusions and implications:
Tolerance and the regional pattern of apparent MOR desensitization were influenced positively by the level of morphine exposure. These results indicate that desensitization of MOR-mediated G-protein activity is more regionally widespread upon induction of high levels of tolerance, suggesting that this response contributes more to high than low levels of tolerance to CNS-mediated effects of morphine.
PMCID: PMC2189837  PMID: 17572699
brainstem; spinal cord; opiate; [35S]GTPγS autoradiography; desensitization; downregulation
22.  Plant roots. Growth, activity and interaction with soils 
Annals of Botany  2007;100(1):318-152.
PMCID: PMC2735306
23.  Phosphate (Pi) and Arsenate Uptake by Two Wheat (Triticum aestivum) Cultivars and Their Doubled Haploid Lines 
Annals of Botany  2006;98(3):631-636.
• Background and Aims Arsenic accumulation in cereal crops represents an important pathway for human exposure to arsenic from the environment. The objectives of the present work were to find whether the relationship between arsenate and phosphate (Pi) uptake rate differs among genotypes and to select genotypes with a low arsenate uptake rate with the aim of improving food safety and human health.
• Methods A hydroponic experiment was conducted using two wheat (Triticum aestivum) cultivars (Hanxuan 10 and Lumai 14) and ten doubled haploid (DH) lines derived from them to investigate Pi and arsenate uptake over 48 h. Ten plants were transferred to bottles containing 50 mL of pre-treatment solution containing 0·5 mm CaCl2 and 5 mm MES set at pH 6.0 with 330 µm Pi as KH2PO4 and 7·33 µm arsenate. The solutions were aerated continuously. At 8, 24 and 48 h after uptake, 1 mL of test solution was sampled for determination of Pi and arsenate concentrations.
• Key Results and Conclusions For each wheat line, Pi and arsenate concentrations in the test solution decreased with uptake time. Exponential (for Pi) or polynomial (for arsenate) regression plots fitted the data closely. For all genotypes, net Pi uptake rates decreased with time (from 0 to 48 h). However, net arsenate uptake rates decreased with time for D5, changed little with time for the male parent, D4 and D6, and increased with time for the others. An inflexion of about 25 µm Pi was observed for the relationship between arsenate and Pi concentrations in the test solution, indicating that 25 µm could be the point where the high-affinity uptake system ‘switches on’, or dominates over low-affinity uptake. In addition, the male parent, D1, D6 and D10 were considered ideal genotypes because they possess Pi transporters that discriminate strongly against arsenate and are expected to accumulate less arsenate in the field.
PMCID: PMC2803564  PMID: 16803848
Arsenic; phosphate transporters; ion selectivity; plant membrane transport
25.  Subjective functional assessments and the return to competitive sport after anterior cruciate ligament reconstruction 
Objectives: To examine (a) return to competitive sport within 12 months of anterior cruciate ligament (ACL) reconstruction, (b) maintenance of competitive participation at follow up, and (c) the relation of the level of sports activity and competitive participation at follow up to subjective functional assessments. Also to address the incidence of continued competitive participation despite notable functional problems with the operated knee at 12 months and follow up.
Methods: All patients were competitive athletes before injury and had undergone ACL reconstruction by the transtibial endoscopic technique with either a bone-patellar tendon-bone or a multiple looped hamstring autograft. Evaluation was carried out a mean of 43 months (range 24–73) after surgery by a postal questionnaire in which the Cincinnati sports activity scale (CSAS) and Cincinnati sports function scales were presented in conjunction with closed questions on change in competitive level and the presence of complaints.
Results: Of 109 selected patients, 77 (71%) responded. At follow up, 62 of 77 patients (81%) reported that they had returned to competition within 12 months of surgery. Within the same time frame, 55 of the above 62 patients (89%) also claimed to have returned to the level at which they were competing before injury (or higher). At follow up, 30 of the above 55 patients (54%) reported to still be competing at this high level. Twelve of the above 55 patients (22%) also admitted to major problems with the operated knee at that time. The overall incidence of patients competing despite major functional impairment in the operated knee was 13 of 62 (21%) at 12 months and six of 47 (13%) at follow up. Thirty eight patients (49%) were active in sport at least four times a week at follow up (CSAS level 1), and, using Spearman's rank correlation between CSAS scores and total sports function scores, r was calculated to be 0.44. Competitive and male patients had higher total sports function scores at follow up than non-competitive (p = 0.005) and female (p = 0.02) patients respectively.
Conclusions: The reported return to competition at the previous level, both within 12 months and at follow up, was high but as expected considering the standard of treatment, patient selection, and study exclusion criteria. Patients with few functional complaints maintained a high level of sporting activity, even after discontinuing competitive participation.
PMCID: PMC1724807  PMID: 15155426

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