The discovery of a novel antibiotic for the treatment of Clostridium difficile infections: a story of an effective academic-industrial partnership

Academic drug discovery is playing an increasingly important role in the identification of new therapies for a wide range of diseases. There is no one model that guarantees success. We describe here a drug discovery story where chance, the ability to capitalise on chance, and the assembling of a range of expertise, have all played important roles in the discovery and subsequent development of an antibiotic chemotype based on the bis-benzimidazole scaffold, with potency against a number of current therapeutically challenging diseases. One compound in this class, SMT19969, has recently entered Phase 2 human clinical trials for the treatment of Clostridium difficile infections

Simpson's Paradox, Lord's Paradox, and Suppression Effects are the same phenomenon – the reversal paradox

This article discusses three statistical paradoxes that pervade epidemiological research: Simpson's paradox, Lord's paradox, and suppression. These paradoxes have important implications for the interpretation of evidence from observational studies. This article uses hypothetical scenarios to illustrate how the three paradoxes are different manifestations of one phenomenon – the reversal paradox – depending on whether the outcome and explanatory variables are categorical, continuous or a combination of both; this renders the issues and remedies for any one to be similar for all three. Although the three statistical paradoxes occur in different types of variables, they share the same characteristic: the association between two variables can be reversed, diminished, or enhanced when another variable is statistically controlled for. Understanding the concepts and theory behind these paradoxes provides insights into some controversial or contradictory research findings. These paradoxes show that prior knowledge and underlying causal theory play an important role in the statistical modelling of epidemiological data, where incorrect use of statistical models might produce consistent, replicable, yet erroneous results

Psychopathic leadership a case study of a corporate psychopath CEO

This longitudinal case study reports on a charity in the UK which gained a new CEO who was reported by two middle managers who worked in the charity, to embody (respectively) all or most of the ten characteristics within a measure of corporate psychopathy. The leadership of this CEO with a high corporate psychopathy score was reported to be so poor that the organisation was described as being one without leadership and as a lost organisation with no direction. This paper outlines the resultant characteristics of the ensuing aimlessness and lack of drive of the organisation involved. Comparisons are made to a previous CEO in the same organisation, who was reportedly an authentic, effective and transformational leader. Outcomes under the CEO with a high corporate psychopathy score were related to bullying, staff withdrawal and turnover as effective employees stayed away from and/or left the organisation. Outcomes also included a marked organisational decline in terms of revenue, employee commitment, creativity and organisational innovativeness. The paper makes a contribution to both leadership and to corporate psychopathy research as it appears to be the first reported study of a CEO with a high corporate psychopathy score

Against quantiles: categorization of continuous variables in epidemiologic research, and its discontents

<p>Abstract</p> <p>Background</p> <p>Quantiles are a staple of epidemiologic research: in contemporary epidemiologic practice, continuous variables are typically categorized into tertiles, quartiles and quintiles as a means to illustrate the relationship between a continuous exposure and a binary outcome.</p> <p>Discussion</p> <p>In this paper we argue that this approach is highly problematic and present several potential alternatives. We also discuss the perceived drawbacks of these newer statistical methods and the possible reasons for their slow adoption by epidemiologists.</p> <p>Summary</p> <p>The use of quantiles is often inadequate for epidemiologic research with continuous variables.</p

The Trypanosoma cruzi vitamin C dependent peroxidase confers protection against oxidative stress but is not a determinant of virulence.

BACKGROUND: The neglected parasitic infection Chagas disease is rapidly becoming a globalised public health issue due to migration. There are only two anti-parasitic drugs available to treat this disease, benznidazole and nifurtimox. Thus it is important to identify and validate new drug targets in Trypanosoma cruzi, the causative agent. T. cruzi expresses an ER-localised ascorbate-dependent peroxidase (TcAPx). This parasite-specific enzyme has attracted interest from the perspective of targeted chemotherapy. METHODOLOGY/PRINCIPAL FINDINGS: To assess the importance of TcAPx in protecting T. cruzi from oxidative stress and to determine if it is essential for virulence, we generated null mutants by targeted gene disruption. Loss of activity was associated with increased sensitivity to exogenous hydrogen peroxide, but had no effect on susceptibility to the front-line Chagas disease drug benznidazole. This suggests that increased oxidative stress in the ER does not play a significant role in its mechanism of action. Homozygous knockouts could proceed through the entire life-cycle in vitro, although they exhibited a significant decrease in their ability to infect mammalian cells. To investigate virulence, we exploited a highly sensitive bioluminescence imaging system which allows parasites to be monitored in real-time in the chronic stage of murine infections. This showed that depletion of enzyme activity had no effect on T. cruzi replication, dissemination or tissue tropism in vivo. CONCLUSIONS/SIGNIFICANCE: TcAPx is not essential for parasite viability within the mammalian host, does not have a significant role in establishment or maintenance of chronic infections, and should therefore not be considered a priority for drug design

Key components of anaphylaxis management plans: consensus findings from a national electronic Delphi study

OBJECTIVES: There is no international consensus on the components of anaphylaxis management plans and responsibility for their design and delivery is contested. We set out to establish consensus among relevant specialist and generalist clinicians on this issue to inform future randomized controlled trials. DESIGN: A two-round electronic Delphi study completed by a 25-person, multidisciplinary expert panel. Participants scored the importance of a range of statements on anaphylaxis management, identified from a systematic review of the literature, on a five-point scale ranging from 'very important' to 'irrelevant'. Consensus was defined a priori as being achieved if 80% or more of panel members rated a statement as 'important' or 'very important' after Round 2. SETTING: Primary and secondary care and academic settings in the UK and Ireland. PARTICIPANTS: Twenty-five medical, nursing and allied health professionals. MAIN OUTCOME MEASURES: Consensus on the key components of anaphylaxis management plans. RESULTS: The response rate was 84% (n = 21) for Round 1 and 96% (n = 24) for Round 2. The key components of emergency care on which consensus was achieved included: awareness of trigger factors (100%); recognition and emergency management of reactions of different severity (100%); and clear information on adrenaline (epinephrine) use (100%). Consensus on longer-term management issues included: clear written guidelines on anaphylaxis management (96%); annual review of plans (87%); and plans that were tailored to individual needs (82%). CONCLUSIONS: This national consensus-building exercise generated widespread agreement that emergency plans need to be simple, clear and generic, making them easy to implement in a crisis. In contrast, long-term plans need to be negotiated between patient/carers and professionals, and tailored to individual needs. The effectiveness of this expert-agreed long-term plan now needs to be evaluated rigorously

Immunodominant Antigens of Leishmania chagasi Associated with Protection against Human Visceral Leishmaniasis

One of the most striking features of infection by Leishmania chagasi is that infection leads to a spectrum of clinical outcomes ranging from asymptomatic infection to active disease. The existence of asymptomatic infected people has served as an incentive to believe that an effective vaccine is possible, but unfortunately no successful immunological characterization of such cases was obtained. Patients recovered from visceral leishmaniasis show a similar immunological profile to asymptomatic infected individuals and both exhibit a strong cell-mediated immune response against Leishmania antigens and are resistant to disease. Since the past decade several approaches were undertaken to try to shed light on the immunological profile associated with such “resistance” to infections, notwithstanding antigenic recognition profile associated to resistance to infection was not successfully explored. In the present manuscript we describe a specific IgG recognizing pattern associated with resistant individuals (asymptomatic infected people and recovery patients to visceral leishmaniasis). These data highlight the possibility of using specific proteins in serological tests for the identification of asymptomatic infected individuals

Identification of new participants in the rainbow trout (Oncorhynchus mykiss) oocyte maturation and ovulation processes using cDNA microarrays

BACKGROUND: The hormonal control of oocyte maturation and ovulation as well as the molecular mechanisms of nuclear maturation have been thoroughly studied in fish. In contrast, the other molecular events occurring in the ovary during post-vitellogenesis have received far less attention. METHODS: Nylon microarrays displaying 9152 rainbow trout cDNAs were hybridized using RNA samples originating from ovarian tissue collected during late vitellogenesis, post-vitellogenesis and oocyte maturation. Differentially expressed genes were identified using a statistical analysis. A supervised clustering analysis was performed using only differentially expressed genes in order to identify gene clusters exhibiting similar expression profiles. In addition, specific genes were selected and their preovulatory ovarian expression was analyzed using real-time PCR. RESULTS: From the statistical analysis, 310 differentially expressed genes were identified. Among those genes, 90 were up-regulated at the time of oocyte maturation while 220 exhibited an opposite pattern. After clustering analysis, 90 clones belonging to 3 gene clusters exhibiting the most remarkable expression patterns were kept for further analysis. Using real-time PCR analysis, we observed a strong up-regulation of ion and water transport genes such as aquaporin 4 (aqp4) and pendrin (slc26). In addition, a dramatic up-regulation of vasotocin (avt) gene was observed. Furthermore, angiotensin-converting-enzyme 2 (ace2), coagulation factor V (cf5), adam 22, and the chemokine cxcl14 genes exhibited a sharp up-regulation at the time of oocyte maturation. Finally, ovarian aromatase (cyp19a1) exhibited a dramatic down-regulation over the post-vitellogenic period while a down-regulation of Cytidine monophosphate-N-acetylneuraminic acid hydroxylase (cmah) was observed at the time of oocyte maturation. CONCLUSION: We showed the over or under expression of more that 300 genes, most of them being previously unstudied or unknown in the fish preovulatory ovary. Our data confirmed the down-regulation of estrogen synthesis genes during the preovulatory period. In addition, the strong up-regulation of aqp4 and slc26 genes prior to ovulation suggests their participation in the oocyte hydration process occurring at that time. Furthermore, among the most up-regulated clones, several genes such as cxcl14, ace2, adam22, cf5 have pro-inflammatory, vasodilatory, proteolytics and coagulatory functions. The identity and expression patterns of those genes support the theory comparing ovulation to an inflammatory-like reaction

Defining Global Gene Expression Changes of the Hypothalamic-Pituitary-Gonadal Axis in Female sGnRH-Antisense Transgenic Common Carp (Cyprinus carpio)

BACKGROUND: The hypothalamic-pituitary-gonadal (HPG) axis is critical in the development and regulation of reproduction in fish. The inhibition of neuropeptide gonadotropin-releasing hormone (GnRH) expression may diminish or severely hamper gonadal development due to it being the key regulator of the axis, and then provide a model for the comprehensive study of the expression patterns of genes with respect to the fish reproductive system. METHODOLOGY/PRINCIPAL FINDINGS: In a previous study we injected 342 fertilized eggs from the common carp (Cyprinus carpio) with a gene construct that expressed antisense sGnRH. Four years later, we found a total of 38 transgenic fish with abnormal or missing gonads. From this group we selected the 12 sterile females with abnormal ovaries in which we combined suppression subtractive hybridization (SSH) and cDNA microarray analysis to define changes in gene expression of the HPG axis in the present study. As a result, nine, 28, and 212 genes were separately identified as being differentially expressed in hypothalamus, pituitary, and ovary, of which 87 genes were novel. The number of down- and up-regulated genes was five and four (hypothalamus), 16 and 12 (pituitary), 119 and 93 (ovary), respectively. Functional analyses showed that these genes involved in several biological processes, such as biosynthesis, organogenesis, metabolism pathways, immune systems, transport links, and apoptosis. Within these categories, significant genes for neuropeptides, gonadotropins, metabolic, oogenesis and inflammatory factors were identified. CONCLUSIONS/SIGNIFICANCE: This study indicated the progressive scaling-up effect of hypothalamic sGnRH antisense on the pituitary and ovary receptors of female carp and provided comprehensive data with respect to global changes in gene expression throughout the HPG signaling pathway, contributing towards improving our understanding of the molecular mechanisms and regulative pathways in the reproductive system of teleost fish