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"Lewis, Michael"
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Development of Trypanosoma cruzi in vitro assays to identify compounds suitable for progression in Chagas’ disease drug discovery
Chagas' disease is responsible for significant mortality and morbidity in Latin America. Current treatments display variable efficacy and have adverse side effects, hence more effective, better tolerated drugs are needed. However, recent efforts have proved unsuccessful with failure of the ergosterol biosynthesis inhibitor posaconazole in phase II clinical trials despite promising in vitro and in vivo studies. The lack of translation between laboratory experiments and clinical outcome is a major issue for further drug discovery efforts. Our goal was to identify cell-based assays that could differentiate current nitro-aromatic drugs nifurtimox and benznidazole from posaconazole. Using a panel of T. cruzi strains including the six major lineages (TcI-VI), we found that strain PAH179 (TcV) was markedly less susceptible to posaconazole in vitro. Determination of parasite doubling and cycling times as well as EdU labelling experiments all indicate that this lack of sensitivity is due to the slow doubling and cycling time of strain PAH179. This is in accordance with ergosterol biosynthesis inhibition by posaconazole leading to critically low ergosterol levels only after multiple rounds of division, and is further supported by the lack of effect of posaconazole on the non-replicative trypomastigote form. A washout experiment with prolonged posaconazole treatment showed that, even for more rapidly replicating strains, this compound cannot clear all parasites, indicative of a heterogeneous parasite population in vitro and potentially the presence of quiescent parasites. Benznidazole in contrast was able to kill all parasites. The work presented here shows clear differentiation between the nitro-aromatic drugs and posaconazole in several assays, and suggests that in vitro there may be clinically relevant heterogeneity in the parasite population that can be revealed in long-term washout experiments. Based on these findings we have adjusted our in vitro screening cascade so that only the most promising compounds are progressed to in vivo experiments.
Journal Article
BOOMERANG : Travels in the New Third World
As Pogo once said, \"We have met the enemy and he is us.\" In this book the author offers a scathing assessment of fiscal blunders in foreign lands, and details how economic repercussions are sure to be felt on American soil. Financial bubbles grew and burst, not only in the U.S. but in countries as diverse as Iceland, Germany, and Greece. Mixing humor with prescient insight, he depicts a precarious situation that demands attention. The tsunami of cheap credit that rolled across the planet between 2002 and 2008 was more than a simple financial phenomenon: it was temptation, offering entire societies the chance to reveal aspects of their characters they could not normally afford to indulge. Icelanders wanted to stop fishing and become investment bankers. The Greeks wanted to turn their country into a piنnata stuffed with cash and allow as many citizens as possible to take a whack at it. The Germans wanted to be even more German; the Irish wanted to stop being Irish. This investigation of bubbles beyond our shores is so sadly hilarious that it leads the American reader to a comfortable complacency: oh, those foolish foreigners. But when he turns a merciless eye on California and Washington, D.C., we see that the narrative is a trap baited with humor, and we understand the reckoning that awaits the greatest and greediest of debtor nations. - Publisher.
Book
The interactions between botulinum-toxin-based facial treatments and embodied emotions
Botulinum toxin (BTX) injections reduce muscle mobility and are commonly used to treat the appearance of glabellar frown lines. Research shows that this cosmetic treatment leads to a reduction in depression. This reduction is consistent with the theory of embodied emotions because patients have a reduced ability to frown and so receive less negative feedback associated with this action. The current research explored this effect and three further hypotheses for the effects of cosmetic BTX injections based on embodied emotions. It was hypothesised that treatment of crow’s feet (or laughter lines) would reduce mood as patients’ Duchenne smiles would be impaired. It was hypothesised that facial BTX treatments would impair emotional expression recognition because the ability to mimic emotions would be reduced. Finally, it was hypothesised that, as BTX treatments prevent facial expressions associated with sexual excitement, sexual function would be impaired after treatment. Twenty four BTX-treated and twelve matched participants (all female) were tested before and after treatment. Results found that BTX treatment of laughter lines was associated with increased depression scores. Further, BTX treatment was associated with reduced emotion recognition ability and sexual function. The current results add to our knowledge of the psychological effects of injections of powerful neurotoxins and broaden the scope of the embodiment of emotions.
Journal Article
Panic : the story of modern financial insanity
An analysis of five financial upheavals in recent history includes coverage of the 1987 stock market crash, the 1998 Russian default (and the consequent collapse of U.S. hedge fund Long-Term Capital Management), the Asian currency crisis of 1999, the Internet bubble of 1995-2001, and the 2008 sub-prime mortgage crisis, in an anecdotal report that reveals how public knowledge differed from what was actually taking place.
Book
Autoimmune atrophic gastritis: current perspectives
At present there is no universally accepted classification for gastritis. The first successful classification (The Sydney System) that is still commonly used by medical professionals was first introduced by Misiewicz et al in Sydney in 1990. In fact, it was the first detailed classification after the discovery of
by Warren and Marshall in 1982. In 1994, the Updated Sydney System was proposed during the International Workshop on the Histopathology of Gastritis followed by the publication in
by Dixon et al. Using the new classification, distinction between atrophic and nonatrophic gastritis was revised, and the visual scale grading was incorporated. According to the Updated Sydney System Classification, atrophic gastritis is categorized into multifocal (
, environmental factors, specific diet) and corpus-predominant (autoimmune). Since metaplasia is a key histological characteristic in patients with atrophic gastritis, it has been recommended to use the word \"metaplastic\" in both variants of atrophic gastritis: autoimmune metaplastic atrophic gastritis (AMAG) and environmental metaplastic atrophic gastritis. Although there are many overlaps in the course of the disease and distinction between those two entities may be challenging, the aim of this review article was to describe the etiology, epidemiology, pathogenesis, diagnosis, clinical manifestations and treatment in patients with AMAG. However, it is important to mention that
is the most common etiologic factor for the development of gastritis in the world.
Journal Article
The VP-function revisited: a survey of the literature on vote and popularity functions after over 40 years
Nannestad and Paldam (Public Choice 79:213–245, 1994) published herein an extremely influential review of the literature linking economics and elections, what they called the \"VP functions.\" In that work, they offered a number of conclusions, in proposition form, about the state of the evidence in this field. We present the key ones (16 in all), and assess the extent to which they continue to hold, in light of the new evidence about what has come to be known as economic voting. As shall be shown, Nannestad and Paldam were prescient in their early establishment of many of the principal results explaining how the economy moves the vote choice.
Journal Article
Flash boys : cracking the money code
The explosive story of how one group of ingenious oddballs and misfits set out to expose what was going on. It's the story of what it's like to declare war on some of the rishest and most powerful people in the world.
Lipopolysaccharide-Induced M2 to M1 Macrophage Transformation for IL-12p70 Production Is Blocked by Candida albicans Mediated Up-Regulation of EBI3 Expression
Macrophages are heterogeneous cell populations that are present in all tissues. Macrophages can be divided into classically activated inflammatory macrophages (M1) and alternatively activated anti-inflammatory macrophages (M2). It has been generally accepted that M1 macrophages are polarised in an inflammatory environment to produce pro-inflammatory cytokines, whilst M2 macrophages are involved in anti-inflammation and aid tissue repair in wound healing. Bacterial endotoxin (lipopolysaccharide; LPS) is a potent factor in infection, which induces M1 macrophages resulting in higher levels of iNOS, TNFα and IL-12p70 which dictate inflammatory T cell responses. M2 macrophages can be transformed into M1 macrophages following LPS stimulation to promote inflammation. Candida albicans is a commensal fungal microorganism, which has been suggested to induce immune tolerance; however, the mechanism of C. albicans-induced immune tolerance has not been investigated in detail. IL-35 is a recently identified anti-inflammatory cytokine which is a heterodimeric protein consisting of the Epstein-Barr virus-induced gene 3 (EBI3) and IL-12p35. IL-35 shares the protein subunit p35, with IL-12p70. IL-12p70 is the most potent cytokine to induce Th1 responses during inflammation. In this study, we demonstrate that heat-killed C. albicans (HKC) strongly suppressed LPS-induced IL-12p70 production in M2 macrophages. Candida albicans induced a high level of EBI3 expression in M2 macrophages, which served as a mechanism for IL-12p70 suppression by competitive binding of the common protein subunit (p35) of IL-35 and IL-12p70. To demonstrate that EBI3 expression had the ability to block IL-12p70 production intracellularly, a Chinese Hamster Ovary (CHO) cell line with biscistronic expression of IL-12p40 and p35 was constructed, followed by ectopic over-expression of EBI3. The over-expression of EBI3 in the IL-12p70 producing cell line effectively suppressed IL-12p70 production. IL-35 secretion was also detected in the cell line, with suppressed IL-12p70 production by immune-precipitation Western blotting. However, this secretion was not evident in M2 macrophages following stimulation by HKC. This can be explained by the constitutive expression of IL-35 receptors (gp130 and IL-12Rβ2) in M2 macrophages for cytokine consumption. Our results have indicated that C. albicans can suppress host inflammatory responses in mucosal skin by suppressing LPS-induced IL-12p70 production. Lower IL-12p70 production may avoid an unnecessary Th1 response in order to retain immune tolerance, which may be one of the mechanisms by which C. albicans achieves a successful commensal lifestyle without having a detrimental effect on the host's health.
Journal Article