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BACKGROUND: Respiratory syncytial virus (RSV) infects the lung epithelium where it stimulates the production of numerous host cytokines that are associated with disease burden and acute lung injury. Characterizing the host cytokine response to RSV infection, the regulation of host cytokines and the impact of neutralizing an RSV-inducible cytokine during infection were undertaken in this study. METHODS: A549, primary human small airway epithelial (SAE) cells and wild-type, TIR-domain-containing adapter-inducing interferon-β (Trif) and mitochondrial antiviral-signaling protein (Mavs) knockout (KO) mice were infected with RSV and cytokine responses were investigated by ELISA, multiplex analysis and qPCR. Neutralizing anti-leukemia inhibitory factor (LIF) IgG or control IgG was administered to a group of wild-type animals prior to RSV infection. RESULTS AND DISCUSSION: RSV-infected A549 and SAE cells release a network of cytokines, including newly identified RSV-inducible cytokines LIF, migration inhibitory factor (MIF), stem cell factor (SCF), CCL27, CXCL12 and stem cell growth factor beta (SCGF-β). These RSV-inducible cytokines were also observed in the airways of mice during an infection. To identify the regulation of RSV inducible cytokines, Mavs and Trif deficient animals were infected with RSV. In vivo induction of airway IL-1β, IL-4, IL-5, IL-6, IL-12(p40), IFN-γ, CCL2, CCL5, CCL3, CXCL1, IP-10/CXCL10, IL-22, MIG/CXCL9 and MIF were dependent on Mavs expression in mice. Loss of Trif expression in mice altered the RSV induction of IL-1β, IL-5, CXCL12, MIF, LIF, CXCL12 and IFN-γ. Silencing of retinoic acid–inducible gene-1 (RIG-I) expression in A549 cells had a greater impact on RSV-inducible cytokines than melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2), and Trif expression. To evaluate the role of LIF in the airways during RSV infection, animals were treated with neutralizing anti-LIF IgG, which enhanced RSV pathology observed with increased airspace protein content, apoptosis and airway hyperresponsiveness compared to control IgG treatment. CONCLUSIONS: RSV infection in the epithelium induces a network of immune factors to counter infection, primarily in a RIG-I dependent manner. Expression of LIF protects the lung from lung injury and enhanced pathology during RSV infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12865-014-0041-4) contains supplementary material, which is available to authorized users. |
Influenza is a perennial problem affecting millions of people annually with the everpresent threat of devastating pandemics. Active prophylaxis by vaccination against influenza virus is currently the main countermeasure supplemented with antivirals. However, disadvantages of this strategy include the impact of antigenic drift, necessitating constant updating of vaccine strain composition, and emerging antiviral drug resistance. The development of other options for influenza prophylaxis, particularly with broad acting agents able to provide protection in the period between the onset of a pandemic and the development of a strain specific vaccine, is of great interest. Exploitation of broad-spectrum mediators could provide barricade protection in the early critical phase of influenza virus outbreaks. Passive immunity has the potential to provide immediate antiviral effects, inhibiting virus replication, reducing virus shedding, and thereby protecting vulnerable populations in the event of an impending influenza pandemic. Here, we review passive broad-spectrum influenza prophylaxis options with a focus on harnessing natural host defenses, including interferons and antibodies. |
Infectious diseases can constitute public health emergencies of international concern when a pathogen arises, acquires new characteristics, or is deliberately released, leading to the potential for loss of human lives as well as societal disruption. A wide range of risk drivers are now known to lead to and/or exacerbate the emergence and spread of infectious disease, including global trade and travel, the overuse of antibiotics, intensive agriculture, climate change, high population densities, and inadequate infrastructures, such as water treatment facilities. Where multiple risk drivers interact, the potential impact of a disease outbreak is amplified. The varying temporal and geographic frequency with which infectious disease events occur adds yet another layer of complexity to the issue. Mitigating the emergence and spread of infectious disease necessitates mapping and prioritising the interdependencies between public health and other sectors. Conversely, during an international public health emergency, significant disruption occurs not only to healthcare systems but also to a potentially wide range of sectors, including trade, tourism, energy, civil protection, transport, agriculture, and so on. At the same time, dealing with a disease outbreak may require a range of critical sectors for support. There is a need to move beyond narrow models of risk to better account for the interdependencies between health and other sectors so as to be able to better mitigate and respond to the risks posed by emerging infectious disease. |
How cells shape and remodel organelles in response to cellular signals is a poorly understood process. Using Xenopus laevis egg extract, we found that increases in cytosolic calcium lead to the activation of an endogenous ribonuclease, XendoU. A fraction of XendoU localizes to the endoplasmic reticulum (ER) and is required for nuclear envelope assembly and ER network formation in a catalysis-dependent manner. Using a purified vesicle fusion assay, we show that XendoU functions on the surface of ER membranes to promote RNA cleavage and ribonucleoprotein (RNP) removal. Additionally, RNA removal from the surface of vesicles by RNase treatment leads to increased ER network formation. Using human tissue culture cells, we found that hEndoU localizes to the ER, where it promotes the formation of ER tubules in a catalysis-dependent manner. Together, these results demonstrate that calcium-activated removal of RNA from membranes by XendoU promotes and refines ER remodeling and the formation of tubular ER. |
An infectious disease that is transmitted from animals to humans, sometimes by a vector, is called zoonosis. The focus of this review article is on the most common emerging and re-emerging bacterial zoonotic diseases. The role of “One Health” approach, public health education, and some measures that can be taken to prevent zoonotic bacterial infections are discussed. Key points: A zoonotic bacterial disease is a disease that can be very commonly transmitted between animals and humans. Global climate changes, overuse of antimicrobials in medicine, more intensified farm settings, and closer interactions with animals facilitate emergence or re-emergence of bacterial zoonotic infections. The global “One Health” approach, which requires interdisciplinary collaborations and communications in all aspects of health care for humans, animals, and the environment, will support public health in general. New strategies for continuous dissemination of multidisciplinary research findings related to zoonotic bacterial diseases are hence needed. |
The blood–brain barrier (BBB) is composed of capillary endothelial cells, pericytes, and perivascular astrocytes, which regulate central nervous system homeostasis. Sonic hedgehog (SHH) released from astrocytes plays an important role in the maintenance of BBB integrity. BBB disruption and microglial activation are common pathological features of various neurologic diseases such as multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease. Interleukin-1β (IL-1β), a major pro-inflammatory cytokine released from activated microglia, increases BBB permeability. Here we show that IL-1β abolishes the protective effect of astrocytes on BBB integrity by suppressing astrocytic SHH production. Astrocyte conditioned media, SHH, or SHH signal agonist strengthened BBB integrity by upregulating tight junction proteins, whereas SHH signal inhibitor abrogated these effects. Moreover, IL-1β increased astrocytic production of pro-inflammatory chemokines such as CCL2, CCL20, and CXCL2, which induce immune cell migration and exacerbate BBB disruption and neuroinflammation. Our findings suggest that astrocytic SHH is a potential therapeutic target that could be used to restore disrupted BBB in patients with neurologic diseases. |
The IFITM3 polymorphism rs12252-C, which encodes an IFITM3 isoform (Δ21 IFITM3) lacking 21 amino acids at the amino terminus, has been controversially associated with poor clinical outcomes in patients with H1N1 influenza A virus (IAV) infections. In vitro studies have shown that Δ21 IFITM3 loses its ability to restrict H1N1 IAV. Subsequent research has also revealed that tyrosine 20 is the key determinant for IFITM3 endocytic trafficking, which is essential for the efficient anti-viral activity of IFITM3. In contrast to previous studies, we demonstrated that both Δ21 IFITM3 and an IFITM3 variant (Y20A IFITM3), in which tyrosine 20 is substituted with alanine, strongly restricted entry mediated by IAV H1, H3, H5, and H7 proteins. Δ21 IFITM3 also efficiently suppressed replication of H1N1 and, to a lesser extent, H3N2 IAV. Δ21 IFITM3 and Y20A IFITM3 had broader subcellular distributions than full-length IFITM3 but an abundant amount of both IFITM3 variants still localized to late endosomes and lysosomes. Our data indicate that tyrosine 20 partially regulates the subcellular localization of IFITM3 but is not functionally essential for IFITM3-mediated IAV restriction. They also suggested that mechanisms, other than viral entry restriction, might contribute to variations in clinical outcomes of H1N1 influenza associated with rs12252-C. |
BACKGROUND: Nasal potential difference (NPD) and intestinal current measurement (ICM) are functional CFTR tests that are used as adjunctive diagnostic tools for cystic fibrosis (CF). Smoking has a systemic negative impact on CFTR function. A diagnostic comparison between NPD and ICM and the impact of smoking on both CFTR tests has not been done. METHODS: The sweat chloride test, NPD, and ICM were performed in 18 patients with CF (sweat chloride >60 mmol/l), including 6 pancreatic sufficient (PS) patients, and 13 healthy controls, including 8 smokers. The NPD CFTR response to Cl-free and isoproterenol perfusion (Δ0Cl(-) + Iso) was compared to the ICM CFTR response to forskolin/IBMX, carbachol, and histamine (ΔI(sc, forskolin/IBMX+ carbachol+histamine)). RESULTS: The mean NPD CFTR response and ICM CFTR response between patients with CF and healthy controls was significantly different (p <0.001), but not between patients with CF who were PS and those who were pancreatic insufficient (PI). Smokers have a decreased CFTR response measured by NPD (p = 0.049). For ICM there is a trend towards decreased CFTR response (NS). Three healthy control smokers had NPD responses within the CF-range. In contrast to NPD, there was no overlap of the ICM response between patients with CF and controls. CONCLUSIONS: ICM is superior to NPD in distinguishing between patients with CF who have a sweat chloride > 60 mmol/l and healthy controls, including smokers. Neither NPD nor ICM differentiated between patients with CF who were PS from those who were PI. Smoking has a negative impact on CFTR function in healthy controls measured by NPD and challenges the diagnostic interpretation of NPD, but not ICM. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2466-14-156) contains supplementary material, which is available to authorized users. |
BACKGROUND: In 2007, a novel bunyavirus was found in Henan Province, China and named fever, thrombocytopenia and leukocytopenia syndrome virus (FTLSV); since then, FTLSV has been found in ticks and animals in many Chinese provinces. Human-to-human transmission has been documented, indicating that FTLSV should be considered a potential public health threat. Determining the historical spread of FTLSV could help curtail its spread and prevent future movement of this virus. METHOD/PRINCIPAL FINDINGS: To examine the pattern of FTLSV evolution and the origin of outbreak strains, as well to examine the rate of evolution, the genome of 12 FTLSV strains were sequenced and a phylogenetic and Bayesian phylogeographic analysis of all available FTLSV sequences in China were performed. Analysis based on the FTLSV L segment suggests that the virus likely originated somewhere in Huaiyangshan circa 1790 (95% highest probability density interval: 1756–1817) and began spreading around 1806 (95% highest probability density interval: 1773–1834). Analysis also indicates that when FTLSV arrived in Jiangsu province from Huaiyangshan, Jiangsu Province became another source for the spread of the disease. Bayesian factor test analysis identified three major transmission routes: Huaiyangshan to Jiangsu, Jiangsu to Liaoning, and Jiangsu to Shandong. The speed of FTLSV movement has increased in recent decades, likely facilitated by modern human activity and ecosystem changes. In addition, evidence of RNA segment reassortment was found in FTLSV; purifying selection appears to have been the dominant force in the evolution of this virus. CONCLUSION: Results presented in the manuscript suggest that the Huaiyangshan area is likely be the origin of FTLSV in China and identified probable viral migration routes. These results provide new insights into the origin and spread of FTLSV in China, and provide a foundation for future virological surveillance and control. |
BACKGROUND: There are no reports of proteomic analyses of inflamed islets in type 1 diabetes. PROCEDURES: Proteins expressed in the islets of enterovirus-associated fulminant type 1 diabetes (FT1DM) with extensive insulitis were identified by laser-capture microdissection mass spectrometry using formalin-fixed paraffin-embedded pancreatic tissues. RESULTS: Thirty-eight proteins were identified solely in FT1DM islets, most of which have not been previously linked to type 1 diabetes. Five protein-protein interacting clusters were identified, and the cellular localization of selected proteins was validated immunohistochemically. Migratory activity-related proteins, including plastin-2 (LCP1), moesin (MSN), lamin-B1 (LMNB1), Ras GTPase-activating-like protein (IQGAP1) and others, were identified in CD8(+) T cells and CD68(+) macrophages infiltrated to inflamed FT1DM islets. Proteins involved in successive signaling in innate/adaptive immunity were identified, including SAM domain and HD domain-containing protein 1 (SAMHD1), Ras GTPase-activating-like protein (IQGAP1), proteasome activator complex subunit 1 (PSME1), HLA class I histocompatibility antigen (HLA-C), and signal transducer and activator of transcription 1-alpha/beta (STAT1). Angiogenic (thymidine phosphorylase (TYMP)) and anti-angiogenic (tryptophan-tRNA ligase (WARS)) factors were identified in migrating CD8(+) T cells and CD68(+) macrophages. Proteins related to virus replication and cell proliferation, including probable ATP-dependent RNA helicase DEAD box helicase 5 (DDX5) and heterogeneous nuclear ribonucleoprotein H (HNRNPH1), were identified. The anti-apoptotic protein T-complex protein 1 subunit epsilon (CCT5), the anti-oxidative enzyme 6-phosphogluconate dehydrogenase (PDG), and the anti-viral and anti-apoptotic proteins serpin B6 (SERPINB6) and heat shock 70 kDa protein1-like (HSPA1L), were identified in FT1DM-affected islet cells. CONCLUSION: The identified FT1DM-characterizing proteins include those involved in aggressive beta cell destruction through massive immune cell migration and proteins involved in angiogenesis and islet vasculature bleeding, cell repair, and anti-inflammatory processes. Several target proteins for future type 1 diabetes interventions were identified. |
BACKGROUND: Early diagnosis and appropriate therapy of sepsis is a daily challenge in intensive care units (ICUs) despite the advances in critical care medicine. Procalcitonin (PCT); an innovative laboratory marker, has been recently proven valuable worldwide in this regard. OBJECTIVES: This study was undertaken to evaluate the utility of PCT in a resource constrained country like ours when compared to the traditional inflammatory markers like C - reactive protein (CRP) to introduce PCT as a routine biochemical tool in regional hospitals. MATERIALS AND METHODS: PCT and CRP were simultaneously measured and compared in 73 medico-surgical ICU patients according to the American College of Chest Physicians (ACCP) criteria based study groups. RESULTS: The clinical presentation of 75% cases revealed a range of systemic inflammatory responses (SIRS). The diagnostic accuracy of PCT was higher (75%) with greater specificity (72%), sensitivity (76%), positive and negative predictive values (89% and 50%), positive likelihood ratio (2.75) as well as the smaller negative likelihood ratio (0.33). Both serum PCT and CRP values in cases with sepsis, severe sepsis and septic shock were significantly higher from that of the cases with SIRS and no SIRS (P < 0.01). CONCLUSION: PCT is found to be superior to CRP in terms of accuracy in identification and to assess the severity of sepsis even though both markers cannot be used in differentiating infectious from noninfectious clinical syndrome. |
Optimal intervention for disease outbreaks is often impeded by severe scientific uncertainty. Adaptive management (AM), long-used in natural resource management, is a structured decision-making approach to solving dynamic problems that accounts for the value of resolving uncertainty via real-time evaluation of alternative models. We propose an AM approach to design and evaluate intervention strategies in epidemiology, using real-time surveillance to resolve model uncertainty as management proceeds, with foot-and-mouth disease (FMD) culling and measles vaccination as case studies. We use simulations of alternative intervention strategies under competing models to quantify the effect of model uncertainty on decision making, in terms of the value of information, and quantify the benefit of adaptive versus static intervention strategies. Culling decisions during the 2001 UK FMD outbreak were contentious due to uncertainty about the spatial scale of transmission. The expected benefit of resolving this uncertainty prior to a new outbreak on a UK-like landscape would be £45–£60 million relative to the strategy that minimizes livestock losses averaged over alternate transmission models. AM during the outbreak would be expected to recover up to £20.1 million of this expected benefit. AM would also recommend a more conservative initial approach (culling of infected premises and dangerous contact farms) than would a fixed strategy (which would additionally require culling of contiguous premises). For optimal targeting of measles vaccination, based on an outbreak in Malawi in 2010, AM allows better distribution of resources across the affected region; its utility depends on uncertainty about both the at-risk population and logistical capacity. When daily vaccination rates are highly constrained, the optimal initial strategy is to conduct a small, quick campaign; a reduction in expected burden of approximately 10,000 cases could result if campaign targets can be updated on the basis of the true susceptible population. Formal incorporation of a policy to update future management actions in response to information gained in the course of an outbreak can change the optimal initial response and result in significant cost savings. AM provides a framework for using multiple models to facilitate public-health decision making and an objective basis for updating management actions in response to improved scientific understanding. |
The continuous expansion of nosocomial infections around the globe has become a precarious situation. Key challenges include mounting dissemination of multiple resistances to antibiotics, the easy transmission and the growing mortality rates of hospital-acquired bacterial diseases. Thus, new ways to rapidly detect these infections are vital. Consequently, researchers around the globe pursue innovative approaches for point-of-care devices. In many cases the specific interaction of an antigen and a corresponding antibody is pivotal. However, the knowledge about suitable antigens is lacking. The aim of this study was to identify novel antigens as specific diagnostic markers. Additionally, these proteins might be aptly used for the generation of vaccines to improve current treatment options. Hence, a cDNA-based expression library was constructed and screened via microarrays to detect novel antigens of Klebsiella pneumoniae, a prominent agent of nosocomial infections well-known for its extensive antibiotics resistance, especially by extended-spectrum beta-lactamases (ESBL). After screening 1536 clones, 14 previously unknown immunogenic proteins were identified. Subsequently, each protein was expressed in full-length and its immunodominant character examined by ELISA and microarray analyses. Consequently, six proteins were selected for epitope mapping and three thereof possessed linear epitopes. After specificity analysis, homology survey and 3d structural modelling, one epitope sequence GAVVALSTTFA of KPN_00363, an ion channel protein, was identified harboring specificity for K. pneumoniae. The remaining epitopes showed ambiguous results regarding the specificity for K. pneumoniae. The approach adopted herein has been successfully utilized to discover novel antigens of Campylobacter jejuni and Salmonella enterica antigens before. Now, we have transferred this knowledge to the key nosocomial agent, K. pneumoniae. By identifying several novel antigens and their linear epitope sites, we have paved the way for crucial future research and applications including the design of point-of-care devices, vaccine development and serological screenings for a highly relevant nosocomial pathogen. |
Classical Swine Fever (CSF) is a highly infectious fatal pig disease, resulting in huge economic loss to the swine industry. Integrins are membrane-bound signal mediators, expressed on a variety of cell surfaces and are known as receptors or co-receptors for many viruses. However, the role of integrin β3 in CSFV infection is unknown. Here, through quantitive PCR, immunofluorescence (IFC) and immunocytohistochemistry (ICC), we revealed that ST (swine testicles epithelial) cells have a prominent advantage in CSFV proliferation as compared to EC (swine umbilical vein endothelial cell), IEC (swine intestinal epithelial cell) and PK (porcine kidney epithelial) cells. Meanwhile, ST cells had remarkably more integrin β3 expression as compared to EC, IEC and PK cells, which was positively correlated with CSFV infection and proliferation. Integrin β3 was up-regulated post CSFV infection in all the four cell lines, while the CSFV proliferation rate was decreased in integrin β3 function-blocked cells. ShRNA1755 dramatically decreased integrin β3, with a deficiency of 96% at the mRNA level and 80% at the protein level. CSFV proliferation was dramatically reduced in integrin β3 constantly-defected cells (ICDC), with the deficiencies of 92.6%, 99% and 81.7% at 24 h, 48 h and 72 h post CSFV infection, respectively. These results demonstrate that integrin β3 is required in CSFV infection and proliferation, which provide a new insight into the mechanism of CSFV infection. |
Brazil holds approximately 1/3 of population living infected with AIDS (acquired immunodeficiency syndrome) in Central and South Americas, and it was also the first developing country to implement a large-scale control and intervention program against AIDS epidemic. In this scenario, we investigate the temporal evolution and current status of the AIDS epidemic in Brazil. Specifically, we analyze records of annual absolute frequency of cases for more than 5000 cities for the first 33 years of the infection in Brazil. We found that (i) the annual absolute frequencies exhibit a logistic-type growth with an exponential regime in the first few years of the AIDS spreading; (ii) the actual reproduction number decaying as a power law; (iii) the distribution of the annual absolute frequencies among cities decays with a power law behavior; (iv) the annual absolute frequencies and the number of inhabitants have an allometric relationship; (v) the temporal evolution of the annual absolute frequencies have different profile depending on the average annual absolute frequencies in the cities. These findings yield a general quantitative description of the AIDS infection dynamics in Brazil since the beginning. They also provide clues about the effectiveness of treatment and control programs against the infection, that has had a different impact depending on the number of inhabitants of cities. In this framework, our results give insights into the overall dynamics of AIDS epidemic, which may contribute to select empirically accurate models. |
Nucleoli are nuclear domains present in almost all eukaryotic cells. They not only specialize in the production of ribosomal subunits but also play roles in many fundamental cellular activities. Concerning ribosome biosynthesis, particular stages of this process, i.e., ribosomal DNA transcription, primary RNA transcript processing, and ribosome assembly proceed in precisely defined nucleolar subdomains. Although eukaryotic nucleoli are conservative in respect of their main function, clear morphological differences between these structures can be noticed between individual kingdoms. In most cases, a plant nucleolus shows well-ordered structure in which four main ultrastructural components can be distinguished: fibrillar centers, dense fibrillar component, granular component, and nucleolar vacuoles. Nucleolar chromatin is an additional crucial structural component of this organelle. Nucleolonema, although it is not always an unequivocally distinguished nucleolar domain, has often been described as a well-grounded morphological element, especially of plant nucleoli. The ratios and morphology of particular subcompartments of a nucleolus can change depending on its metabolic activity which in turn is correlated with the physiological state of a cell, cell type, cell cycle phase, as well as with environmental influence. Precise attribution of functions to particular nucleolar subregions in the process of ribosome biosynthesis is now possible using various approaches. The presented description of plant nucleolar morphology summarizes previous knowledge regarding the function of nucleoli as well as of their particular subdomains not only in the course of ribosome biosynthesis. |
BACKGROUND: Live poultry traders (LPTs) have greater risk to avian influenza due to occupational exposure to poultry. This study investigated knowledge, attitudes and practices of LPTs relating to influenza A (H7N9). METHODS: Using multi-stage cluster sampling, 306 LPTs were interviewed in Guangzhou by a standardized questionnaire between mid-May to June, 2013. Hierarchical logistic regression models were used to identify factors associated with preventive practices and attitudes towards various control measures implemented in live poultry markets against H7N9. RESULTS: Only 46.1% of the respondents recognized risks associated with contacts with bird secretions or droppings, and only 22.9% perceived personally "likely/very likely" to contract H7N9 infection. Around 60% of the respondents complied with hand-washing and wearing gloves, and only 20% reported wearing face masks. Only 16.3% of the respondents agreed on introducing central slaughtering of poultry. Being younger, involving in slaughtering poultry, having longer working hours, less access to H7N9-related information and poorer knowledge, and perceiving lower personal susceptibility to H7N9 infection were negatively associated with preventive practices. Comparing with previous studies conducted when human cases of H5N1 avian influenza infection was first identified in Guangdong, LPTs' perceived susceptibility to novel influenza viruses increased significantly but acceptance for central slaughtering of poultry remained low. CONCLUSIONS: Information on avian influenza provided through multiple communication tools may be necessary to promote knowledge among poultry traders. Familiarity with risk may have led to the lower perceived vulnerability to avian influenza and less protective actions among the LPTs particularly for those involving more risky exposure to live poultry. Reasons for the consistently low acceptance for central slaughtering of poultry await further exploration. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-014-0554-8) contains supplementary material, which is available to authorized users. |
BACKGROUND: In early 2013, a new type of avian influenza, H7N9, emerged in China. It quickly became an issue of great public concern and a widely discussed topic on the Internet. A considerable volume of relevant information was made publicly available on the Internet through various sources. OBJECTIVE: This study aimed to describe the outbreak of H7N9 in China based on data openly available on the Internet and to validate our investigation by comparing our findings with a well-conducted conventional field epidemiologic study. METHODS: We searched publicly accessible Internet data on the H7N9 outbreak primarily from government and major mass media websites in China up to February 10, 2014. Two researchers independently extracted, compared, and confirmed the information of each confirmed H7N9 case using a self-designed data extraction form. We summarized the epidemiological and clinical characteristics of confirmed H7N9 cases and compared them with those from the field study. RESULTS: According to our data updated until February 10, 2014, 334 confirmed H7N9 cases were identified. The median age was 58 years and 67.0% (219/327) were males. Cases were reported in 15 regions in China. Five family clusters were found. Of the 16.8% (56/334) of the cases with relevant data, 69.6% (39/56) reported a history of exposure to animals. Of the 1751 persons with a close contact with a confirmed case, 0.6% (11/1751) of them developed respiratory symptoms during the 7-day surveillance period. In the 97.9% (327/334) of the cases with relevant data, 21.7% (71/327) died, 20.8% (68/327) were discharged from a hospital, and 57.5% (188/327) were of uncertain status. We compared our findings before February 10, 2014 and those before December 1, 2013 with those from the conventional field study, which had the latter cutoff date of ours in data collection. Our study showed most epidemiological and clinical characteristics were similar to those in the field study, except for case fatality (71/327, 21.7% for our data before February 10; 45/138, 32.6% for our data before December 1; 47/139, 33.8% for the field study), time from illness onset to first medical care (4 days, 3 days, and 1 day), and time from illness onset to death (16.5 days, 17 days, and 21 days). CONCLUSIONS: Findings from our Internet-based investigation were similar to those from the conventional field study in most epidemiological and clinical aspects of the outbreak. Importantly, publicly available Internet data are open to any interested researchers and can thus greatly facilitate the investigation and control of such outbreaks. With improved efforts for Internet data provision, Internet-based investigation has a great potential to become a quick, economical, novel approach to investigating sudden issues of great public concern that involve a relatively small number of cases like this H7N9 outbreak. |
Frequently, patients with hepatitis C virus (HCV) chronic infection have high levels of serum anti-thyroperoxidase and/or anti-thyroglobulin autoantibodies, ultrasonographic signs of chronic autoimmune thyroiditis, and subclinical hypothyroidism, in female gender versus healthy controls, or hepatitis B virus infected patients. In patients with “HCV-associated mixed cryoglobulinemia” (MC + HCV), a higher prevalence of thyroid autoimmune disorders was shown not only compared to controls, but also versus HCV patients without cryoglobulinemia. Patients with MC + HCV or HCV chronic infection show a higher prevalence of papillary thyroid cancer than controls, in particular in patients with autoimmune thyroiditis. Patients with HCV chronic infection, or with MC + HCV, in presence of autoimmune thyroiditis, show higher serum levels of T-helper (Th)1 (C-X-C motif) ligand 10 (CXCL10) chemokine, but normal levels of Th2 (C-C motif) ligand 2 chemokine, than patients without thyroiditis. HCV thyroid infection could act by upregulating CXCL10 gene expression and secretion in thyrocytes recruiting Th1 lymphocytes that secrete interferon-γ and tumor necrosis factor-α. These cytokines might induce a further CXCL10 secretion by thyrocytes, thus perpetuating the immune cascade, which may lead to the appearance of autoimmune thyroid disorders in genetically predisposed subjects. A careful monitoring of thyroid function, particularly where nodules occur, is recommended in HCV patients. |
Innate immunity is key to the fight against the daily onslaught from viruses that our bodies are subjected to. Essential to this response are the interferons (IFNs) that prime our cells to block viral pathogens. Recent evidence suggests that the Type III (λ) IFNs are intimately associated with the immune response to hepatitis C virus (HCV) infection. Genome-wide association studies have identified polymorphisms within the IFN-λ gene locus that correlate with response to IFNα-based antiviral therapy and with spontaneous clearance of HCV infection. The mechanisms for these correlations are incompletely understood. Restricted expression of the IFN-λ receptor, and the ability of IFN-λ to induce IFN-stimulated genes in HCV-infected cells, suggest potential roles for IFN-λ in HCV therapy even in this era of directly acting antivirals. This review summarizes our current understanding of the IFN-λ family and the role of λ IFNs in the natural history of HCV infection. |
The rodent arenavirus glycoprotein complex encodes a stable signal peptide (SSP) that is an essential structural component of mature virions. The SSP, GP1, and GP2 subunits of the trimeric glycoprotein complex noncovalently interact to stud the surface of virions and initiate arenavirus infectivity. Nascent glycoprotein production undergoes two proteolytic cleavage events: first within the endoplasmic reticulum (ER) to cleave SSP from the remaining precursor GP1/2 (glycoprotein complex [GPC]) glycoprotein and second within the Golgi stacks by the cellular SKI-1/S1P for GP1/2 processing to yield GP1 and GP2 subunits. Cleaved SSP is not degraded but retained as an essential glycoprotein subunit. Here, we defined functions of the 58-amino-acid lymphocytic choriomeningitis virus (LCMV) SSP in regard to glycoprotein complex processing and maturation. Using molecular biology techniques, confocal microscopy, and flow cytometry, we detected SSP at the plasma membrane of transfected cells. Further, we identified a sorting signal (FLLL) near the carboxyl terminus of SSP that is required for glycoprotein maturation and trafficking. In the absence of SSP, the glycoprotein accumulated within the ER and was unable to undergo processing by SKI-1/S1P. Mutation of this highly conserved FLLL motif showed impaired glycoprotein processing and secretory pathway trafficking, as well as defective surface expression and pH-dependent membrane fusion. Immunoprecipitation of SSP confirmed an interaction between the signal peptide and the GP2 subunit; however, mutations within this FLLL motif disrupted the association of the GP1 subunit with the remaining glycoprotein complex. |
Cat impoundments were increasing at the municipal San Jose animal shelter in 2009, despite long-term successful low cost sterilization programs and attempts to lower the euthanasia rate of treatable-rehabilitatable impounds beginning in 2008. San Jose Animal Care and Services implemented a new strategy designed to control overall feral cat reproduction by altering and returning feral cats entering the shelter system, rather than euthanizing the cats. The purpose of this case study was to determine how the program affected the shelter cat intakes over time. In just over four years, 10,080 individual healthy adult feral cats, out of 11,423 impounded at the shelter during this time frame, were altered and returned to their site of capture. Included in the 11,423 cats were 862 cats impounded from one to four additional times for a total of 958 (9.5%) recaptures of the previously altered 10,080 cats. The remaining 385 healthy feral cats were euthanized at the shelter from March 2010 to June 2014. Four years into the program, researchers observed cat and kitten impounds decreased 29.1%; euthanasia decreased from over 70% of intakes in 2009, to 23% in 2014. Euthanasia in the shelter for Upper Respiratory Disease decreased 99%; dead cat pick up off the streets declined 20%. Dog impounds did not similarly decline over the four years. No other laws or program changes were implemented since the beginning of the program. |
BACKGROUND: Extensive variations in human surfactant protein D (SP-D) levels in circulation as measured by ELISA exist in the published literature. In order to determine the source of these variations, factors influencing the measurement by ELISA were explored. MATERIALS AND METHODS: Peripheral blood from healthy individuals was collected into various vacutainers during the same blood draw. Recombinant SP-D was diluted into different matrices and used for a standard curve. Samples were analyzed by capture ELISA using one of two distinct detection antibodies. RESULTS: The type of matrix had some effects on detection of recombinant SP-D. The type of anticoagulant used and dilution factor had very little effect, except for in plasma collected in EDTA vacutainers. The extent of variation in published values seemed to be due to the ELISA configuration employed, and, in agreement with this, we found that by switching the detection antibody, there was a 50% decrease in the extrapolated SP-D value of serum and plasma samples. Storage of samples resulted in slight changes in measured SP-D levels. CONCLUSIONS: The ELISA configuration employed to measure circulating levels of SP-D has a significant effect on the extrapolated values. In both configurations tested, the use of EDTA as a coagulant resulted in inconsistent values, and we, therefore, suggest the avoidance of this anticoagulant when assaying for SP-D by ELISA. While the demonstrated effects of several factors on measurement of SP-D may not account for all the disparities amongst the previous studies, they stress that variations in methodologies for measuring the same protein can result in very inconsistent results. |
Ovine rinderpest or goat plague is an economically important and contagious viral disease of sheep and goats, caused by the Peste des petits ruminants virus (PPRV). Differences in susceptibility to goat plague among different breeds and water buffalo exist. The host innate immune system discriminates between pathogen associated molecular patterns and self antigens through surveillance receptors known as Toll like receptors (TLR). We investigated the role of TLR and cytokines in differential susceptibility of goat breeds and water buffalo to PPRV. We examined the replication of PPRV in peripheral blood mononuclear cells (PBMC) of Indian domestic goats and water buffalo and demonstrated that the levels of TLR3 and TLR7 and downstream signalling molecules correlation with susceptibility vs resistance. Naturally susceptible goat breeds, Barbari and Tellichery, had dampened innate immune responses to PPRV and increased viral loads with lower basal expression levels of TLR 3/7. Upon stimulation of PBMC with synthetic TLR3 and TLR7 agonists or PPRV, the levels of proinflammatory cytokines were found to be significantly higher while immunosuppressive interleukin (IL) 10 levels were lower in PPRV resistant Kanni and Salem Black breeds and water buffalo at transcriptional level, correlating with reduced viralloads in infected PBMC. Water buffalo produced higher levels of interferon (IFN) α in comparison with goats at transcriptional and translational levels. Pre-treatment of Vero cells with human IFNα resulted in reduction of PPRV replication, confirming the role of IFNα in limiting PPRV replication. Treatment with IRS66, a TLR7 antagonist, resulted in the reduction of IFNα levels, with increased PPRV replication confirming the role of TLR7. Single nucleotide polymorphism analysis of TLR7 of these goat breeds did not show any marked nucleotide differences that might account for susceptibility vs resistance to PPRV. Analyzing other host genetic factors might provide further insights on susceptibility to PPRV and genetic polymorphisms in the host. |
In the recent years, it has been demonstrated that the biological activity of mesenchymal stem cells (MSCs) is mediated through the release of paracrine factors. Many of these factors are released into exosomes, which are small membranous vesicles that participate in cell–cell communication. Exosomes from MSCs are thought to have similar functions to MSCs such as repairing and regeneration of damaged tissue, but little is known about the immunomodulatory effect of these vesicles. Based on an extensive bibliography where the immunomodulatory capacity of MSCs has been demonstrated, here we hypothesized that released exosomes from MSCs may have an immunomodulatory role on the differentiation, activation and function of different lymphocyte subsets. According to this hypothesis, in vitro experiments were performed to characterize the immunomodulatory effect of human adipose MSCs derived exosomes (exo-hASCs) on in vitro stimulated T cells. The phenotypic characterization of cytotoxic and helper T cells (activation and differentiation markers) together with functional assays (proliferation and IFN-γ production) demonstrated that exo-hASCs exerted an inhibitory effect in the differentiation and activation of T cells as well as a reduced T cell proliferation and IFN-γ release on in vitro stimulated cells. In summary, here we demonstrate that MSCs-derived exosomes are a cell-derived product that could be considered as a therapeutic agent for the treatment of inflammation-related diseases. |
The 2005 International Health Regulations (IHR) came into force for all Member States of the World Health Organization (WHO) in June 2007 and the deadline for achieving compliance was June 2012. The purpose of the IHR is to prevent, protect against, control – and provide a public health response to – international spread of disease. The territory of the United Kingdom of Great Britain and Northern Ireland and that of several other Member States, such as China, Denmark, France, the Netherlands and the United States of America, include overseas territories, which cover a total population of approximately 15 million people. Member States have a responsibility to ensure that all parts of their territory comply with the IHR. Since WHO has not provided specific guidance on compliance in the special circumstances of the overseas territories of Member States, compliance by these territories is an issue for self-assessment by Member States themselves. To date, no reports have been published on the assessment of IHR compliance in countries with overseas territories. We describe a gap analysis done in the United Kingdom to assess IHR compliance of its overseas territories. The findings and conclusions are broadly applicable to other countries with overseas territories which may have yet to assess their compliance with the IHR. Such assessments are needed to ensure compliance across all parts of a Member States’ territory and to increase global health security. |
There is an emerging paradigm that the human microbiome is central to many aspects of health and may have a role in preventing enteric infection. Entamoeba histolytica is a major cause of amebic diarrhea in developing countries. It colonizes the colon lumen in close proximity to the gut microbiota. Interestingly, not all individuals are equally susceptible to E. histolytica infection. Therefore, as the microbiota is highly variable within individuals, we sought to determine if a component of the microbiota could regulate susceptibility to infection. In studies utilizing a murine model, we demonstrated that colonization of the gut with the commensal Clostridia-related bacteria known as segmented filamentous bacteria (SFB) is protective during E. histolytica infection. SFB colonization in this model was associated with elevated cecal levels of interleukin 17A (IL-17A), dendritic cells, and neutrophils. Bone marrow-derived dendritic cells (BMDCs) from SFB-colonized mice had higher levels of IL-23 production in response to stimulation with trophozoites. Adoptive transfer of BMDCs from an SFB(+) to an SFB(−) mouse was sufficient to provide protection against E. histolytica. IL-17A induction during BMDC transfer was necessary for this protection. This work demonstrates that intestinal colonization with a specific commensal bacterium can provide protection during amebiasis in a murine model. Most importantly, this work demonstrates that the microbiome can mediate protection against an enteric infection via extraintestinal effects on bone marrow-derived dendritic cells. |
BACKGROUND: Respiratory syncytial virus (RSV) infection is the second most important cause of death in the first year of life, and early RSV infections are associated with the development of asthma. Breastfeeding and serum IgG have been shown to protect against RSV infection. Yet, many infants depend on bovine milk-based nutrition, which at present lacks intact immunoglobulins. OBJECTIVE: To investigate whether IgG purified from bovine milk (bIgG) can modulate immune responses against human RSV. METHODS: ELISAs were performed to analyse binding of bIgG to human respiratory pathogens. bIgG or hRSV was coated to plates to assess dose-dependent binding of bIgG to human Fcγ receptors (FcγR) or bIgG-mediated binding of myeloid cells to hRSV respectively. S. Epidermidis and RSV were used to test bIgG-mediated binding and internalisation of pathogens by myeloid cells. Finally, the ability of bIgG to neutralise infection of HEp2 cells by hRSV was evaluated. RESULTS: bIgG recognised human RSV, influenza haemagglutinin and Haemophilus influenza. bIgG bound to FcγRII on neutrophils, monocytes and macrophages, but not to FcγRI and FcγRIII, and could bind simultaneously to hRSV and human FcγRII on neutrophils. In addition, human neutrophils and dendritic cells internalised pathogens that were opsonised with bIgG. Finally, bIgG could prevent infection of HEp2 cells by hRSV. CONCLUSIONS: The data presented here show that bIgG binds to hRSV and other human respiratory pathogens and induces effector functions through binding to human FcγRII on phagocytes. Thus bovine IgG may contribute to immune protection against RSV. |
Transcription of hepatitis B virus (HBV) from the covalently closed circular DNA (cccDNA) template is essential for its replication. Suppressing the level and transcriptional activity of cccDNA might have anti-HBV effect. Although cellular transcription factors, such as CREB, which mediate HBV transcription, have been well described, transcriptional coactivators that facilitate this process are incompletely understood. In this study we showed that CREB-regulated transcriptional coactivator 1 (CRTC1) is required for HBV transcription and replication. The steady-state levels of CRTC1 protein were elevated in HBV-positive hepatoma cells and liver tissues. Ectopic expression of CRTC1 or its homolog CRTC2 or CRTC3 in hepatoma cells stimulated the activity of the preS2/S promoter of HBV, whereas overexpression of a dominant inactive form of CRTC1 inhibited HBV transcription. CRTC1 interacts with CREB and they are mutually required for the recruitment to the preS2/S promoter on cccDNA and for the activation of HBV transcription. Accumulation of pregenomic RNA (pgRNA) and cccDNA was observed when CRTC1 or its homologs were overexpressed, whereas the levels of pgRNA, cccDNA and secreted HBsAg were diminished when CRTC1 was compromised. In addition, HBV transactivator protein HBx stabilized CRTC1 and promoted its activity on HBV transcription. Our work reveals an essential role of CRTC1 coactivator in facilitating and supporting HBV transcription and replication. |
The archaeal exosome is a phosphorolytic 3′–5′ exoribonuclease complex. In a reverse reaction it synthesizes A-rich RNA tails. Its RNA-binding cap comprises the eukaryotic orthologs Rrp4 and Csl4, and an archaea-specific subunit annotated as DnaG. In Sulfolobus solfataricus DnaG and Rrp4 but not Csl4 show preference for poly(rA). Archaeal DnaG contains N- and C-terminal domains (NTD and CTD) of unknown function flanking a TOPRIM domain. We found that the NT and TOPRIM domains have comparable, high conservation in all archaea, while the CTD conservation correlates with the presence of exosome. We show that the NTD is a novel RNA-binding domain with poly(rA)-preference cooperating with the TOPRIM domain in binding of RNA. Consistently, a fusion protein containing full-length Csl4 and NTD of DnaG led to enhanced degradation of A-rich RNA by the exosome. We also found that DnaG strongly binds native and in vitro transcribed rRNA and enables its polynucleotidylation by the exosome. Furthermore, rRNA-derived transcripts with heteropolymeric tails were degraded faster by the exosome than their non-tailed variants. Based on our data, we propose that archaeal DnaG is an RNA-binding protein, which, in the context of the exosome, is involved in targeting of stable RNA for degradation. |
Identification of the full complement of genes and other functional elements in any virus is crucial to fully understand its molecular biology and guide the development of effective control strategies. RNA viruses have compact multifunctional genomes that frequently contain overlapping genes and non-coding functional elements embedded within protein-coding sequences. Overlapping features often escape detection because it can be difficult to disentangle the multiple roles of the constituent nucleotides via mutational analyses, while high-throughput experimental techniques are often unable to distinguish functional elements from incidental features. However, RNA viruses evolve very rapidly so that, even within a single species, substitutions rapidly accumulate at neutral or near-neutral sites providing great potential for comparative genomics to distinguish the signature of purifying selection. Computationally identified features can then be efficiently targeted for experimental analysis. Here we analyze alignments of protein-coding virus sequences to identify regions where there is a statistically significant reduction in the degree of variability at synonymous sites, a characteristic signature of overlapping functional elements. Having previously tested this technique by experimental verification of discoveries in selected viruses, we now analyze sequence alignments for ∼700 RNA virus species to identify hundreds of such regions, many of which have not been previously described. |
Recently bats have been associated with the emergence of diseases, both as reservoirs for several new viral diseases in humans and other animals and, in the northern Americas, as hosts for a devastating fungal disease that threatens to drive several bat species to regional extinction. However, despite these catastrophic events little Information is available on bat defences or how they interact with their pathogens. Even less is known about the response of bats to infection during torpor or long-term hibernation. Using tissue samples collected at the termination of an experiment to explore the pathogenesis of White Nose Syndrome in Little Brown Bats, we determined if hibernating bats infected with the fungus Pseudogymnoascus destructans could respond to infection by activating genes responsible for innate immune and stress responses. Lesions due to fungal infection and, in some cases, secondary bacterial infections, were restricted to the skin. However, we were unable to obtain sufficient amounts of RNA from these sites. We therefore examined lungs for response at an epithelial surface not linked to the primary site of infection. We found that bats responded to infection with a significant increase in lungs of transcripts for Cathelicidin (an anti-microbial peptide) as well as the immune modulators tumor necrosis factor alpha and interleukins 10 and 23. In conclusion, hibernating bats can respond to experimental P. destructans infection by activating expression of innate immune response genes. |
INTRODUCTION: Inherited variability in host immune responses influences susceptibility and outcome of Influenza A virus (IAV) infection, but these factors remain largely unknown. Components of the innate immune response may be crucial in the first days of the infection. The collectins surfactant protein (SP)-A1, -A2, and -D and mannose-binding lectin (MBL) neutralize IAV infectivity, although only SP-A2 can establish an efficient neutralization of poorly glycosylated pandemic IAV strains. METHODS: We studied the role of polymorphic variants at the genes of MBL (MBL2), SP-A1 (SFTPA1), SP-A2 (SFTPA2), and SP-D (SFTPD) in 93 patients with H1N1 pandemic 2009 (H1N1pdm) infection. RESULTS: Multivariate analysis showed that two frequent SFTPA2 missense alleles (rs1965708-C and rs1059046-A) and the SFTPA2 haplotype 1A(0) were associated with a need for mechanical ventilation, acute respiratory failure, and acute respiratory distress syndrome. The SFTPA2 haplotype 1A(1) was a protective variant. Kaplan-Meier analysis and Cox regression also showed that diplotypes not containing the 1A(1) haplotype were associated with a significantly shorter time to ICU admission in hospitalized patients. In addition, rs1965708-C (P = 0.0007), rs1059046-A (P = 0.0007), and haplotype 1A(0) (P = 0.0004) were associated, in a dose-dependent fashion, with lower PaO(2)/FiO(2) ratio, whereas haplotype 1A(1) was associated with a higher PaO(2)/FiO(2) ratio (P = 0.001). CONCLUSIONS: Our data suggest an effect of genetic variants of SFTPA2 on the severity of H1N1pdm infection and could pave the way for a potential treatment with haplotype-specific (1A(1)) SP-A2 for future IAV pandemics. |
The central nervous system (CNS), once viewed as an immune-privileged site protected by the blood–brain barrier (BBB), is now known to be a dynamic immunological environment through which immune cells migrate to prevent and respond to events such as localized infection. During these responses, endogenous glial cells, including astrocytes and microglia, become highly reactive and may secrete inflammatory mediators that regulate BBB permeability and recruit additional circulating immune cells. Here, we discuss the various roles played by astrocytes, microglia, and infiltrating immune cells during host immunity to non-tumor antigens in the CNS, focusing first on bacterial and viral infections, and then turning to responses directed against self-antigens in the setting of CNS autoimmunity. |
BACKGROUND: In many applications, a family of nucleotide or protein sequences classified into several subfamilies has to be modeled. Profile Hidden Markov Models (pHMMs) are widely used for this task, modeling each subfamily separately by one pHMM. However, a major drawback of this approach is the difficulty of dealing with subfamilies composed of very few sequences. One of the most crucial bioinformatical tasks affected by the problem of small-size subfamilies is the subtyping of human immunodeficiency virus type 1 (HIV-1) sequences, i.e., HIV-1 subtypes for which only a small number of sequences is known. RESULTS: To deal with small samples for particular subfamilies of HIV-1, we introduce a novel model-based information sharing protocol. It estimates the emission probabilities of the pHMM modeling a particular subfamily not only based on the nucleotide frequencies of the respective subfamily but also incorporating the nucleotide frequencies of all available subfamilies. To this end, the underlying probabilistic model mimics the pattern of commonality and variation between the subtypes with regards to the biological characteristics of HI viruses. In order to implement the proposed protocol, we make use of an existing HMM architecture and its associated inference engine. CONCLUSIONS: We apply the modified algorithm to classify HIV-1 sequence data in the form of partial HIV-1 sequences and semi-artificial recombinants. Thereby, we demonstrate that the performance of pHMMs can be significantly improved by the proposed technique. Moreover, we show that our algorithm performs significantly better than Simplot and Bootscanning. |
Oct4 is a key component of the pluripotency regulatory network, and its reciprocal interaction with Cdx2 has been shown to be a determinant of either the self-renewal of embryonic stem cells (ESCs) or their differentiation into trophoblast. Oct4 of maternal origin is postulated to play critical role in defining totipotency and inducing pluripotency during embryonic development. However, the genetic elimination of maternal Oct4 using a Cre-lox approach in mouse revealed that the establishment of totipotency in maternal Oct4–depleted embryos was not affected, and that these embryos could complete full-term development without any obvious defect. These results indicate that Oct4 is not essential for the initiation of pluripotency, in contrast to its critical role in maintaining pluripotency. This conclusion is further supported by the formation of Oct4-GFP– and Nanog- expressing inner cell masses (ICMs) in embryos with complete inactivation of both maternal and zygotic Oct4 expression and the reprogramming of fibroblasts into fully pluripotent cells by Oct4-deficient oocytes. |
The viral protein U (Vpu) encoded by HIV-1 has been shown to assist in the detachment of virion particles from infected cells. Vpu forms cation-specific ion channels in host cells, and has been proposed as a potential drug target. An understanding of the mechanism of ion transport through Vpu is desirable, but remains limited because of the unavailability of an experimental structure of the channel. Using a structure of the pentameric form of Vpu – modeled and validated based on available experimental data – umbrella sampling molecular dynamics simulations (cumulative simulation time of more than 0.4 µs) were employed to elucidate the energetics and the molecular mechanism of ion transport in Vpu. Free energy profiles corresponding to the permeation of Na(+) and K(+) were found to be similar to each other indicating lack of ion selection, consistent with previous experimental studies. The Ser23 residue is shown to enhance ion transport via two mechanisms: creating a weak binding site, and increasing the effective hydrophilic length of the channel, both of which have previously been hypothesized in experiments. A two-dimensional free energy landscape has been computed to model multiple ion permeation, based on which a mechanism for ion conduction is proposed. It is shown that only one ion can pass through the channel at a time. This, along with a stretch of hydrophobic residues in the transmembrane domain of Vpu, explains the slow kinetics of ion conduction. The results are consistent with previous conductance studies that showed Vpu to be a weakly conducting ion channel. |
Repeat-associated disorders caused by expansions of short sequences have been classified as coding and noncoding and are thought to be caused by protein gain-of-function and RNA gain-of-function mechanisms, respectively. The boundary between such classifications has recently been blurred by the discovery of repeat-associated non-AUG (RAN) translation reported in spinocerebellar ataxia type 8, myotonic dystrophy type 1, fragile X tremor/ataxia syndrome and C9ORF72 amyotrophic lateral sclerosis and frontotemporal dementia. This noncanonical translation requires no AUG start codon and can initiate in multiple frames of CAG, CGG and GGGGCC repeats of the sense and antisense strands of disease-relevant transcripts. RNA structures formed by the repeats have been suggested as possible triggers; however, the precise mechanism of the translation initiation remains elusive. Templates containing expansions of microsatellites have also been shown to challenge translation elongation, as frameshifting has been recognized across CAG repeats in spinocerebellar ataxia type 3 and Huntington's disease. Determining the critical requirements for RAN translation and frameshifting is essential to decipher the mechanisms that govern these processes. The contribution of unusual translation products to pathogenesis needs to be better understood. In this review, we present current knowledge regarding RAN translation and frameshifting and discuss the proposed mechanisms of translational challenges imposed by simple repeat expansions. |
The thiazolidinedione class peroxisome proliferator-activated receptor gamma (PPARγ) agonists are restricted in clinical use as antidiabetic agents because of side effects such as edema, weight gain, and heart failure. The single and selective agonism of PPARγ is the main cause of these side effects. Multitargeted PPARα/γ/δ pan agonist development is the hot topic in the antidiabetic drug research field. In order to identify PPARα/γ/δ pan agonists, a compound database was established by core hopping of rosiglitazone, which was then docked into a PPARα/γ/δ active site to screen out a number of candidate compounds with a higher docking score and better interaction with the active site. Further, absorption, distribution, metabolism, excretion, and toxicity prediction was done to give eight compounds. Molecular dynamics simulation of the representative Cpd#1 showed more favorable binding conformation for PPARs receptor than the original ligand. Cpd#1 could act as a PPARα/γ/δ pan agonist for novel antidiabetic drug research. |
BACKGROUND: The Syrian hamster (golden hamster, Mesocricetus auratus) is gaining importance as a new experimental animal model for multiple pathogens, including emerging zoonotic diseases such as Ebola. Nevertheless there are currently no publicly available transcriptome reference sequences or genome for this species. RESULTS: A cDNA library derived from mRNA and snRNA isolated and pooled from the brains, lungs, spleens, kidneys, livers, and hearts of three adult female Syrian hamsters was sequenced. Sequence reads were assembled into 62,482 contigs and 111,796 reads remained unassembled (singletons). This combined contig/singleton dataset, designated as the Syrian hamster transcriptome, represents a total of 60,117,204 nucleotides. Our Mesocricetus auratus Syrian hamster transcriptome mapped to 11,648 mouse transcripts representing 9,562 distinct genes, and mapped to a similar number of transcripts and genes in the rat. We identified 214 quasi-complete transcripts based on mouse annotations. Canonical pathways involved in a broad spectrum of fundamental biological processes were significantly represented in the library. The Syrian hamster transcriptome was aligned to the current release of the Chinese hamster ovary (CHO) cell transcriptome and genome to improve the genomic annotation of this species. Finally, our Syrian hamster transcriptome was aligned against 14 other rodents, primate and laurasiatheria species to gain insights about the genetic relatedness and placement of this species. CONCLUSIONS: This Syrian hamster transcriptome dataset significantly improves our knowledge of the Syrian hamster's transcriptome, especially towards its future use in infectious disease research. Moreover, this library is an important resource for the wider scientific community to help improve genome annotation of the Syrian hamster and other closely related species. Furthermore, these data provide the basis for development of expression microarrays that can be used in functional genomics studies. |
Marine photosynthetic microorganisms are the basis of marine food webs and are responsible for nearly 50% of the global primary production. Emiliania huxleyi forms massive oceanic blooms that are routinely terminated by large double-stranded DNA coccolithoviruses. The cellular mechanisms that govern the replication cycle of these giant viruses are largely unknown. We used diverse techniques, including fluorescence microscopy, transmission electron microscopy, cryoelectron tomography, immunolabeling and biochemical methodologies to investigate the role of autophagy in host–virus interactions. Hallmarks of autophagy are induced during the lytic phase of E. huxleyi viral infection, concomitant with up-regulation of autophagy-related genes (ATG genes). Pretreatment of the infected cells with an autophagy inhibitor causes a major reduction in the production of extracellular viral particles, without reducing viral DNA replication within the cell. The host-encoded Atg8 protein was detected within purified virions, demonstrating the pivotal role of the autophagy-like process in viral assembly and egress. We show that autophagy, which is classically considered as a defense mechanism, is essential for viral propagation and for facilitating a high burst size. This cellular mechanism may have a major impact on the fate of the viral-infected blooms, and therefore on the cycling of nutrients within the marine ecosystem. |
Human bocavirus (HBoV) was identified as the second human parvovirus with pathogenic potential in 2005 in respiratory samples from children suffering from viral respiratory infections of unknown etiology. Since its first description, a large number of clinical studies have been performed that address the clinical significance of HBoV detection and the molecular biology of the virus. This review summarizes the most important steps taken in HBoV research to date and addresses open questions that need to be answered in the future to provide a better understanding of the role of a virus that is difficult to grow in cell culture and is suspected to be a pathogen, although it has not yet fulfilled Koch’s postulates. |
The 3′ untranslated region (3′UTR) of human astroviruses (HAstV) consists of two hairpin structures (helix I and II) joined by a linker harboring a conserved PTB/hnRNP1 binding site. The identification and characterization of cellular proteins that interact with the 3′UTR of HAstV-8 virus will help to uncover cellular requirements for viral functions. To this end, mobility shift assays and UV cross-linking were performed with uninfected and HAstV-8-infected cell extracts and HAstV-8 3′UTR probes. Two RNA-protein complexes (CI and CII) were recruited into the 3′UTR. Complex CII formation was compromised with cold homologous RNA, and seven proteins of 35, 40, 45, 50, 52, 57/60 and 75 kDa were cross-linked to the 3′UTR. Supermobility shift assays indicated that PTB/hnRNP1 is part of this complex, and 3′UTR-crosslinked PTB/hnRNP1 was immunoprecipitated from HAstV-8 infected cell-membrane extracts. Also, immunofluorescence analyses revealed that PTB/hnRNP1 is distributed in the nucleus and cytoplasm of uninfected cells, but it is mainly localized perinuclearly in the cytoplasm of HAstV-8 infected cells. Furthermore, the minimal 3′UTR sequences recognized by recombinant PTB are those conforming helix I, and an intact PTB/hnRNP1-binding site. Finally, small interfering RNA-mediated PTB/hnRNP1 silencing reduced synthesis viral genome and virus yield in CaCo2 cells, suggesting that PTB/hnRNP1 is required for HAstV replication. In conclusion, PTB/hnRNP1 binds to the 3′UTR HAstV-8 and is required or participates in viral replication. |
Viruses readily mutate and gain the ability to infect novel hosts, but few data are available regarding the number of possible host range-expanding mutations allowing infection of any given novel host, and the fitness consequences of these mutations on original and novel hosts. To gain insight into the process of host range expansion, we isolated and sequenced 69 independent mutants of the dsRNA bacteriophage Φ6 able to infect the novel host, Pseudomonas pseudoalcaligenes. In total, we found at least 17 unique suites of mutations among these 69 mutants. We assayed fitness for 13 of 17 mutant genotypes on P. pseudoalcaligenes and the standard laboratory host, P. phaseolicola. Mutants exhibited significantly lower fitnesses on P. pseudoalcaligenes compared to P. phaseolicola. Furthermore, 12 of the 13 assayed mutants showed reduced fitness on P. phaseolicola compared to wildtype Φ6, confirming the prevalence of antagonistic pleiotropy during host range expansion. Further experiments revealed that the mechanistic basis of these fitness differences was likely variation in host attachment ability. In addition, using computational protein modeling, we show that host-range expanding mutations occurred in hotspots on the surface of the phage's host attachment protein opposite a putative hydrophobic anchoring domain. |
BACKGROUND: In the current information age, the use of data has become essential for decision making in public health at the local, national, and global level. Despite a global commitment to the use and sharing of public health data, this can be challenging in reality. No systematic framework or global operational guidelines have been created for data sharing in public health. Barriers at different levels have limited data sharing but have only been anecdotally discussed or in the context of specific case studies. Incomplete systematic evidence on the scope and variety of these barriers has limited opportunities to maximize the value and use of public health data for science and policy. METHODS: We conducted a systematic literature review of potential barriers to public health data sharing. Documents that described barriers to sharing of routinely collected public health data were eligible for inclusion and reviewed independently by a team of experts. We grouped identified barriers in a taxonomy for a focused international dialogue on solutions. RESULTS: Twenty potential barriers were identified and classified in six categories: technical, motivational, economic, political, legal and ethical. The first three categories are deeply rooted in well-known challenges of health information systems for which structural solutions have yet to be found; the last three have solutions that lie in an international dialogue aimed at generating consensus on policies and instruments for data sharing. CONCLUSIONS: The simultaneous effect of multiple interacting barriers ranging from technical to intangible issues has greatly complicated advances in public health data sharing. A systematic framework of barriers to data sharing in public health will be essential to accelerate the use of valuable information for the global good. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2458-14-1144) contains supplementary material, which is available to authorized users. |
BACKGROUND: The extracellular domains of cytokine receptors are released during inflammation, but little is known about the shedding of Toll-like receptors (TLR) and whether they can be used as diagnostic biomarkers. METHODS: The release of sTLR2 and sTLR4 was studied in in-vitro stimulations, as well as in-vivo during experimental human endotoxemia (n = 11, 2 ng/kg LPS), and in plasma of 394 patients with infections (infectious mononucleosis, measles, respiratory tract infections, bacterial sepsis and candidemia) or non-infectious inflammation (Crohn’s disease, gout, rheumatoid arthritis, autoinflammatory syndromes and pancreatitis). Using C-statistics, the value of sTLR2 and sTLR4 levels for discrimination between infections and non-infectious inflammatory diseases, as well as between viral and bacterial infections was analyzed. RESULTS: In-vitro, peripheral blood mononuclear cells released sTLR2 and sTLR4 by exposure to microbial ligands. During experimental human endotoxemia, plasma concentrations peaked after 2 hours (sTLR4) and 4 hours (sTLR2). sTLR4 did not correlate with cytokines, but sTLR2 correlated positively with TNFα (r(s) = 0.80, P < 0.05), IL-6 (r(s) = 0.65, P < 0.05), and IL-1Ra (r(s) = 0.57, P = 0.06), and negatively with IL-10 (r(s) = -0.58, P = 0.06), respectively. sTLR4 had a similar area under the ROC curve [AUC] for differentiating infectious and non-infectious inflammation compared to CRP: 0.72 (95% CI 0.66-0.79) versus 0.74 (95% CI 0.69-0.80) [P = 0.80], while sTLR2 had a lower AUC: 0.60 (95% CI 0.54-0.66) [P = 0.0004]. CRP differentiated bacterial infections better from viral infections than sTLR2 and sTLR4: AUC 0.94 (95% CI 0.90-0.96) versus 0.58 (95% CI 0.51-0.64) and 0.75 (95% CI 0.70-0.80), respectively [P < 0.0001 for both]. CONCLUSIONS: sTLRs are released into the circulation, and suggest the possibility to use sTLRs as diagnostic tool in inflammatory conditions. |
BACKGROUND: This systematic literature review aimed to summarize evidence for the added value of drug sales data analysis for the surveillance of infectious diseases. METHODS: A search for relevant publications was conducted in Pubmed, Embase, Scopus, Cochrane Library, African Index Medicus and Lilacs databases. Retrieved studies were evaluated in terms of objectives, diseases studied, data sources, methodologies and performance for real-time surveillance. Most studies compared drug sales data to reference surveillance data using correlation measurements or indicators of outbreak detection performance (sensitivity, specificity, timeliness of the detection). RESULTS: We screened 3266 articles and included 27 in the review. Most studies focused on acute respiratory and gastroenteritis infections. Nineteen studies retrospectively compared drug sales data to reference clinical data, and significant correlations were observed in 17 of them. Four studies found that over-the-counter drug sales preceded clinical data in terms of incidence increase. Five studies developed and evaluated statistical algorithms for selecting drug groups to monitor specific diseases. Another three studies developed models to predict incidence increase from drug sales. CONCLUSIONS: Drug sales data analyses appear to be a useful tool for surveillance of gastrointestinal and respiratory disease, and OTC drugs have the potential for early outbreak detection. Their utility remains to be investigated for other diseases, in particular those poorly surveyed. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-014-0604-2) contains supplementary material, which is available to authorized users. |
BACKGROUND: Tuberculosis (TB) during pregnancy may lead to severe consequences affecting both mother and child. Prenatal care could be a very good opportunity for TB care, especially for women who have limited access to health services. The aim of this review was to gather and evaluate studies on TB care for pregnant women. METHODS: We used a combination of the terms “tuberculosis” and “pregnancy”, limited to human, to search for published articles. Studies reflecting original data and focusing on TB care for pregnant women were included. All references retrieved were collected using the Reference Manager software (Version 11). RESULTS: Thirty five studies were selected for review and their data showed that diagnosis was often delayed because TB symptoms during pregnancy were not typical. TB prophylaxis and anti-TB therapy appeared to be safe and effective for pregnant women and their babies when suitable follow up and early initiation were present, but the compliance rate to TB prophylaxis is still low due to lack of follow up and referral services. TB care practices in the reviewed studies were in line in principle with the WHO International Standards for Tuberculosis Care (ISTC). CONCLUSIONS: Integration of TB care within prenatal care would improve TB diagnosis and treatment for pregnant women. To improve the quality of TB care, it is necessary to develop national level guidelines based on the ISTC with detailed guidelines for pregnant women. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-014-0617-x) contains supplementary material, which is available to authorized users. |
RATIONALE: The family of natriuretic peptides (NPs), including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), exert important and diverse actions for cardiovascular and renal homeostasis. The autocrine and paracrine functions of the NPs are primarily mediated through the cellular membrane bound guanylyl cyclase-linked receptors GC-A (NPR-A) and GC-B (NPR-B). As the ligands and receptors each contain disulfide bonds, a regulatory role for the cell surface protein disulfide isomerase (PDI) was investigated. OBJECTIVE: We utilized complementary in vitro and in vivo models to determine the potential role of PDI in regulating the ability of the NPs to generate its second messenger, cyclic guanosine monophosphate. METHODS AND RESULTS: Inhibition of PDI attenuated the ability of ANP, BNP and CNP to generate cGMP in human mesangial cells (HMCs), human umbilical vein endothelial cells (HUVECs), and human aortic smooth muscle cells (HASMCs), each of which were shown to express PDI. In LLC-PK1 cells, where PDI expression was undetectable by immunoblotting, PDI inhibition had a minimal effect on cGMP generation. Addition of PDI to cultured LLC-PK1 cells increased intracellular cGMP generation mediated by ANP. Inhibition of PDI in vivo attenuated NP-mediated generation of cGMP by ANP. Surface Plasmon Resonance demonstrated modest and differential binding of the natriuretic peptides with immobilized PDI in a cell free system. However, PDI was shown to co-localize on the surface of cells with GC-A and GC-B by co-immunoprecpitation and immunohistochemistry. CONCLUSION: These data demonstrate for the first time that cell surface PDI expression and function regulate the capacity of natriuretic peptides to generate cGMP through interaction with their receptors. |
INTRODUCTION: The production of antimicrobial peptides by airway epithelial cells is an important component of the innate immune response to pulmonary infection and inflammation. Hepcidin is a β-defensin-like antimicrobial peptide and acts as a principal iron regulatory hormone. Hepcidin is mostly produced by hepatocytes, but is also expressed by other cells, such as airway epithelial cells. However, nothing is known about its function in lung infections and inflammatory diseases. We therefore sought to investigate the role of airway epithelial cell-derived hepcidin in sepsis-induced acute lung injury. METHODS: Acute lung injury was induced by polymicrobial sepsis via cecal ligation and puncture (CLP) surgery. Adenovirus-mediated short hairpin RNA specific for the mouse hepcidin gene hepc1 and control adenovirus were intratracheally injected into mice. The adenovirus-mediated knockdown of hepcidin in airway epithelial cells was evaluated in vivo. Lung injury and the seven-day survival rate were assessed. The levels of hepcidin-related iron export protein ferroportin were measured, and the iron content and function of alveolar macrophages were evaluated. RESULTS: The hepcidin level in airway epithelial cells was upregulated during polymicrobial sepsis. The knockdown of airway epithelial cell-derived hepcidin aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased mortality (53.33% in Ad-shHepc1-treated mice versus 12.5% in Ad-shNeg-treated mice, P <0.05). The knockdown of hepcidin in airway epithelial cells also led to reduced ferroportin degradation and a low intracellular iron content in alveolar macrophages. Moreover, alveolar macrophages form the airway epithelial cell-derived hepcidin knockdown mice showed impaired phagocytic ability than those from the control mice. CONCLUSIONS: Airway epithelial cell-derived hepcidin plays an important role in CLP-induced acute lung injury. The severe lung injury in the airway epithelial cell-derived hepcidin knockdown mice is at least partially related to the altered intracellular iron level and function of alveolar macrophages. |
BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is associated with high mortality. However, few studies have so far reviewed analyses of autopsy findings in patients with AE-IPF. METHODS: We retrospectively reviewed 52 consecutive patients with AE-IPF who underwent autopsies at five university hospitals and one municipal hospital between 1999 and 2013. The following variables were abstracted from the medical records: demographic and clinical data, autopsy findings and complications during the clinical course until death. RESULTS: The median age at autopsy was 71 years (range 47–86 years), and the subjects included 38 (73.1%) males. High-dose corticosteroid therapy was initiated in 45 (86.5%) patients after AE-IPF. The underling fibrotic lesion was classified as having the usual interstitial pneumonia (UIP) pattern in all cases. Furthermore, 41 (78.8%) patients had diffuse alveolar damage (DAD), 15 (28.8%) exhibited pulmonary hemorrhage, nine (17.3%) developed pulmonary thromboembolism and six (11.5%) were diagnosed with lung carcinoma. In addition, six (11.5%) patients developed pneumothorax prior to death and 26 (53.1%) developed diabetes that required insulin treatment after the administration of high-dose corticosteroid therapy. In addition, 15 (28.8%) patients presented with bronchopneumonia during their clinical course and/or until death, including fungal (seven, 13.5%), cytomegalovirus (six, 11.5%) and bacterial (five, 9.6%) infections. CONCLUSIONS: The pathological findings in patients with AE-IPF represent not only DAD, but also a variety of pathological conditions. Therefore, making a diagnosis of AE-IPF is often difficult, and the use of cautious diagnostic approaches is required for appropriate treatment. |
INTRODUCTION: Since 2008, severe cases of emerging human adenovirus type 55 (HAdV-55) in immunocompetent adults have been reported sporadically in China. The clinical features and outcomes of the most critically ill patients with severe acute respiratory distress syndrome (ARDS) caused by HAdV-55 requiring invasive mechanical ventilation (IMV) and/or extracorporeal membrane oxygenation (ECMO) are lacking. METHODS: We conducted a prospective, single-center observational study of pneumonia with ARDS in immunocompetent adults admitted to our respiratory ICU. We prospectively collected and analyzed clinical, laboratory, radiological characteristics, sequential tests of viral load in respiratory tract and blood, treatments and outcomes. RESULTS: The results for a total of five consecutive patients with severe ARDS with confirmed HAdV-55 infection were included. All five patients were immunocompetent young men with a median age of 32 years. The mean time from onset to dyspnea was 5 days. Arterial blood gas analysis at ICU admission revealed profound hypoxia. Mean partial oxygen pressure/fraction of inspired oxygen was 58.1. Mean durations from onset to a single-lobe consolidation shown on chest X-rays (CXRs) and, from the first positive CXR to bilateral multilobar lung infiltrates, were 2 days and 4.8 days, respectively. The viral load was higher than 1 × 10(8) copies in three patients and was 1 × 10(4) in one patient. It was negative in the only patient who survived. The mean duration for noninvasive positive pressure ventilation (NPPV) failure and IMV failure were 30.8 hours and 6.2 days, respectively. Four patients received venovenous ECMO. Four (80%) of the five patients died despite receiving appropriate respiratory support. CONCLUSIONS: HAdV-55 may cause severe ARDS in immunocompetent young men. Persistent high fever, dyspnea and rapid progression to respiratory failure within 2 weeks, together with bilateral consolidations and infiltrates, are the most frequent clinical manifestations of HAdV-55-induced severe ARDS. Viral load monitoring may help predict disease severity and outcome. The NPPV and IMV failure rates were very high, but ECMO may still be the respiratory support therapy of choice. TRIAL REGISTRATION: Clinicaltrials.gov NCT01585922. Registered 20 April 2012 |
Understanding infection dynamics of respiratory diseases requires the identification and quantification of behavioural, social and environmental factors that permit the transmission of these infections between humans. Little empirical information is available about contact patterns within real-world social networks, let alone on differences in these contact networks between populations that differ considerably on a socio-cultural level. Here we compared contact network data that were collected in the Netherlands and Thailand using a similar online respondent-driven method. By asking participants to recruit contact persons we studied network links relevant for the transmission of respiratory infections. We studied correlations between recruiter and recruited contacts to investigate mixing patterns in the observed social network components. In both countries, mixing patterns were assortative by demographic variables and random by total numbers of contacts. However, in Thailand participants reported overall more contacts which resulted in higher effective contact rates. Our findings provide new insights on numbers of contacts and mixing patterns in two different populations. These data could be used to improve parameterisation of mathematical models used to design control strategies. Although the spread of infections through populations depends on more factors, found similarities suggest that spread may be similar in the Netherlands and Thailand. |
Considering the high morbidity of hepatitis B in China, many epidemiological studies based on classic medical statistical analysis have been started but lack spatial information. However, spatial information such as the spatial distribution, autocorrelation and risk factors of the disease is of great help in studying patients with hepatitis B. This study examined 2851 cases of hepatitis B that were hospitalized in Shenzhen in 2010 and studied the spatial distribution, risk factors and spatial access to health services using spatial interpolation, Pearson correlation analysis and the improved two-step floating catchment area method. The results showed that the spatial distribution of hepatitis B, along with risk factors as well as spatial access to the regional medical resources, was uneven and mainly concentrated in the south and southwest of Shenzhen in 2010. In addition, the distribution characteristics of hepatitis B revealed a positive correlation between four types of service establishments and risk factors for the disease. The Pearson correlation coefficients are 0.566, 0.515, 0.626, 0.538 corresponding to bath centres, beauty salons, massage parlours and pedicure parlours (p < 0.05). Additionally, the allocation of medical resources for hepatitis B is adequate, as most patients could be treated at nearby hospitals. |
BACKGROUND: Clinical differentiation of influenza from dengue and other febrile illnesses (OFI) is difficult, and available rapid diagnostic tests have limited sensitivity. METHODS: We conducted a retrospective study to compare clinical and laboratory findings between (i) influenza and dengue and (ii) influenza and OFI. RESULTS: Of 849 enrolled patients, the mean time between illness onset and hospital presentation was 1.7, 3.7, and 3 days for influenza, dengue, and OFI, respectively. Among pediatric patients (≤18 years) (445 influenza, 24 dengue, and 130 OFI), we identified absence of rashes, no leukopenia, and no marked thrombocytopenia (platelet counts <100 × 10(9) cells/L) as predictors to distinguish influenza from dengue, whereas rhinorrhea, malaise, sore throat, and mild thrombocytopenia (platelet counts 100-149 × 10(9)/L) were predictors that differentiated influenza from OFI. Among adults (>18 years) (81 influenza, 124 dengue, and 45 OFI), no leukopenia and no marked thrombocytopenia distinguished influenza from dengue, while rhinorrhea and malaise differentiated influenza from OFI. A diagnostic algorithm developed to distinguish influenza from dengue using rash, leukopenia, and marked thrombocytopenia showed >90% sensitivity to identify influenza in pediatric patients. CONCLUSIONS: This study identified simple clinical and laboratory parameters that can assist clinicians to distinguish influenza from dengue and OFI. These findings may help clinicians diagnose influenza and facilitate appropriate management of affected patients, particularly in resource-poor settings. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-014-0623-z) contains supplementary material, which is available to authorized users. |
BACKGROUND: Infectious disease surveillance is a process the product of which reflects both actual disease trends and public awareness of the disease. Decisions made by patients, health care providers, and public health professionals about seeking and providing health care and about reporting cases to health authorities are all influenced by the information environment, which changes constantly. Biases are therefore imbedded in surveillance systems; these biases need to be characterized to provide better situational awareness for decision-making purposes. Our goal is to develop a statistical framework to characterize influenza surveillance systems, particularly their correlation with the information environment. METHODS: We identified Hong Kong influenza surveillance data systems covering healthcare providers, laboratories, daycare centers and residential care homes for the elderly. A Bayesian hierarchical statistical model was developed to examine the statistical relationships between the influenza surveillance data and the information environment represented by alerts from HealthMap and web queries from Google. Different models were fitted for non-pandemic and pandemic periods and model goodness-of-fit was assessed using common model selection procedures. RESULTS: Some surveillance systems — especially ad hoc systems developed in response to the pandemic flu outbreak — are more correlated with the information environment than others. General practitioner (percentage of influenza-like-illness related patient visits among all patient visits) and laboratory (percentage of specimen tested positive) seem to proportionally reflect the actual disease trends and are less representative of the information environment. Surveillance systems using influenza-specific code for reporting tend to reflect biases of both healthcare seekers and providers. CONCLUSIONS: This study shows certain influenza surveillance systems are less correlated with the information environment than others, and therefore, might represent more reliable indicators of disease activity in future outbreaks. Although the patterns identified in this study might change in future outbreaks, the potential susceptibility of surveillance data is likely to persist in the future, and should be considered when interpreting surveillance data. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2458-14-850) contains supplementary material, which is available to authorized users. |
Cancer is one of the leading health concerns for human and animal health. Since the tumorigenesis process is not completely understood and it is known that some viruses can induce carcinogenesis, it is highly important to identify novel oncoviruses and extensively study underlying oncogenic mechanisms. Here, we investigated a case of diffuse histiocytic sarcoma in a 22 year old slow loris (Nycticebus coucang), using a broad spectrum virus discovery technique. A novel parvovirus was discovered and the phylogenetic analysis performed on its fully sequenced genome demonstrated that it represents the first member of a novel genus. The possible causative correlation between this virus and the malignancy was further investigated and 20 serum and 61 organ samples from 25 animals (N. coucang and N. pygmaeus) were screened for the novel virus but only samples collected from the originally infected animal were positive. The virus was present in all tested organs (intestine, liver, spleen, kidneys, and lungs) and in all banked serum samples collected up to 8 years before death. All attempts to identify a latent viral form (integrated or episomal) were unsuccessful and the increase of variation in the viral sequences during the years was consistent with absence of latency. Since it is well known that parvoviruses are dependent on cell division to successfully replicate, we hypothesized that the virus could have benefitted from the constantly dividing cancer cells and may not have been the cause of the histiocytic sarcoma. It is also possible to conjecture that the virus had a role in delaying the tumor progression and this report might bring new exciting opportunities in recognizing viruses to be used in cancer virotherapy. |
Several studies investigated associations of IFN-γ rs2430561 T/A, IL28B rs12979860 C/T and ERα rs2077647 T/C gene polymorphisms with outcomes of hepatitis B virus (HBV) infection, but the results were controversial. Therefore, we performed a meta-analysis of all published observational studies to address this inconsistency. Literature was searched in online database and a systematic review was conducted based on the search results. A total of 24 studies were included and dichotomous data were presented as odds ratio (OR) with a 95% confidence interval (CI). The rs2430561 T allele was associated with reduced persistent HBV infection risk (T vs. A: OR, 0.690; 95% CI, [0.490, 0.971]), while the rs2077647 T allele significantly increased the risk of persistent HBV infection (T vs. C: OR, 1.678; 95% CI, [1.212, 2.323]). Rs 2077647 CC might play a role in protecting individuals against HBV persistence (TT vs. CC: OR, 4.109; 95% CI, [2.609, 6.473]). Furthermore, carriers of the rs2430561 TT genotype were more likely to clear HBV spontaneously compared with those of the AA genotype (TT vs. AA: OR, 0.555; 95% CI, [0.359, 0.856]). For rs12979860 C/T polymorphism, no significant correlation with HBV infection outcomes was found. In subgroup analyses, the results were similar to those of overall analysis. However, for rs2077647 TT vs. TC+CC, significantly increased risks were observed in the Asian and hospital-based population, but not in the overall analysis. IFN-γ rs2430561 T/A and ERα rs2077647 T/C genetic polymorphisms were associated with outcomes of HBV infection, but no association was found between IL28B rs12979860 C/T and HBV infection. |
A nested PCR assay was used to determine the viral RNA and proviral DNA status of naturally infected cats. Selected samples that were FeLV-positive by PCR were subjected to sequencing, phylogenetic analysis, and motifs search. Of the 39 samples that were positive for FeLV p27 antigen, 87.2% (34/39) were confirmed positive with nested PCR. FeLV proviral DNA was detected in 38 (97.3%) of p27-antigen negative samples. Malaysian FeLV isolates are found to be highly similar with a homology of 91% to 100%. Phylogenetic analysis revealed that Malaysian FeLV isolates divided into two clusters, with a majority (86.2%) sharing similarity with FeLV-K01803 and fewer isolates (13.8%) with FeLV-GM1 strain. Different enhancer motifs including NF-GMa, Krox-20/WT1I-del2, BAF1, AP-2, TBP, TFIIF-beta, TRF, and TFIID are found to occur either in single, duplicate, triplicate, or sets of 5 in different positions within the U3-LTR-gag region. The present result confirms the occurrence of FeLV viral RNA and provirus DNA in naturally infected cats. Malaysian FeLV isolates are highly similar, and a majority of them are closely related to a UK isolate. This study provides the first molecular based information on FeLV in Malaysia. Additionally, different enhancer motifs likely associated with FeLV related pathogenesis have been identified. |
MicroRNAs (miRNAs) are small, non-coding RNAs that negatively regulate gene expression. It has been reported that miRNAs are involved in host-virus interaction, but evidence that cellular miRNAs promote virus replication has been limited. Here, we found that miR-23a promoted the replication of human herpes simplex virus type 1 (HSV-1) in HeLa cells, as demonstrated by a plaque-formation assay and quantitative real-time PCR. Furthermore, interferon regulatory factor 1 (IRF1), an innate antiviral molecule, is targeted by miR-23a to facilitate viral replication. MiR-23a binds to the 3′UTR of IRF1 and down-regulates its expression. Suppression of IRF1 expression reduced RSAD2 gene expression, augmenting HSV-1 replication. Ectopic expression of IRF1 abrogated the promotion of HSV-1 replication induced by miR-23a. Notably, IRF1 contributes to innate antiviral immunity by binding to IRF-response elements to regulate the expression of interferon-stimulated genes (ISGs) and apoptosis, revealing a complex interaction between miR-23a and HSV-1. MiR-23a thus contributes to HSV-1 replication through the regulation of the IRF1-mediated antiviral signal pathway, which suggests that miR-23a may represent a promising target for antiviral treatments. |
Accurate identification of mycetoma causative agent is a priority for treatment. However, current identification tools are far from being satisfactory for both reliable diagnosis and epidemiological investigations. A rapid, simple, and highly efficient molecular based method for identification of agents of black grain eumycetoma is introduced, aiming to improve diagnostic in endemic areas. Rolling Circle Amplification (RCA) uses species-specific padlock probes and isothermal DNA amplification. The tests were based on ITS sequences and developed for Falciformispora senegalensis, F. tompkinsii, Madurella fahalii, M. mycetomatis, M. pseudomycetomatis, M. tropicana, Medicopsis romeroi, and Trematosphaeria grisea. With the isothermal RCA assay, 62 isolates were successfully identified with 100% specificity and no cross reactivity or false results. The main advantage of this technique is the low-cost, high specificity, and simplicity. In addition, it is highly reproducible and can be performed within a single day. |
Despite safe and efficacious vaccines against peste des petits ruminants virus (PPRV), this virus has emerged as the cause of a highly contagious disease with serious economic consequences for small ruminant agriculture across Asia, the Middle East, and Africa. We used complete and partial genome sequences of all 4 lineages of the virus to investigate evolutionary and epidemiologic dynamics of PPRV. A Bayesian phylogenetic analysis of all PPRV lineages mapped the time to most recent common ancestor and initial divergence of PPRV to a lineage III isolate at the beginning of 20th century. A phylogeographic approach estimated the probability for root location of an ancestral PPRV and individual lineages as being Nigeria for PPRV, Senegal for lineage I, Nigeria/Ghana for lineage II, Sudan for lineage III, and India for lineage IV. Substitution rates are critical parameters for understanding virus evolution because restrictions in genetic variation can lead to lower adaptability and pathogenicity. |
BACKGROUND: We assessed the occurrence of dengue fever in association with travel in a non-endemic hilly region. The clinical presentation and laboratory parameters of febrile patients with a travel history to an endemic region were studied, and the role of the laboratory in the diagnosis was affirmed. MATERIALS AND METHODS: Febrile patients presenting with clinical features defining dengue with a history of travel to an endemic area constituted the study group. Serum samples were tested for dengue-specific NS1 antigen and IgM, IgG antibodies. The demographic data were retrieved from the hospital information system. A hematological and biochemical workup was done and the results analyzed using percentage, proportion, mean, and median. RESULTS: Out of 189 febrile patients, 58 were reactive to serological tests for dengue, with 47 (81%) males. The presenting features were chills and rigors, myalgia, cough, sweating, and vomiting. Thrombocytopenia (74.35%), lymphopenia (52.94%), and leucopenia (47.05%) were present in early disease, with AST >34 IU/L in 58.97% of the patients. The NS1 antigen was detectable between three and seven days of fever and the IgM antibodies after five days. The positivities to only NS1, both NS1 and IgM, and IgM alone were 60.34, 27.58, and 10.34%, respectively, and the median duration of fever was five, seven, and ten days, respectively. One case of dengue hemorrhagic fever and one of probable secondary dengue infection with detectable IgG were encountered. CONCLUSION: Dengue fever remains unsuspected in febrile cases in non-endemic regions. History of travel is an essential criterion to suspect dengue. A non-specific clinical presentation eludes diagnosis. Serological tests for antigen and antibodies, and hematological and biochemical markers are vital for distinguishing the diagnosis. |
Generation of energy in mitochondria is subjected to physiological regulation at many levels, and its malfunction may result in mitochondrial diseases. Mitochondrial dysfunction is associated with different environmental influences or certain genetic conditions, and can be artificially induced by inhibitors acting at different steps of the mitochondrial electron transport chain (ETC). We found that a short-term (5 h) inhibition of ETC complex III with myxothiazol results in the phosphorylation of translation initiation factor eIF2α and upregulation of mRNA for the activating transcription factor 4 (ATF4) and several ATF4-regulated genes. The changes are characteristic for the adaptive integrated stress response (ISR), which is known to be triggered by unfolded proteins, nutrient and metabolic deficiency, and mitochondrial dysfunctions. However, after a prolonged incubation with myxothiazol (13–17 h), levels of ATF4 mRNA and ATF4-regulated transcripts were found substantially suppressed. The suppression was dependent on the p53 response, which is triggered by the impairment of the complex III-dependent de novo biosynthesis of pyrimidines by mitochondrial dihydroorotate dehydrogenase. The initial adaptive induction of ATF4/ISR acted to promote viability of cells by attenuating apoptosis. In contrast, the induction of p53 upon a sustained inhibition of ETC complex III produced a pro-apoptotic effect, which was additionally stimulated by the p53-mediated abrogation of the pro-survival activities of the ISR. Interestingly, a sustained inhibition of ETC complex I by piericidine did not induce the p53 response and stably maintained the pro-survival activation of ATF4/ISR. We conclude that a downregulation of mitochondrial ETC generally induces adaptive pro-survival responses, which are specifically abrogated by the suicidal p53 response triggered by the genetic risks of the pyrimidine nucleotide deficiency. |
Aromatase inhibitors are the most important targets in treatment of estrogen-dependent cancers. In order to search for potent steroidal aromatase inhibitors (SAIs) with lower side effects and overcome cellular resistance, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of SAIs to build 3D QSAR models. The reliable and predictive CoMFA and CoMSIA models were obtained with statistical results (CoMFA: q(2) = 0.636, r(2)(ncv) = 0.988, r(2)(pred) = 0.658; CoMSIA: q(2) = 0.843, r(2)(ncv) = 0.989, r(2)(pred) = 0.601). This 3D QSAR approach provides significant insights that can be used to develop novel and potent SAIs. In addition, Genetic algorithm with linear assignment of hypermolecular alignment of database (GALAHAD) was used to derive 3D pharmacophore models. The selected pharmacophore model contains two acceptor atoms and four hydrophobic centers, which was used as a 3D query for virtual screening against NCI2000 database. Six hit compounds were obtained and their biological activities were further predicted by the CoMFA and CoMSIA models, which are expected to design potent and novel SAIs. |
BACKGROUND: Plasmodium vivax causes almost half of all malaria cases in Asia and is recognised as a significant cause of morbidity. In recent years it has been associated with severe and fatal disease. The extent to which P. vivax contributes to death is not known. METHODS: To define the epidemiology of mortality attributable to vivax malaria in southern Papua, Indonesia, a retrospective clinical records-based audit was conducted of all deaths in patients with vivax malaria at a tertiary referral hospital. RESULTS: Between January 2004 and September 2009, hospital surveillance identified 3,495 inpatients with P. vivax monoinfection and 65 (1.9%) patients who subsequently died. Charts for 54 of these 65 patients could be reviewed, 40 (74%) of whom had pure P. vivax infections on cross-checking. Using pre-defined conservative criteria, vivax malaria was the primary cause of death in 6 cases, a major contributor in 17 cases and a minor contributor in a further 13 cases. Extreme anaemia was the most common primary cause of death. Malnutrition, sepsis with respiratory and gastrointestinal manifestations, and chronic diseases were the commonest attributed causes of death for patients in the latter two categories. There were an estimated 293,763 cases of pure P. vivax infection in the community during the study period giving an overall minimum case fatality of 0.12 per 1,000 infections. The corresponding case fatality in hospitalised patients was 10.3 per 1,000 infections. CONCLUSIONS: Although uncommonly directly fatal, vivax malaria is an important indirect cause of death in southern Papua in patients with malnutrition, sepsis syndrome and chronic diseases, including HIV infection. |
For entry and infection viruses have developed numerous strategies to subjugate indispensable cellular factors and functions. Host cell lipids and cellular lipid synthesis machinery are no exception. Not only do viruses exploit existing lipid signalling and modifications for virus entry and trafficking, they also reprogram lipid synthesis, metabolism, and compartmentalization for assembly and egress. Here we review these various concepts and highlight recent progress in understanding viral interactions with host cell lipids during entry and assembly. |
Acute respiratory distress syndrome (ARDS) is defined as an acute-onset, progressive, hypoxic condition with radiographic bilateral lung infiltration, which develops after several diseases or injuries, and is not derived from hydrostatic pulmonary edema. One specific pathological finding of ARDS is diffuse alveolar damage. In 2012, in an effort to increase diagnostic specificity, a revised definition of ARDS was published in JAMA. However, no new parameters or biomarkers were adopted by the revised definition. Discriminating between ARDS and other similar diseases is critically important; however, only a few biomarkers are currently available for diagnostic purposes. Furthermore, predicting the severity, response to therapy, or outcome of the illness is also important for developing treatment strategies for each patient. However, the PaO(2)/FIO(2) ratio is currently the sole clinical parameter used for this purpose. In parallel with progress in understanding the pathophysiology of ARDS, various humoral factors induced by inflammation and molecules derived from activated cells or injured tissues have been shown as potential biomarkers that may be applied in clinical practice. In this review, the current understanding of the basic pathophysiology of ARDS and associated candidate biomarkers will be discussed. |
Porcine torovirus (PToV) strain PToV-NPL/2013 was identified from a pig that tested positive for porcine epidemic diarrhea virus (PEDV). The spike protein-encoding gene from PToV-NPL/2013 had 92% identity with PToV-SH1, suggesting that PToV circulating in the United States is slightly different from the isolates circulating in China. To our knowledge, this is the first report of PToV in the United States. |
Natural compounds are becoming popular for the treatment of illnesses and health promotion, but the mechanisms of action and safety profiles are often unknown. Xyloketal B (XKB) is a novel marine compound isolated from the mangrove fungus Xylaria sp., with potent antioxidative, neuroprotective, and cardioprotective effects. However, its molecular targets and effects on drug-metabolizing enzymes are unknown. This study aimed to investigate the potential molecular targets of XKB using bioinformatic approaches and to examine the effect of XKB on the expression and activity of rat cytochrome P450 3a (Cyp3a) subfamily members using midazolam as a model probe. DDI-CPI, a server that can predict drug–drug interactions via the chemical–protein interactome, was employed to predict the targets of XKB, and the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to analyze the pathways of the predicted targets of XKB. Homology modeling was performed using the Discovery Studio program 3.1. The activity and expression of rat hepatic Cyp3a were examined after the rats were treated with XKB at 7 and 14 mg/kg for 8 consecutive days. Rat plasma concentrations of midazolam and its metabolite 1′-OH-midazolam were determined using a validated high-performance liquid chromatographic method. Bioinformatic analysis showed that there were over 324 functional proteins and 61 related signaling pathways that were potentially regulated by XKB. A molecular docking study showed that XKB bound to the active site of human cytochrome P450 3A4 and rat Cyp3a2 homology model via the formation of hydrogen bonds. The in vivo study showed that oral administration of XKB at 14 mg/kg to rats for 8 days significantly increased the area under the plasma concentration-time curve (AUC) of midazolam, with a concomitant decrease in the plasma clearance and AUC ratio of 1′-OH-midazolam over midazolam. Further, oral administration of 14 mg/kg XKB for 8 days markedly reduced the activity and expression of hepatic Cyp3a in rats. Taken together, the results show that XKB could regulate networks of molecular proteins and related signaling pathways and that XKB downregulated hepatic Cyp3a in rats. XKB might cause drug interactions through modulation of the activity and expression of Cyp3a members. More studies are warranted to confirm the mechanisms of action of XKB and to investigate the underlying mechanism for the regulating effect of XKB on Cyp3a subfamily members. |
BACKGROUND: Sepsis causes neutrophil sequestration in the lung which leads to acute lung injury (ALI). Radix Ginseng (RG), a traditional herb used as herbal remedy in eastern Asia for thousands of years, which has been traditionally used in China to improve blood circulation and ameliorate pathological hemostasis. This study investigated whether Ginsenoside Rb1, the main components of RG, can attenuate ALI induced by LPS. METHODS: In vivo, 30 male Wistar rats were divided into three groups (n = 10 each groups) on the basis of the reagent used, which were subjected to LPS injection with or without Ginsenoside Rb1 (5 mg/kg) treatments to induce ALI model. Lung injury was assessed by pulmonary histology, lung wet-weight to dry-weight (W/D) ratio, the number of myeloperoxidase (MPO) positive cells, immunohistochemical analysis of intercellular adhesion molecule-1 (ICAM-1), gene expression of ICAM-1, ultrastructure changes of pulmonary microvasculature, concentration of inflammatory markers and in plasma. In vitro, pulmonary microvascular endothelial cells (PMVECs) were stimulated with LPS in the presence and absence of Ginsenoside Rb1 (50 mM), nuclear factor-κB (NF-κB) p65 was measured by immunocytochemistry staining and western blotting. RESULTS: Infusion of LPS induced lung injury, in vivo, as demonstrated by pulmonary edema with infiltration of neutrophils and hemorrhage, the increase in lung W/D ratio, the number of MPO positive cells, the level of inflammatory markers such as TNF-α, MCP-1 and IL-8, enhanced expression of ICAM-1 and ICAM-1 gene. Moreover, resulted in the changes of intercellular junctions in the endothelial cells of pulmonary microvasculature. In vitro, the significant increased release of NF-κB p65 and its subsequent translocation into the nucleus in PMVECs were observed. In contrast, Ginsenoside Rb1 treatment significantly ameliorated the LPS-induced lung injury, as judged by the marked improvement in all these indices. CONCLUSIONS: These results indicate that Ginsenoside Rb1 attenuated LPS-induced lung injury through an inhibition of the inflammatory signaling pathway, besides the direct inhibitory effect on proinflammatory molecules. |
Within the last decade new technologies have been developed and implemented which employ light, often in the presence of a photosensitizer, to inactivate pathogens that reside in human blood products for the purpose of transfusion. These pathogen reduction technologies attempt to find the proper balance between pathogen kill and cell quality. Each system utilizes various chemistries that not only impact which pathogens they can inactivate and how, but also how the treatments affect the plasma and cellular proteins and to what degree. This paper aims to present the various chemical mechanisms for pathogen reduction in transfusion medicine that are currently practiced or in development. |
The advancement of high throughput omic technologies during the past few years has made it possible to perform many complex assays in a much shorter time than the traditional approaches. The rapid accumulation and wide availability of omic data generated by these technologies offer great opportunities to unravel disease mechanisms, but also presents significant challenges to extract knowledge from such massive data and to evaluate the findings. To address these challenges, a number of pathway and network based approaches have been introduced. This review article evaluates these methods and discusses their application in cancer biomarker discovery using hepatocellular carcinoma (HCC) as an example. |
Cyclic adenosine monophosphate (cAMP) is a crucial intracellular second messenger molecule that converts extracellular molecules to intracellular signal transduction pathways generating cell- and stimulus-specific effects. Importantly, specific phosphodiesterase (PDE) subtypes control the amplitude and duration of cAMP-induced physiological processes and are therefore a prominent pharmacological target currently used in a variety of fields. Here we tested the extracts from traditional Chinese medicine, Forsythia suspense seeds, which have been used for more than 2000 years to relieve respiratory symptoms. Using structural-functional analysis we found its major lignin, Forsynthin, acted as an immunosuppressant by inhibiting PDE4 in inflammatory and immune cell. Moreover, several novel, selective small molecule derivatives of Forsythin were tested in vitro and in murine models of viral and bacterial pneumonia, sepsis and cytokine-driven systemic inflammation. Thus, pharmacological targeting of PDE4 may be a promising strategy for immune-related disorders characterized by amplified host inflammatory response. |
Collectively, viruses have the greatest genetic diversity on Earth, occupy extremely varied niches and are likely able to infect all living organisms. Viral infections are an important issue for human health and cause considerable economic losses when agriculturally important crops or husbandry animals are infected. The advent of metagenomics has provided a precious tool to study viruses by sampling them in natural environments and identifying the genomic composition of a sample. However, reaching a clear recognition and taxonomic assignment of the identified viruses has been hampered by the computational difficulty of these problems. In this perspective paper we examine the trends in current research for the identification of viral sequences in a metagenomic sample, pinpoint the intrinsic computational difficulties for the identification of novel viral sequences within metagenomic samples, and suggest possible avenues to overcome them. |
Our current recognition of the renin-angiotensin system is more convoluted than originally thought due to the discovery of multiple novel enzymes, peptides, and receptors inherent to this interactive biochemical cascade. Over the last decade angiotensin converting enzyme 2 (ACE2) has emerged as a key player in the pathophysiology of hypertension and cardiovascular and renal disease due to its pivotal role in metabolizing vasoconstrictive/hypertrophic/proliferative angiotensin II into favorable angiotensin-(1-7). This review addresses a considerable advancement in research on the role of tissue ACE2 in development and progression of hypertension and cardiorenal injury. We also summarize the results from recent clinical and experimental studies suggesting that serum or urine soluble ACE2 may serve as a novel biomarker or independent risk factor relevant for diagnosis and prognosis of cardiorenal disease. Recent proceedings on novel therapeutic approaches to enhance ACE2/angiotensin-(1-7) axis are also reviewed. |
The potential for therapeutic application of splice-switching oligonucleotides (SSOs) to modulate pre-mRNA splicing is increasingly evident in a number of diseases. However, the primary drawback of this approach is poor cell and in vivo oligonucleotide uptake efficacy. Biological activities can be significantly enhanced through the use of synthetically conjugated cationic cell penetrating peptides (CPPs). Studies to date have focused on the delivery of a single SSO conjugated to a CPP, but here we describe the conjugation of two phosphorodiamidate morpholino oligonucleotide (PMO) SSOs to a single CPP for simultaneous delivery and pre-mRNA targeting of two separate genes, exon 23 of the Dmd gene and exon 5 of the Acvr2b gene, in a mouse model of Duchenne muscular dystrophy. Conjugations of PMOs to a single CPP were carried out through an amide bond in one case and through a triazole linkage (‘click chemistry’) in the other. The most active bi-specific CPP–PMOs demonstrated comparable exon skipping levels for both pre-mRNA targets when compared to individual CPP–PMO conjugates both in cell culture and in vivo in the mdx mouse model. Thus, two SSOs with different target sequences conjugated to a single CPP are biologically effective and potentially suitable for future therapeutic exploitation. |
The replication enzyme of RNA viruses must preferentially recognize their RNAs in an environment that contains an abundance of cellular RNAs. The factors responsible for specific RNA recognition are not well understood, in part because viral RNA synthesis takes place within enzyme complexes associated with modified cellular membrane compartments. Recombinant RNA-dependent RNA polymerases (RdRps) from the human norovirus and the murine norovirus (MNV) were found to preferentially recognize RNA segments that contain the promoter and a short template sequence for subgenomic RNA synthesis. Both the promoter and template sequence contribute to stable RdRp binding, accurate initiation of the subgenomic RNAs and efficient RNA synthesis. Using a method that combines RNA crosslinking and mass spectrometry, residues near the template channel of the MNV RdRp were found to contact the hairpin RNA motif. Mutations in the hairpin contact site in the MNV RdRp reduced MNV replication and virus production in cells. This work demonstrates that the specific recognition of the norovirus subgenomic promoter is through binding by the viral RdRp. |
BACKGROUND: Zoonotic infections, which transmit from animals to humans, form the majority of new human pathogens. Following zoonotic transmission, the pathogen may already have, or may acquire, the ability to transmit from human to human. With infections such as Lassa fever (LF), an often fatal, rodent-borne, hemorrhagic fever common in areas of West Africa, rodent-to-rodent, rodent-to-human, human-to-human and even human-to-rodent transmission patterns are possible. Indeed, large hospital-related outbreaks have been reported. Estimating the proportion of transmission due to human-to-human routes and related patterns (e.g. existence of super-spreaders), in these scenarios is challenging, but essential for planned interventions. METHODOLOGY/PRINCIPAL FINDINGS: Here, we make use of an innovative modeling approach to analyze data from published outbreaks and the number of LF hospitalized patients to Kenema Government Hospital in Sierra Leone to estimate the likely contribution of human-to-human transmission. The analyses show that almost [Image: see text] of the cases at KGH are secondary cases arising from human-to-human transmission. However, we found much of this transmission is associated with a disproportionally large impact of a few individuals (‘super-spreaders’), as we found only [Image: see text] of human cases result in an effective reproduction number (i.e. the average number of secondary cases per infectious case) [Image: see text], with a maximum value up to [Image: see text]. CONCLUSIONS/SIGNIFICANCE: This work explains the discrepancy between the sizes of reported LF outbreaks and a clinical perception that human-to-human transmission is low. Future assessment of risks of LF and infection control guidelines should take into account the potentially large impact of super-spreaders in human-to-human transmission. Our work highlights several neglected topics in LF research, the occurrence and nature of super-spreading events and aspects of social behavior in transmission and detection. |
BACKGROUND: Cryptococcal meningitis (CM) is a severe AIDS-defining illness with 90-day case mortality as high as 70% in sub-Saharan Africa, despite treatment. It is the leading cause of death in HIV patients in Asia and Africa. No major advance has been made in the treatment of CM since the 1970s. The mainstays of induction therapy are amphotericin B and flucytosine, but these are often poorly available where the disease burden is highest. Adjunctive treatments, such as dexamethasone, have had dramatic effects on mortality in other neurologic infections, but are untested in CM. Given the high death rates in patients receiving current optimal treatment, and the lack of new agents on the horizon, adjuvant treatments, which offer the potential to reduce mortality in CM, should be tested. The principal research question posed by this study is as follows: does adding dexamethasone to standard antifungal therapy for CM reduce mortality? Dexamethasone is a cheap, readily available, and practicable intervention. METHOD: A double-blind placebo-controlled trial with parallel arms in which patients are randomised to receive either dexamethasone or placebo, in addition to local standard of care. The study recruits patients in both Asia and Africa to ensure the relevance of its results to the populations in which the disease burden is highest. The 10-week mortality risk in the control group is expected to be between 30% and 50%, depending on location, and the target hazard ratio of 0.7 corresponds to absolute risk reductions in mortality from 30% to 22%, or from 50% to 38%. Assuming an overall 10-week mortality of at least 30% in our study population, recruitment of 824 patients will be sufficient to observe the expected number of deaths. Allowing for some loss to follow-up, the total sample size for this study is 880 patients. To generate robust evidence across both continents, we aim to recruit roughly similar numbers of patients from each continent. The primary end point is 10-week mortality. Ethical approval has been obtained from Oxford University’s Tropical Research Ethics Committee (OxTREC), and as locally mandated at each site. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN59144167 26-July-2012 |
BACKGROUND: Hepatitis B is endemic in the Indigenous communities of the Northern Territory of Australia and significantly contributes to liver-related morbidity and mortality. It is recognised that low health literacy levels, different worldviews and English as a second language all contribute to the difficulties health workers often have in explaining biomedical health concepts, relevant to hepatitis B infection, to patients. The aim of this research project was to explore the knowledge, perceptions and experiences of remote dwelling Indigenous adults and their health care providers relating to hepatitis B infection with a view to using this as the evidence base to develop a culturally appropriate educational tool. METHODS: The impetus for this project came from health clinic staff at a remote community in Arnhem Land in the Northern Territory, in partnership with a visiting specialist liver clinic from the Royal Darwin Hospital. Participants were clinic patients with hepatitis B (n = 12), community members (n = 9) and key informants (n = 13); 25 were Indigenous individuals. A participatory action research project design was used with purposive sampling to identify participants. Semi-structured interviews were undertaken to explore: current understanding of hepatitis B, desire for knowledge, and perspectives on how people could acquire the information needed. All individuals were offered the use of an interpreter. The data were examined using deductive and inductive thematic analysis. RESULTS: Low levels of biomedical knowledge about Hepatitis B, negative perceptions of Hepatitis B, communication (particularly language) and culture were the major themes that emerged from the data. Accurate concepts grounded in Indigenous culture such as “only your blood can tell the story” were present but accompanied by a feeling of disempowerment due to perceived lack of “medical” understanding, and informed partnerships between caregiver and patient. Culturally appropriate discussions in a patient’s first language using visual aids were identified as vital to improving communication. CONCLUSIONS: Having an educational tool in Indigenous patient’s first language is crucial in developing treatment partnerships for Indigenous patients with hepatitis B. Using a culturally appropriate worldview as the foundation for development should help to reduce disempowerment and improve health literacy. |
Glycyrrhiza glabra, commonly known as licorice, is a popular herbal supplement used for the treatment of chronic inflammatory conditions and as sweetener in the food industry. This species contains a myriad of phytochemicals including the major saponin glycoside glycyrrhizin (G) of Glycyrrhetinic acid (GA) aglycone. In this study, 2D-ROESY NMR technique was successfully applied for distinguishing 18α and 18β glycyrrhetinic acid (GA). ROESY spectra acquired from G. glabra, Glycyrrhiza uralensis and Glycyrrhiza inflata crude extracts revealed the presence of G in its β-form. Anti-inflammatory activity of four Glycyrrhiza species, G, glabra, G. uralensis, G. inflata, and G. echinata roots was assessed against COX-1 inhibition revealing that phenolics rather than glycyrrhizin are biologically active in this assay. G. inflata exhibits a strong cytotoxic effect against PC3 and HT29 cells lines, whereas other species are inactive. This study presents an effective NMR method for G isomer assignment in licorice extracts that does not require any preliminary chromatography or any other purification step. |
Live poultry markets are a source of human infection with avian influenza A (H7N9) virus. On February 21, 2014, a poultry farmer infected with H7N9 virus was identified in Jilin, China, and H7N9 and H9N2 viruses were isolated from the patient's farm. Reassortment between these subtype viruses generated five genotypes, one of which caused the human infection. The date of H7N9 virus introduction to the farm is estimated to be between August 21, 2013 (95% confidence interval [CI] June 6, 2013-October 6, 2013) and September 25, 2013 (95% CI May 28, 2013-January 4, 2014), suggesting that the most likely source of virus introduction was the first batch of poultry purchased in August 2013. The reassortment event that led to the human virus may have occurred between January 2, 2014 (95% CI November 8, 2013-February 12, 2014) and February 12, 2014 (95% CI January 19, 2014-February 18, 2014). Our findings demonstrate that poultry farms could be a source of reassortment between H7N9 virus and H9N2 virus as well as human infection, which emphasizes the importance to public health of active avian influenza surveillance at poultry farms. |
BACKGROUND: Adverse events are associated with significant morbidity, mortality and cost in hospitalized patients. Measuring adverse events is necessary for quality improvement, but current detection methods are inaccurate, untimely and expensive. The advent of electronic health records and the development of automated methods for encoding and classifying electronic narrative data, such as natural language processing, offer an opportunity to identify potentially better methods. The objective of this study is to determine the accuracy of using automated methods for detecting three highly prevalent adverse events: a) hospital-acquired pneumonia, b) catheter-associated bloodstream infections, and c) in-hospital falls. METHODS/DESIGN: This validation study will be conducted at two large Canadian academic health centres: the McGill University Health Centre (MUHC) and The Ottawa Hospital (TOH). The study population consists of all medical, surgical and intensive care unit patients admitted to these centres between 2008 and 2014. An automated detection algorithm will be developed and validated for each of the three adverse events using electronic data extracted from multiple clinical databases. A random sample of MUHC patients will be used to develop the automated detection algorithms (cohort 1, development set). The accuracy of these algorithms will be assessed using chart review as the reference standard. Then, receiver operating characteristic curves will be used to identify optimal cut points for each of the data sources. Multivariate logistic regression and the areas under curve (AUC) will be used to identify the optimal combination of data sources that maximize the accuracy of adverse event detection. The most accurate algorithms will then be validated on a second random sample of MUHC patients (cohort 1, validation set), and accuracy will be measured using chart review as the reference standard. The most accurate algorithms validated at the MUHC will then be applied to TOH data (cohort 2), and their accuracy will be assessed using a reference standard assessment of the medical chart. DISCUSSION: There is a need for more accurate, timely and efficient measures of adverse events in acute care hospitals. This is a critical requirement for evaluating the effectiveness of preventive interventions and for tracking progress in patient safety through time. |
Animal production and health (APH) is an important sector in the world economy, representing a large proportion of the budget of all member states in the European Union and in other continents. APH is a highly competitive sector with a strong emphasis on innovation and, albeit with country to country variations, on scientific research. Proteomics (the study of all proteins present in a given tissue or fluid – i.e. the proteome) has an enormous potential when applied to APH. Nevertheless, for a variety of reasons and in contrast to disciplines such as plant sciences or human biomedicine, such potential is only now being tapped. To counter such limited usage, 6 years ago we created a consortium dedicated to the applications of Proteomics to APH, specifically in the form of a Cooperation in Science and Technology (COST) Action, termed FA1002 – Proteomics in Farm Animals: www.cost-faproteomics.org. In 4 years, the consortium quickly enlarged to a total of 31 countries in Europe, as well as Israel, Argentina, Australia and New Zealand. This article has a triple purpose. First, we aim to provide clear examples on the applications and benefits of the use of proteomics in all aspects related to APH. Second, we provide insights and possibilities on the new trends and objectives for APH proteomics applications and technologies for the years to come. Finally, we provide an overview and balance of the major activities and accomplishments of the COST Action on Farm Animal Proteomics. These include activities such as the organization of seminars, workshops and major scientific conferences, organization of summer schools, financing Short-Term Scientific Missions (STSMs) and the generation of scientific literature. Overall, the Action has attained all of the proposed objectives and has made considerable difference by putting proteomics on the global map for animal and veterinary researchers in general and by contributing significantly to reduce the East–West and North–South gaps existing in the European farm animal research. Future activities of significance in the field of scientific research, involving members of the action, as well as others, will likely be established in the future. |
Carefully calibrated transmission models have the potential to guide public health officials on the nature and scale of the interventions required to control epidemics. In the context of the ongoing Ebola virus disease (EVD) epidemic in Liberia, Drake and colleagues, in this issue of PLOS Biology, employed an elegant modeling approach to capture the distributions of the number of secondary cases that arise in the community and health care settings in the context of changing population behaviors and increasing hospital capacity. Their findings underscore the role of increasing the rate of safe burials and the fractions of infectious individuals who seek hospitalization together with hospital capacity to achieve epidemic control. However, further modeling efforts of EVD transmission and control in West Africa should utilize the spatial-temporal patterns of spread in the region by incorporating spatial heterogeneity in the transmission process. Detailed datasets are urgently needed to characterize temporal changes in population behaviors, contact networks at different spatial scales, population mobility patterns, adherence to infection control measures in hospital settings, and hospitalization and reporting rates. |
BACKGROUND: A total of 453 laboratory-confirmed cases infected with avian influenza A (H7N9) virus (including 175 deaths) have been reported till October 2,2014, of which 30.68% (139/453) of the cases were identified from Zhejiang Province. We describe the largest reported cluster of virologically confirmed H7N9 cases, comprised by a fatal Index case and two mild secondary cases. METHODS: A retrospective investigation was conducted in January of 2014. Three confirmed cases, their close contacts, and relevant environments samples were tested by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), viral culture, and sequencing. Serum samples were tested by haemagglutination inhibition (HI) assay. RESULTS: The Index case, a 49-year-old farmer with type II diabetes, who lived with his daughter (Case 2, aged 24) and wife (Case 3, aged 43) and his son-in-law (H7N9 negative). The Index case and Case 3 worked daily in a live bird market. Onset of illness in Index case occurred in January 13, 2014 and subsequently, he died of multi-organ failure on January 20. Case 2 presented with mild symptoms on January 20 following frequent unprotected bed-side care of the Index case between January 14 to 19, and exposed to live bird market on January 17. Case 3 became unwell on January 23 after providing bedside care to the Index case on January 17 to 18, and following the contact with Case 2 during January 21 to 22 at the funeral of the Index case. The two secondary cases were discharged on February 2 and 5 separately after early treatment with antiviral medication. Four virus strains were isolated and genome analyses showed 99.6 ~100% genetic homology, with two amino mutations (V192I in NS and V280A in NP). 42% (11/26) of environmental samples collected in January were H7N9 positive. Twenty-five close contacts remained well and were negative for H7N9 infection by RT-PCR and HI assay. CONCLUSIONS: In the present study, the Index case was infected from a live bird market while the two secondary cases were infected by the Index case during unprotected exposure. This family cluster is, therefore, compatible with non-sustained person-to-person transmission of avian influenza A/H7N9. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-014-0698-6) contains supplementary material, which is available to authorized users. |
We are currently faced with a global infectious disease crisis which has been anticipated for decades. While many promising biotherapeutics are being tested, the search for a small molecule has yet to deliver an approved drug or therapeutic for the Ebola or similar filoviruses that cause haemorrhagic fever. Two recent high throughput screens published in 2013 did however identify several hits that progressed to animal studies that are FDA approved drugs used for other indications. The current computational analysis uses these molecules from two different structural classes to construct a common features pharmacophore. This ligand-based pharmacophore implicates a possible common target or mechanism that could be further explored. A recent structure based design project yielded nine co-crystal structures of pyrrolidinone inhibitors bound to the viral protein 35 (VP35). When receptor-ligand pharmacophores based on the analogs of these molecules and the protein structures were constructed, the molecular features partially overlapped with the common features of solely ligand-based pharmacophore models based on FDA approved drugs. These previously identified FDA approved drugs with activity against Ebola were therefore docked into this protein. The antimalarials chloroquine and amodiaquine docked favorably in VP35. We propose that these drugs identified to date as inhibitors of the Ebola virus may be targeting VP35. These computational models may provide preliminary insights into the molecular features that are responsible for their activity against Ebola virus in vitro and in vivo and we propose that this hypothesis could be readily tested. |
BACKGROUND: Theory suggests that individual behavioral responses impact the spread of flu-like illnesses, but this has been difficult to empirically characterize. Social distancing is an important component of behavioral response, though analyses have been limited by a lack of behavioral data. Our objective is to use media data to characterize social distancing behavior in order to empirically inform explanatory and predictive epidemiological models. METHODS: We use data on variation in home television viewing as a proxy for variation in time spent in the home and, by extension, contact. This behavioral proxy is imperfect but appealing since information on a rich and representative sample is collected using consistent techniques across time and most major cities. We study the April-May 2009 outbreak of A/H1N1 in Central Mexico and examine the dynamic behavioral response in aggregate and contrast the observed patterns of various demographic subgroups. We develop and calibrate a dynamic behavioral model of disease transmission informed by the proxy data on daily variation in contact rates and compare it to a standard (non-adaptive) model and a fixed effects model that crudely captures behavior. RESULTS: We find that after a demonstrable initial behavioral response (consistent with social distancing) at the onset of the outbreak, there was attenuation in the response before the conclusion of the public health intervention. We find substantial differences in the behavioral response across age subgroups and socioeconomic levels. We also find that the dynamic behavioral and fixed effects transmission models better account for variation in new confirmed cases, generate more stable estimates of the baseline rate of transmission over time and predict the number of new cases over a short horizon with substantially less error. CONCLUSIONS: Results suggest that A/H1N1 had an innate transmission potential greater than previously thought but this was masked by behavioral responses. Observed differences in behavioral response across demographic groups indicate a potential benefit from targeting social distancing outreach efforts. |
Infection with hepatitis B virus (HBV) may lead to subclinical, acute or chronic hepatitis. In the prevaccination era, HBV infections were endemic due to frequent mother to child transmission in large regions of the world. However, there are still estimated 240 million chronic HBV carriers today and ca. 620,000 patients die per year due to HBV-related liver diseases. Recommended treatment of chronic hepatitis B with interferon-α and/or nucleos(t)ide analogues does not lead to satisfactory results. Induction of HBV-specific T cells by therapeutic vaccination or immunomodulation may be an innovative strategy to overcome virus persistence. Vaccination with commercially available HBV vaccines in patients with or without therapeutic reduction of viral load did not result in effective immune control of HBV infection, suggesting that combination of antiviral treatment with new formulations of therapeutic vaccines is needed. The woodchuck (Marmota monax) and its HBV-like woodchuck hepatitis virus are a useful preclinical animal model for developing new therapeutic approaches in chronic hepadnaviral infections. Several innovative approaches combining antiviral treatments using nucleos(t)ide analogues, with prime-boost vaccination using DNA vaccines, new hepadnaviral antigens or recombinant adenoviral vectors were tested in the woodchuck model. In this review, we summarize these encouraging results obtained with these therapeutic vaccines. In addition, we present potential innovations in immunostimulatory strategies by blocking the interaction of the inhibitory programmed death receptor 1 with its ligand in this animal model. |
BACKGROUND: For disease surveillance, manual data collection using paper-based questionnaires can be time consuming and prone to errors. We introduced smartphone data collection to replace paper-based data collection for an influenza sentinel surveillance system in four hospitals in Kenya. We compared the quality, cost and timeliness of data collection between the smartphone data collection system and the paper-based system. METHODS: Since 2006, the Kenya Ministry of Health (MoH) with technical support from the Kenya Medical Research Institute/Centers for Disease Control and Prevention (KEMRI/CDC) conducted hospital-based sentinel surveillance for influenza in Kenya. In May 2011, the MOH replaced paper-based collection with an electronic data collection system using Field Adapted Survey Toolkit (FAST) on HTC Touch Pro2 smartphones at four sentinel sites. We compared 880 paper-based questionnaires dated Jan 2010-Jun 2011 and 880 smartphone questionnaires dated May 2011-Jun 2012 from the four surveillance sites. For each site, we compared the quality, cost and timeliness of each data collection system. RESULTS: Incomplete records were more likely seen in data collected using pen-and-paper compared to data collected using smartphones (adjusted incidence rate ratio (aIRR) 7, 95% CI: 4.4-10.3). Errors and inconsistent answers were also more likely to be seen in data collected using pen-and-paper compared to data collected using smartphones (aIRR: 25, 95% CI: 12.5-51.8). Smartphone data was uploaded into the database in a median time of 7 days while paper-based data took a median of 21 days to be entered (p < 0.01). It cost USD 1,501 (9.4%) more to establish the smartphone data collection system ($17,500) than the pen-and-paper system (USD $15,999). During two years, however, the smartphone data collection system was $3,801 (7%) less expensive to operate ($50,200) when compared to pen-and-paper system ($54,001). CONCLUSIONS: Compared to paper-based data collection, an electronic data collection system produced fewer incomplete data, fewer errors and inconsistent responses and delivered data faster. Although start-up costs were higher, the overall costs of establishing and running the electronic data collection system were lower compared to paper-based data collection system. Electronic data collection using smartphones has potential to improve timeliness, data integrity and reduce costs. |
In recent years, the within-host viral dynamics of dengue infections have been increasingly characterized, and the relationship between aspects of these dynamics and the manifestation of severe disease has been increasingly probed. Despite this progress, there are few mathematical models of within-host dengue dynamics, and the ones that exist focus primarily on the general role of immune cells in the clearance of infected cells, while neglecting other components of the immune response in limiting viraemia. Here, by considering a suite of mathematical within-host dengue models of increasing complexity, we aim to isolate the critical components of the innate and the adaptive immune response that suffice in the reproduction of several well-characterized features of primary and secondary dengue infections. By building up from a simple target cell limited model, we show that only the innate immune response is needed to recover the characteristic features of a primary symptomatic dengue infection, while a higher rate of viral infectivity (indicative of antibody-dependent enhancement) and infected cell clearance by T cells are further needed to recover the characteristic features of a secondary dengue infection. We show that these minimal models can reproduce the increased risk of disease associated with secondary heterologous infections that arises as a result of a cytokine storm, and, further, that they are consistent with virological indicators that predict the onset of severe disease, such as the magnitude of peak viraemia, time to peak viral load, and viral clearance rate. Finally, we show that the effectiveness of these virological indicators to predict the onset of severe disease depends on the contribution of T cells in fuelling the cytokine storm. |
Eukaryotic translation is a complex process composed of three main steps: initiation, elongation, and termination. During infections by RNA- and DNA-viruses, the eukaryotic translation machinery is used to assure optimal viral protein synthesis. Human immunodeficiency virus type I (HIV-1) uses several non-canonical pathways to translate its own proteins, such as leaky scanning, frameshifting, shunt, and cap-independent mechanisms. Moreover, HIV-1 modulates the host translation machinery by targeting key translation factors and overcomes different cellular obstacles that affect protein translation. In this review, we describe how HIV-1 proteins target several components of the eukaryotic translation machinery, which consequently improves viral translation and replication. |
Vaccination is regarded as one of the biggest triumphs in the history of medicine. We are living in the most successful period of vaccine development. The accumulation of multidisciplinary knowledge and the investment of massive funding have enabled the development of vaccines against many infectious diseases as well as other diseases including malignant tumors. The paradigm of clinical vaccine evaluation and licensure has also been modernized based on scientific improvements and historical experience. However, there remain a number of hurdles to overcome. Continuous efforts are focused on increasing the efficacy and reducing the risks related to vaccine use. Cutting-edge knowledge about immunology and microbiology is being rapidly translated to vaccine development. Thus, physicians and others involved in the clinical development of vaccines should have sufficient understanding of the recent developmental trends in vaccination and the diseases of interest. |
A new influenza virus, genus D, isolated in US pigs and cattle, has also been circulating in cattle in France. It was first identified there in 2011, and an increase was detected in 2014. The virus genome in France is 94%–99% identical to its US counterpart, which suggests intercontinental spillover. |
This study investigated the diarrhoea seasonality and its potential drivers as well as potential opportunities for future diarrhoea control and prevention in China. Data on weekly infectious diarrhoea cases in 31 provinces of China from 2005 to 2012, and data on demographic and geographic characteristics, as well as climatic factors, were complied. A cosinor function combined with a Poisson regression was used to calculate the three seasonal parameters of diarrhoea in different provinces. Regression tree analysis was used to identify the predictors of diarrhoea seasonality. Diarrhoea cases in China showed a bimodal distribution. Diarrhoea in children <5 years was more likely to peak in fall-winter seasons, while diarrhoea in persons > = 5 years peaked in summer. Latitude was significantly associated with spatial pattern of diarrhoea seasonality, with peak and trough times occurring earlier at high latitudes (northern areas), and later at low latitudes (southern areas). The annual amplitudes of diarrhoea in persons > = 5 years increased with latitude (r = 0.62, P<0.001). Latitude 27.8° N and 38.65° N were the latitudinal thresholds for diarrhoea seasonality in China. Regional-specific diarrhoea control and prevention strategies may be optimal for China. More attention should be paid to diarrhoea in children <5 years during fall-winter seasons. |
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