Efficacy of stimulants in adult ADHD

OBJECTIVE: To review the literature regarding the efficacy of stimulants to treat attention-deficit-hyperactivity disorder (ADHD) in adults. DATA SOURCES: The relevant pharmaceutical manufacturers were contacted, and searches of MEDLINE (1966–December 2002) and the reference sections of each article obtained were performed using the key search terms: adult ADHD, stimulants, methylphenidate, amphetamines, and pemoline. STUDY SELECTION AND DATA EXTRACTION: All English-language original studies identified from the data sources were evaluated and all information deemed relevant was included in the review. DATA SYNTHESIS: Studies involving methylphenidate, amphetamines, and pemoline were identified. There was evidence for the efficacy of amphetamines from 5 studies (4 controlled, 1 open). Methylphenidate data from 6 controlled trials were conflicting. Three studies indicated efficacy; 2 studies failed to show efficacy, possibly due to methodologic reasons; and the results from 1 study were conflicting. The limited data from 1 controlled and 1 open study indicated that pemoline may be less effective than methylphenidate and amphetamines. CONCLUSIONS: While the current limited data indicate that stimulants may be effective in adult ADHD, more data are required to confirm long-term efficacy

Loss of skeletal muscle in cancer: biochemical mechanisms

Patients with cancer often undergo a specific loss of skeletal muscle mass, while the visceral protein reserves are preserved. This condition known as cachexia reduces the quality of life and eventually results in death through erosion of the respiratory muscles. Nutritional supplementation or appetite stimulants are unable to restore the loss of lean body mass, since protein catabolism is increased mainly as a result of the activation of the ATP-ubiquitin-dependent proteolytic pathway. Several mediators have been proposed. An enhanced protein degradation is seen in skeletal muscle of mice administered tumour necrosis factor (TNF), which appears to be mediated by oxidative stress. There is some evidence that this may be a direct effect and is associated with an increase in total cellular-ubiquitin-conjugated muscle proteins. Another cytokine, interleukin-6 (IL-6), may play a role in muscle wasting in certain animal tumours, possibly through both lysosomal (cathepsin) and non-lysosomal (proteasome) pathways. A tumour product, proteolysis-inducing factor (PIF) is produced by cachexia-inducing murine and human tumours and initiates muscle protein degradation directly through activation of the proteasome pathway. The action of PIF is blocked by eicosapentaenoic acid (EPA), which has been shown to attenuate the development of cachexia in pancreatic cancer patients. When combined with nutritional supplementation EPA leads to accumulation of lean body mass and prolongs survival. Further knowledge on the biochemical mechanisms of muscle protein catabolism will aid the development of effective therapy for cachexia.

Analysis of Transglutaminase-2 in macrophage function

Programmed cell death, apoptosis, is a highly regulated process that removes damaged or unwanted cells in vivo and has significant immunological implications. Defective clearance of apoptotic cells by macrophages (professional phagocytes) is known to result in chronic inflammatory and autoimmune disease. Transglutaminase-2 (TG2) is a Ca2+-dependent protein crosslinking enzyme known to play an important role in apoptotic cell clearance by macrophages through an ill-defined mechanism. Several studies have implicated TG2 in the apoptosis programme e.g. raised TG2 levels in cells undergoing apoptosis; increased cell death with down-regulation of TG2; up-regulation of TG2 in monocytes upon differentiation into macrophages. Defective clearance of apoptotic cells by TG2 null mice has been described though in this context the role of TG2 is yet to be elucidated. Here we aim to characterise the role of TG2 in macrophage function with a focus on apoptotic cell clearance. THP-1 monocytes were induced to differentiate to macrophage-like cells by three different stimulants and were analysed for the presence of TG2. Macrophage-apoptotic cell interaction studies in the presence and absence of irreversible TG2 inhibitors resulted in significant inhibition of interaction indicating a possible role for TG2 in apoptotic cell clearance. TG2 was expressed at the macrophage cell surface and its association with ß3 integrin expression suggests the possible link between TG2 and ß3 integrins. Our current findings suggest that TG2 had got a crucial but yet to be defined role in apoptotic cell clearance.

The control of mitosis in mammalian tissues

The question of which factors are central in determining whether a cell will undertake a new round of mitosis or will decycle has been examined in the isolated thymic lymphocyte model. Such cell populations possess both in vivo and in vitro a subpopulation of quiescent lymphoblasts which may be induced to reinitiate their mitotic programme. In the intact animal the major determinant of proliferative activity is the plasma ionised calcium concentration. However it has been established in culture that a variety of hormones, ions, cyclic nucleotides, plant lectins and ionophores may like calcium elicit a mitogenic response. These agents do not appear however to initiate DNA synthesis in an identical fashion. Rather there are two distinct intracellular mitogenic axes. The first axis includes a number of adenylate cyclase stimulants, cyclic AMP, phosphodiesterase inhibitors and magnesium ions. It was found that all these mitogens required extracellular magnesium ions to exhibit their stimulatory capacity. This dichotomy in mitogenic activity was further emphasised by the observation that these mitogens are all inhibited by testosterone, whilst the magnesium-independent mitogens were insensitive to this androgen. Indeed this second group of stimulatory factors required the presence of calcium ions in the extracellular milieu for activity, and were, in contrast to the magnesium-dependent mitogens inhibited by the presence of oestradiol in the culture. By examining the interrelationships between these various mitogens and inhibitors it has been possible to propose a mechanism to describe the activation process in the thymocyte. Studies of the metabolism of cyclic nucleotides, membrane potential and transmembrane ion fluxes indicate that there may be a complex relationship between membrane fluidity, ion balance and cyclic nucleotide levels which may individually or in concert promote the initiation of DNA synthesis. A number of possible mechanisms are discussed to account for these observations.

Oxidized phospholipid inhibition of toll-like receptor (TLR) signaling is restricted to TLR2 and TLR4 roles for cd14, lps-binding protein, and md2 as targets for specificity of inhibition

The generation of reactive oxygen species is a central feature of inflammation that results in the oxidation of host phospholipids. Oxidized phospholipids, such as 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC), have been shown to inhibit signaling induced by bacterial lipopeptide or lipopolysac-charide (LPS), yet the mechanisms responsible for the inhibition of Toll-like receptor (TLR) signaling by OxPAPC remain incompletely understood. Here, we examined the mechanisms by which OxPAPC inhibits TLR signaling induced by diverse ligands in macrophages, smooth muscle cells, and epithelial cells. OxPAPC inhibited tumor necrosis factor- production, IB degradation, p38 MAPK phosphorylation, and NF-B-dependent reporter activation induced by stimulants of TLR2 and TLR4 (Pam3CSK4 and LPS) but not by stimulants of other TLRs (poly(I·C), flagellin, loxoribine, single-stranded RNA, or CpG DNA) in macrophages and HEK-293 cells transfected with respective TLRs and significantly reduced inflammatory responses in mice injected subcutaneously or intraperitoneally with Pam3CSK4. Serum proteins, including CD14 and LPS-binding protein, were identified as key targets for the specificity of TLR inhibition as supplementation with excess serum or recombinant CD14 or LBP reversed TLR2 inhibition by OxPAPC, whereas serum accessory proteins or expression of membrane CD14 potentiated signaling via TLR2 and TLR4 but not other TLRs. Binding experiments and functional assays identified MD2 as a novel additional target of OxPAPC inhibition of LPS signaling. Synthetic phospholipid oxidation products 1-palmitoyl-2-(5-oxovaleryl)-sn-glycero-3-phosphocholine and 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine inhibited TLR2 signaling from 30 µM. Taken together, these results suggest that oxidized phospholipid-mediated inhibition of TLR signaling occurs mainly by competitive interaction with accessory proteins that interact directly with bacterial lipids to promote signaling via TLR2 or TLR4.

The use of antidepressants to treat attention deficit hyperactivity disorder in adults

There is increasing evidence that children continue to experience attention deficit hyperactivity disorder (ADHD) symptoms into adult life. The two main treatments for ADHD are antidepressants and stimulants. Here, the effectiveness data relating to the use of antidepressants in adults with ADHD are reviewed. Four controlled and six open studies were identified. Although, there is only limited data currently available, antidepressants may offer an effective therapy for adult ADHD. Controlled trials have studied desipramine, atomoxetine and bupropion, with most evidence supporting the efficacy of desipramine. The initial data indicate that atomoxetine is less effective than desipramine. The efficacy of bupropion is unclear. Initial published open data suggest a response rate of 50-78% with venlafaxine. Controlled studies are required to confirm this efficacy. Most of the present data are short-term, therefore long-term effectiveness data are required.

Low-emission vehicle adoption in a UK local authority fleet:economic barriers and air quality benefits

Local air quality was one of the main stimulants for low carbon vehicle development during the 1990s. Issues of national fuel security and global air quality (climate change) have added pressure for their development, stimulating schemes to facilitate their deployment in the UK. In this case study, Coventry City Council aimed to adopt an in-house fleet of electric and hybrid-electric vehicles to replace business mileage paid for in employee's private vehicles. This study made comparisons between the proposed vehicle technologies, in terms of costs and air quality, over projected scenarios of typical use. The study found that under 2009 conditions, the electric and hybrid fleet could not compete on cost with the current business model because of untested assumptions, but certain emissions were significantly reduced >50%. Climate change gas emissions were most drastically reduced where electric vehicles were adopted because the electricity supply was generated by renewable energy sources. The study identified the key cost barriers and benefits to adoption of low-emission vehicles in current conditions in the Coventry fleet. Low-emission vehicles achieved significant air pollution-associated health cost and atmospheric emission reductions per vehicle, and widespread adoption in cities could deliver significant change. © The Author 2011. Published by Oxford University Press. All rights reserved.

The complements towards developing a new risk management framework and Its applicability to the Nigerian power sector

The availability of regular supply has been identified as one of the major stimulants for the growth and development of any nation and is thus important for the economic well-being of a nation. The problems of the Nigerian power sector stems from a lot of factors culminating in her slow developmental growth and inability to meet the power demands of her citizens regardless of the abundance of human and natural resources prevalent in the nation. The research therefore had the main aim of investigating the importance and contributions of risk management to the success of projects specific to the power sector. To achieve this aim it was pertinent to examine the efficacy of risk management process in practice and elucidate the various risks typically associated with projects (Construction, Contractual, Political, Financial, Design, Human resource and Environmental risk factors) in the power sector as well as determine the current situation of risk management practice in Nigeria. To address this factors inhibiting the proficiency of the overarching and prevailing issue which have only been subject to limited in-depth academic research, a rigorous mixed research method was adopted (quantitative and qualitative data analysis). A review of the Nigeria power sector was also carried out as a precursor to the data collection stage. Using purposive sampling technique, respondents were identified and a questionnaire survey was administered. The research hypotheses were tested using inferential statistics (Pearson correlation, Chi-square test, t-test and ANOVA technique) and the findings revealed the need for the development of a new risk management implementation Framework. The proposed Framework was tested within a company project, for interpreting the dynamism and essential benefits of risk management with the aim of improving the project performances (time), reducing the level of fragmentation (quality) and improving profitability (cost) within the Nigerian power sector in order to bridge a gap between theory and practice. It was concluded that Nigeria’s poor risk management practices have prevented it from experiencing strong growth and development. The study however, concludes that the successful implementation of the developed risk management framework may help it to attain this status by enabling it to become more prepared and flexible, to face challenges that previously led to project failures, and thus contributing to its prosperity. The research study provides an original contribution theoretically, methodologically and practically which adds to the project risk management body of knowledge and to the Nigerian power sector.