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The Case for the Use of PPARγ Agonists as an Adjunctive Therapy for Cerebral Malaria
Lena Serghides
PPAR Research , 2012, DOI: 10.1155/2012/513865
Abstract: Cerebral malaria is a severe complication of Plasmodium falciparum infection associated with high mortality even when highly effective antiparasitic therapy is used. Adjunctive therapies that modify the pathophysiological processes caused by malaria are a possible way to improve outcome. This review focuses on the utility of PPARγ agonists as an adjunctive therapy for the treatment of cerebral malaria. The current knowledge of PPARγ agonist use in malaria is summarized. Findings from experimental CNS injury and disease models that demonstrate the potential for PPARγ agonists as an adjunctive therapy for cerebral malaria are also discussed. 1. Introduction Few diseases have the global health and economic impact of malaria [1]. In 2009, an estimated 225 million people were infected with malaria and close to a million people succumbed to their infection [2]. Malaria is caused by apicomplexan parasites belonging to the genus Plasmodium. Five species infect humans, Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and most recently, P. knowlesi [3]. The majority of morbidity and mortality is caused by P. falciparum infection, with the highest burden born by children and pregnant women. In the absence of prompt and effective treatment, P. falciparum infection can progress quickly, rapidly becoming severe and fatal. The rise in drug-resistant parasites complicates the administration of effective treatment. Severe malaria has multiple manifestations that can occur singly or in combination. They include hyperparasitemia, high fever, haemoglobinuria, acute renal failure, acute pulmonary edema, metabolic acidosis and respiratory distress, hypoglycemia, anemia, and cerebral malaria, which is characterized by coma and convulsions. Cerebral malaria has the highest mortality rate of all the severe complications and is associated with long-term cognitive and neurological deficits in surviving children [4–6]. Intravenous artesunate is now the standard of care for severe malaria in both adults and children following the landmark SEAQUAMAT and AQUAMAT trials that demonstrated the superiority of artesunate over quinine in adults and in children [7, 8]. However, even with the improved efficacy of artesunate, fatality rates remained high, 15% in adults and 10.9% in children. Adjunctive therapies, defined as therapies administered in combination with antiparasitic drugs that modify pathophysiological processes caused by malaria, have been pursued as a way to improve the outcome of severe malaria. Adjunctive therapies may also help extend the efficacy of antiparasitic
Inhaled Nitric Oxide Reduces Endothelial Activation and Parasite Accumulation in the Brain, and Enhances Survival in Experimental Cerebral Malaria
Lena Serghides,Hani Kim,Ziyue Lu,Dylan C. Kain,Chris Miller,Roland C. Francis,W. Conrad Liles,Warren M. Zapol,Kevin C. Kain
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0027714
Abstract: The host immune response contributes to the onset and progression of severe malaria syndromes, such as cerebral malaria. Adjunctive immunomodulatory strategies for severe malaria may improve clinical outcome beyond that achievable with artemisinin-based therapy alone. Here, we report that prophylaxis with inhaled nitric oxide significantly reduced systemic inflammation (lower TNF, IFNγ and MCP-1 in peripheral blood) and endothelial activation (decreased sICAM-1 and vWF, and increased angiopoeitin-1 levels in peripheral blood) in an experimental cerebral malaria model. Mice that received inhaled nitric oxide starting prior to infection had reduced parasitized erythrocyte accumulation in the brain, decreased brain expression of ICAM-1, and preserved vascular integrity compared to control mice.
HIV Impairs Opsonic Phagocytic Clearance of Pregnancy-Associated Malaria Parasites
Jessica Keen,Lena Serghides,Kodjo Ayi,Samir N Patel,John Ayisi,Anne van Eijk,Richard Steketee,Venkatachalam Udhayakumar,Kevin C Kain
PLOS Medicine , 2007, DOI: 10.1371/journal.pmed.0040181
Abstract: Background Primigravid (PG) women are at risk for pregnancy-associated malaria (PAM). Multigravid (MG) women acquire protection against PAM; however, HIV infection impairs this protective response. Protection against PAM is associated with the production of IgG specific for variant surface antigens (VSA-PAM) expressed by chondroitin sulfate A (CSA)-adhering parasitized erythrocytes (PEs). We hypothesized that VSA-PAM-specific IgG confers protection by promoting opsonic phagocytosis of PAM isolates and that HIV infection impairs this response. Methods and Findings We assessed the ability of VSA-PAM-specific IgG to promote opsonic phagocytosis of CSA-adhering PEs and the impact of HIV infection on this process. Opsonic phagocytosis assays were performed using the CSA-adherent parasite line CS2 and human and murine macrophages. CS2 PEs were opsonized with plasma or purified IgG subclasses from HIV-negative or HIV-infected PG and MG Kenyan women or sympatric men. Levels of IgG subclasses specific for VSA-PAM were compared in HIV-negative and HIV-infected women by flow cytometry. Plasma from HIV-negative MG women, but not PG women or men, promoted the opsonic phagocytosis of CSA-binding PEs (p < 0.001). This function depended on VSA-PAM-specific plasma IgG1 and IgG3. HIV-infected MG women had significantly lower plasma opsonizing activity (median phagocytic index 46 [interquartile range (IQR) 18–195] versus 251 [IQR 93–397], p = 0.006) and levels of VSA-PAM-specific IgG1 (mean fluorescence intensity [MFI] 13 [IQR 11–20] versus 30 [IQR 23–41], p < 0.001) and IgG3 (MFI 17 [IQR 14–23] versus 28 [IQR 23–37], p < 0.001) than their HIV-negative MG counterparts. Conclusions Opsonic phagocytosis may represent a novel correlate of protection against PAM. HIV infection may increase the susceptibility of multigravid women to PAM by impairing this clearance mechanism.
C5a Enhances Dysregulated Inflammatory and Angiogenic Responses to Malaria In Vitro: Potential Implications for Placental Malaria
Andrea Conroy, Lena Serghides, Constance Finney, Simon O. Owino, Sanjeev Kumar, D. Channe Gowda, W. Conrad Liles, Julie M. Moore, Kevin C. Kain
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004953
Abstract: Background Placental malaria (PM) is a leading cause of maternal and infant mortality. Although the accumulation of parasitized erythrocytes (PEs) and monocytes within the placenta is thought to contribute to the pathophysiology of PM, the molecular mechanisms underlying PM remain unclear. Based on the hypothesis that excessive complement activation may contribute to PM, in particular generation of the potent inflammatory peptide C5a, we investigated the role of C5a in the pathogenesis of PM in vitro and in vivo. Methodology and Principal Findings Using primary human monocytes, the interaction between C5a and malaria in vitro was assessed. CSA- and CD36-binding PEs induced activation of C5 in the presence of human serum. Plasmodium falciparum GPI (pfGPI) enhanced C5a receptor expression (CD88) on monocytes, and the co-incubation of monocytes with C5a and pfGPI resulted in the synergistic induction of cytokines (IL-6, TNF, IL-1β, and IL-10), chemokines (IL-8, MCP-1, MIP1α, MIP1β) and the anti-angiogenic factor sFlt-1 in a time and dose-dependent manner. This dysregulated response was abrogated by C5a receptor blockade. To assess the potential role of C5a in PM, C5a plasma levels were measured in malaria-exposed primigravid women in western Kenya. Compared to pregnant women without malaria, C5a levels were significantly elevated in women with PM. Conclusions and Significance These results suggest that C5a may contribute to the pathogenesis of PM by inducing dysregulated inflammatory and angiogenic responses that impair placental function.
PPARγ Agonists Improve Survival and Neurocognitive Outcomes in Experimental Cerebral Malaria and Induce Neuroprotective Pathways in Human Malaria
Lena Serghides ,Chloe R. McDonald equal contributor,Ziyue Lu equal contributor,Miriam Friedel,Cheryl Cui,Keith T. Ho,Howard T. J. Mount,John G. Sled,Kevin C. Kain
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1003980
Abstract: Cerebral malaria (CM) is associated with a high mortality rate, and long-term neurocognitive impairment in approximately one third of survivors. Adjunctive therapies that modify the pathophysiological processes involved in CM may improve outcome over anti-malarial therapy alone. PPARγ agonists have been reported to have immunomodulatory effects in a variety of disease models. Here we report that adjunctive therapy with PPARγ agonists improved survival and long-term neurocognitive outcomes in the Plasmodium berghei ANKA experimental model of CM. Compared to anti-malarial therapy alone, PPARγ adjunctive therapy administered to mice at the onset of CM signs, was associated with reduced endothelial activation, and enhanced expression of the anti-oxidant enzymes SOD-1 and catalase and the neurotrophic factors brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brains of infected mice. Two months following infection, mice that were treated with anti-malarials alone demonstrated cognitive dysfunction, while mice that received PPARγ adjunctive therapy were completely protected from neurocognitive impairment and from PbA-infection induced brain atrophy. In humans with P. falciparum malaria, PPARγ therapy was associated with reduced endothelial activation and with induction of neuroprotective pathways, such as BDNF. These findings provide insight into mechanisms conferring improved survival and preventing neurocognitive injury in CM, and support the evaluation of PPARγ agonists in human CM.
The Impact of CBSE’s Activities on E-Commerce Applications  [PDF]
Lena Khaled
iBusiness (IB) , 2013, DOI: 10.4236/ib.2013.51A005

Component based technology is widely used for both academicians and business. There are numbers of benefits for using this type of technology. First, it helps to increase the efficiency and maintainability of software. Second, it improves quality and helps to enhance productivity. Third, the reuse approach that supports component based technology decreases the time to market. Component based e-commerce can be used to solve e-commerce difficulties at application level as well as at system level. This paper introduces how component based activities have effect mainly on building the framework of the e-commerce. It also discusses how the architectural design of the application can be synthesized.

The Health and Well-Being among Children with Diabetes and Low HbA1c—A Qualitative Study in Sweden  [PDF]
Lena Lendahls, Ingrid Edvardsson
Health (Health) , 2018, DOI: 10.4236/health.2018.105044
Abstract: Aims and objectives: To examine health and well-being, as well as the need for support among children and parents where the child has T1DM with low HbA1c (<52 mmol/mole). The purpose was also to investigate the extent to which children’s and parents’ experiences match. Introduction: Studies have shown that children with diabetes type 1 (T1DM) rate their lives as worse than healthy peer ratings. In Sweden, views have been expressed that children, as well as their parents, feel pressurized by the diabetes teams to achieve low HbA1c values, which can lead to poorer mental health for the family. Design: A qualitative study. Methods: A consecutive sample of 11 children and their parents (one father, ten mothers) was interviewed together but individually guided by a semi structured interview guide. Interviews were analyzed using thematic content analysis. Results: Four main categories were consistent across children and their parents; 1) attitude to the illness, 2) sadness about diabetes, 3) the importance of the social network, and 4) the importance of the diabetes team. Worries about hyperglycemia were more prominent than worries about hypoglycemia in both children and parents. A distinguishing feature of the interviewed children was that they were responsible, strict and targeted. Many of them were competitive and took part in various sports, even at a very advanced level. Conclusions: This study shows that children with low HbA1c values experience good health and good well-being. Family support, good planning, and high acceptance of their illness contributed to this.
A liberdade de imprensa em chave marxiana / Freedom of the press in a marxian perspective
Helio Lena Lena
Revista Direito e Práxis , 2011,
Abstract: Resumo O presente artigo tem por objetivo discutir, mesmo que preliminarmente, a idéia de liberdade de imprensa em Karl Marx, Wladimir Lênin e Leon Trotsky. Acreditamos que, a práxis política destes atores sociais estava condicionada pela existência de uma liberdade de express o como reflexo da organiza o política. Todavia, nem sempre o que se verificou na prática, foi a liberdade de imprensa dada pelos governantes aos opositores; para tanto, os atores supracitados acreditavam que a liberdade de imprensa constituía um direito alienável dos cidad os. Palavras-chave: Liberdade de imprensa, jornalismo proletário, comunismo Abstract This article intends to argue, even though on preliminary basis, the idea of press freedom in the thought of Karl Marx, Wladimir Lenin and Leon Trotsky. We believe that the political praxis of these social actors was conditioned by the existence of free speech as a reflex of the political organization. On another hand, not always was press freedom actually given by governments to oppositionists; in order to achieve it, the previously mentioned actors believed that press freedom was an alienable right of citizens. Keywords: Freedom of the press, proletarian journalism, communism
Caries Detection Methods Based on Changes in Optical Properties between Healthy and Carious Tissue
Lena Karlsson
International Journal of Dentistry , 2010, DOI: 10.1155/2010/270729
Abstract: A conservative, noninvasive or minimally invasive approach to clinical management of dental caries requires diagnostic techniques capable of detecting and quantifying lesions at an early stage, when progression can be arrested or reversed. Objective evidence of initiation of the disease can be detected in the form of distinct changes in the optical properties of the affected tooth structure. Caries detection methods based on changes in a specific optical property are collectively referred to as optically based methods. This paper presents a simple overview of the feasibility of three such technologies for quantitative or semiquantitative assessment of caries lesions. Two of the techniques are well-established: quantitative light-induced fluorescence, which is used primarily in caries research, and laser-induced fluorescence, a commercially available method used in clinical dental practice. The third technique, based on near-infrared transillumination of dental enamel is in the developmental stages. 1. Introduction Dental caries is one of the most prevalent chronic diseases of humans worldwide. When different stages of the disease are taken into account, from the initial to the clinically manifest lesion, very few individuals are truly unaffected. In most industrialised countries 60%–90% of school-aged children are affected. The prevalence among adults is even higher and in most countries the disease affects nearly 100% of the population [1]. During the last thirty years, however, major changes have occurred in the pattern of the disease. Progression of enamel caries is now slower [2], allowing time for preventive intervention before irreversible destruction of tooth substance occurs. During the early stages of the disease the process is reversible and can be arrested: noninvasive intervention can convert a lesion from an active to an inactive state [3, 4]. Appropriate diagnostic techniques are necessary to support such decisions about management of the individual lesion. The clinician needs to be able to monitor the outcome of noninvasive measures and in cases where there is evidence of lesion progression, make a timely decision to intervene, using minimally invasive techniques and restoring damaged tooth structure without weakening the tooth. Applying strategies to control, arrest, or reverse the disease process can reduce the economic burden, pain, and suffering of placing and replacing restorations [5]. This modern, conservative approach to clinical management of dental caries, which has been evolving during the past twenty years, has necessitated a
The first Finnish malariologist, Johan Haartman, and the discussion about malaria in 18th century Turku, Finland
Lena Hulden
Malaria Journal , 2011, DOI: 10.1186/1475-2875-10-43
Abstract: Already in the beginning of the 18th century Swedish physicians recommended Peruvian bark as medication and they also emphasized that bleeding or blood-letting a malaria patient was harmful. Although malaria was a common disease in the kingdom, the situation was worst in the SW-part of Finland which consisted of the town of Turku and a large archipelago in the Baltic. The farmers had no opportunity to get modern healthcare until Johan Haartman was appointed district physician in 1754. To improve the situation he wrote a medical handbook intended for both the farmers and for persons of rank.Haartman's work was first published 1759 and he discussed all the different cures and medications. His aim was to recommend the best ones and warn against the harmful. His first choice was Peruvian bark, but he knew that the farmers could not afford it.Haartman was appointed professor in medicine at the Royal Academy of Turku in 1765. The malaria situation in Finland grew worse in the 1770's and Haartman analysed the situation. He found the connection between the warm summers and the spring epidemics next year.In a later thesis, Haartman analysed the late summer/early autumn malaria epidemics in the archipelago. Althouh Haartman did not know the connection between malaria and the vector, he gave astute advice and encouraged the farmers to build their cottages in windy places away from the shallow bays in which the Anopheles females hatched. Haartman died in 1788. After his death malaria research in Turku declined. His medical handbook would not be replaced until 1844.After the Great Northern War (1700-1721), Sweden lost the major part of its Baltic provinces and Karelia in Eastern Finland. The autocracy was replaced by the power of the estates of the realm. The military budget was decreased. More resources were invested in the development of universities, academies and research. Swedish science, with names as Anders Celsius, Carolus Linnaeus and Pehr Wargentin, made the Swedish ac
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