Determinants of emerging and re-emerging infectious diseases.

In the 1960s and 1970s, many public health experts assumed that infectious diseases could at long last be conquered as had occurred with smallpox. In the last two decades, reports warned that infectious diseases were clearly not a problem of the past. They could not be considered as a unique or isolated event of wild and faraway regions, but penetrated every corner of the globe. Emerging infectious diseases have been recently described as clinically distinct conditions whose incidence in humans has increased regionally or worldwide within the past two decades. Emergence may be due to the introduction of new agents to or the recognition of an existing disease that has gone undetected, and re-emergence may describe the re-appearance of known diseases after a decline in incidence. In this article a global, multidisciplinary and integrated approach in different fields of demography, epidemiology, economy, ecology, anthropology and environment at science has been considered to describe the different determinants responsible for the emergence and re-emergence of infectious diseases.     

Japan's innovation for global health – GHIT's catalytic role

The global fight against infectious diseases, both emerging and re-emerging, endures. Japan's commitments and reputation as a good global citizen and its responsibility to uphold domestic and international human security mean that it is in Japan's best interest to leverage its innovative and technological capabilities for global infectious disease prevention and control. The Global Health Innovative Technology Fund (GHIT Fund), an international non-profit organization based in Tokyo, Japan, was established by the Japanese government, multiple Japanese pharmaceutical companies, and the Bill & Melinda Gates Foundation as the first fund of its kind, with an aim to tackle the global burden of infectious diseases by facilitating and funding global health R&D of drugs, vaccines, and diagnostics. Since its inception in 2013, the GHIT Fund has invested more than 209 million USD in more than 90 projects, which consist of collaborations among Japanese and non-Japanese entities, six of which have already progressed to clinical stage development. Japan will continue to play a major role in the global health arena by further advancing R&D innovations for infectious diseases.     

Rhabdovirus Replication in Enucleated Host Cells

Infection of enucleated TC-7 monkey cells with rabies virus resulted in the synthesis of virus-directed RNA and the production of rabies antigens but not of infectious virus. The yield of infectious vesicular stomatitis virus from enucleated TC-7 cells, on the other hand, was almost as high as that from intact cells. Inhibition of the mitochondrial functions of enucleated cells by treatment with ethidium bromide did not influence the development of rabies antigens or the production of infectious vesicular stomatitis virus.     

2006～2008年我院法定报告传染病疫情分析

目的了解鹰潭市人民医院法定传染病报告情况,分析其流行病学特点,为制定传染病防治对策及降低传染病的发生提供科学依据。方法对鹰潭市人民医院2006～2008年法定传染病疫情资料进行分析．结果共报告法定传染病19种,累计报告发病4170例,其中无甲类传染病报告。主要病种为感染性腹泻、肺结核、病毒性肝炎、流行性腮腺炎、菌痢,占报告总数的93．62％;死亡13例（5个病种）．结论肺结核、乙型肝炎、肠道传染病是今后传染病防治工作的重点和难点,应加大管理力度．做好传染病的预防和控制工作．     

新形势下的传染病医院医疗应急后勤保障工作

传染病因其不可预测性和突发性,已经成为人类生存的大敌。随着气候的变化和环境的破坏,新老传染病（SARS、甲型H1N1流感、禽流感、TB等）相继出现及复燃,人民的健康不时受到威胁,传染病医院肩负着防治疾病的重任并面临巨大挑战。因此如何做好医疗应急后勤保障工作是当今新形势下传染病医院工作的重中之重。     

Capacity for Infectious HIV-1 Virion Capture Differs by Envelope Antibody Specificity

Antibody capacity to recognize infectious virus is a prerequisite of many antiviral functions. We determined the infectious virion capture index (IVCI) of different antibody specificities. Whereas broadly neutralizing antibodies (bNAbs), except for an MPER bNAb, selectively captured infectious virions, non-bNAbs and mucosal human immunodeficiency virus type 1 (HIV-1)-positive IgG captured subsets of both infectious and noninfectious virions. Infectious virion capture was additive with a mixture of antibodies, providing proof of concept for vaccine-induced antibodies that together have improved capacity to recognize infectious virions.     

Basic problems of serological laboratory diagnosis

Serological laboratory diagnosis is inflicted with at least two kinds of basic problems. One type relates to the fact that the serological diagnosis of infectious diseases is double indirect: First, to diagnose an infectious disease, the identification of the microbial agent is sought that caused the disease. Second, to identify this infectious agent, the patient’s immune response to potential agents is measured. So, the serological test is neither measuring directly disease nor the cause of the disease, but the patient’s immune system. Another type of problem is based on the fact that each person’s immune system is very individual. The exact physicochemical properties of antibodies are unique for each clone of antibodies. The way an individual’s immune system sees an infectious agent depends not only on the genetic makeup of the person but also on the personal experience from former encounters with infectious agents. Both types of problems lead to complexities in selecting the appropriate test, in interpreting the results, and in standardizing serological tests. Therefore, a close collaboration of the laboratory with the clinic is mandatory to avoid erroneous conclusions from serological test results, which might lead to wrong decisions in patient care.     

Mapping of alterations in noninfectious proviruses of spleen necrosis virus.

Ten recombinant lambda phage containing proviruses of spleen necrosis virus (SNV) were previously obtained. Six of the proviruses are infectious and four are not infectious in infectious DNA assays. In this paper, we show that these noninfectious proviruses are not infectious because of alterations in the viral DNA. We constructed recombinants between infectious and noninfectious proviruses and tested these recombinants in an infectious DNA assay. In addition, we carried out cotransfection of a noninfectious provirus with a restriction endonuclease-generated fragment of viral DNA. The alterations in the viral DNA resulting in lack of infectivity were mapped to regions of viral DNA of 1 to 2 kilobase pairs. These results and other biochemical data indicate that alterations in retrovirus proviruses occur at a high frequency.     

Effects of treatment and drug resistance on the transmission dynamics of malaria in endemic areas

We present a mathematical model for malaria treatment and spread of drug resistance in an endemic population. The model considers treated humans that remain infectious for some time and partially immune humans who are also infectious to mosquitoes although their infectiousness is always less than their non immune counterparts. The model is formulated by considering delays in the latent periods in both mosquito and human populations and in the period within which partial immunity is lost. Qualitative analysis of the model including positivity and boundedness of solutions is performed. Analysis of the reproductive numbers shows that if the treated humans become immediately uninfectious to mosquitoes then treatment will always reduce the number of sensitive infections. If however treated humans are infectious then for treatment to effectively reduce the number of sensitive infections, the ratio of the infectious period of the treated humans to the infectious period of the untreated humans multiplied by the ratio of the transmission rate from a treated human to the transmission rate of an untreated human should be less than one. Our results show that the spread of drug resistance with treatment as a control strategy depends on the ratio of the infectious periods of treated and untreated humans and on the transmission rates from infectious humans with resistant and sensitive infections. Numerical analysis is performed to assess the effects of treatment on the spread of resistance and infection. The study provides insight into the possible intervention strategies to be employed in malaria endemic populations with resistant parasites by identifying important parameters.     

AIDS research and its role in China’s AIDS prevention and control policies

By the end of 2005, the estimated number of HIV infected people in China was 650,000. The seriousness of the epidemic calls for effective control measures to tackle the problems in order to avoid the tragedy in Africa from happening in China. “Prevention First” is the cornerstone of the country’s health policy. On 2003 World AIDS Day, Premier Jiabao Wen announced a new national AIDS control policy, “Four Frees and One Care”. This policy clearly shows that the Chinese government has once again taken full responsibility to solve public health problems and has profound impact far beyond the AIDS field. In early 2006, the central government put scientific and technology innovation as a national priority and set the target to build an innovative China by year 2020. Since then, the government has been increasing investment in science and technology with major emphasis on both infectious diseases control and new drug research and development. For the first time, development of 100 new drugs and control of major infectious diseases (AIDS, HBV, TB and other emerging infectious diseases) have been selected as national key scientific projects. China’s best minds in related fields will be pooled to work together in order to remove the technical barriers blocking efficient control of the major infectious disease in China. Knowledge on molecular epidemiology, immunology, pathogenesis, HAART, as well as HIVDR strains will certainly provide urgently needed scientific information for China’s AIDS control program. Only evidence-based strategy from good research will provide long-term effective control of AIDS.      

The Prion Challenge to the `Central Dogma' of Molecular Biology, 1965–1991: Part II: The Problem with Prions

Since the 1930s, scientists studying the neurological disease scrapie had assumed that the infectious agent was a virus. By the mid 1960s, however, several unconventional properties had arisen that were difficult to reconcile with the standard viral model. Evidence for nucleic acid within the pathogen was lacking, and some researchers considered the possibility that the infectious agent consisted solely of protein. In 1982, Stanley Prusiner coined the term `prion' to emphasize the agent's proteinaceous nature. This infectious protein hypothesis was denounced by many scientists as `heretical'.This two-part essay asks why the concept of an infectious protein was considered controversial. Some biologists justified their evaluation of this hypothesis on the grounds that an infectious protein contradicted the `central dogma of molecular biology'. Others referred to vague theoretical constraints such as molecular biology's `theoretical structure' or `framework'. Examination of the objections raised by researchers reveals exactly what generalizations were being challenged by a protein model of infection.This two-part survey of scrapie and prion research reaches several conclusions: (1) A theoretical framework is present in molecular biology, exerting its influence in hypothesis formation and evaluation; (2) This framework consists of several related, yet separable, generalizations or `elements', including Francis Crick's Central Dogma and Sequence Hypothesis, plus notions concerning infection, replication, protein synthesis, and protein folding; (3) The term `central dogma' has stretched beyond Crick's original 1958 definition to encompass at least two other `framework elements': replication and protein synthesis; and (4) From the study of scrapie and related diseases, biological information has been delineated into at least two classes: sequential and what I call `conformational'.In Part I of this essay, a brief review of the central dogma was given, and the developments in scrapie research from 1965 to 1972 were traced. This section summarized many of the puzzling, non-virus-like properties of the scrapie agent. Alternative hypotheses to the viral explanation were presented, including early versions of a protein-only hypothesis. Part II of this essay will follow the developments in scrapie and prion research from the mid-1970s through 1991. The growing prominence of a protein-only model of infection will be countered by continued objections from many researchers to a pathogen devoid of nucleic acid. These objections will help illuminate those generalizations in molecular biology that were indeed challenged by a protein-only model of infection.     

Spontaneous splenic rupture in infectious mononucleosis: a review.

Spontaneous rupture of the spleen is a rare complication of infectious mononucleosis (IM) occurring in 0.1-0.5 percent of patients with proven IM [1]. Although splenectomy has been advocated as the definitive therapy in the past, numerous recent reports have documented favorable outcomes with non-operative management. A review of the literature suggests that non-operative management can be successful if appropriate criteria, such as hemodynamic stability and transfusion requirements are applied in patient selection. We report the case of a 36 year old man with infectious mononucleosis who had a spontaneous splenic rupture and who was successfully managed by splenectomy. Based on review of the literature, an approach to management of a spontaneously ruptured spleen secondary to IM is suggested.     

Emerging and Reemerging Infectious Diseases: Biocomplexity as an Interdisciplinary Paradigm

Understanding factors responsible for reemergence of diseases believed to have been controlled and outbreaks of previously unknown infectious diseases is one of the most difficult scientific problems facing society today. Significant knowledge gaps exist for even the most studied emerging infectious diseases. Coupled with failures in the response to the resurgence of infectious diseases, this lack of information is embedded in a simplistic view of pathogens and disconnected from a social and ecological context, and assumes a linear response of pathogens to environmental change. In fact, the natural reservoirs and transmission rates of most emerging infectious diseases primarily are affected by environmental factors, such as seasonality or meteorological events, typically producing nonlinear responses that are inherently unpredictable. A more realistic view of emerging infectious diseases requires a holistic perspective that incorporates social as well as physical, chemical, and biological dimensions of our planet’s systems. The notion of biocomplexity captures this depth and richness, and most importantly, the interactions of human and natural systems. This article provides a brief review and a synthesis of interdisciplinary approaches and insights employing the biocomplexity paradigm and offers a social–ecological approach for addressing and garnering an improved understanding of emerging infectious diseases. Drawing on findings from studies of cholera and other examples of emerging waterborne, zoonotic, and vectorborne diseases, a “blueprint” for the proposed interdisciplinary research framework is offered which integrates biological processes from the molecular level to that of communities and regional systems, incorporating public health infrastructure and climate aspects.     

Glycosaminoglycans and sialylated glycans sequentially facilitate Merkel cell polyomavirus infectious entry

Merkel cell polyomavirus (MCV or MCPyV) appears to be a causal factor in the development of Merkel cell carcinoma, a rare but highly lethal form of skin cancer. Although recent reports indicate that MCV virions are commonly shed from apparently healthy human skin, the precise cellular tropism of the virus in healthy subjects remains unclear. To begin to explore this question, we set out to identify the cellular receptors or co-receptors required for the infectious entry of MCV. Although several previously studied polyomavirus species have been shown to bind to cell surface sialic acid residues associated with glycolipids or glycoproteins, we found that sialylated glycans are not required for initial attachment of MCV virions to cultured human cell lines. Instead, glycosaminoglycans (GAGs), such as heparan sulfate (HS) and chondroitin sulfate (CS), serve as initial attachment receptors during the MCV infectious entry process. Using cell lines deficient in GAG biosynthesis, we found that N-sulfated and/or 6-O-sulfated forms of HS mediate infectious entry of MCV reporter vectors, while CS appears to be dispensable. Intriguingly, although cell lines deficient in sialylated glycans readily bind MCV capsids, the cells are highly resistant to MCV reporter vector-mediated gene transduction. This suggests that sialylated glycans play a post-attachment role in the infectious entry process. Results observed using MCV reporter vectors were confirmed using a novel system for infectious propagation of native MCV virions. Taken together, the findings suggest a model in which MCV infectious entry occurs via initial cell binding mediated primarily by HS, followed by secondary interactions with a sialylated entry co-factor. The study should facilitate the development of inhibitors of MCV infection and help shed light on the infectious entry pathways and cellular tropism of the virus.     

Bacterial Analysis of Breast Milk: A Tool to Differentiate Raynaud’s Phenomenon from Infectious Mastitis During Lactation

Lactational Raynaud’s syndrome may be misdiagnosed as infectious mastitis on the basis of the breast pain. The objective of this work was to elucidate if microbiological analysis of milk may contribute to the differentiation of both conditions. Ten lactating women clinically diagnosed by Spanish lactation consultants were included in the study. Of these, five suffered from mastitis and the remaining five suffered from Raynaud’s syndrome. Breast milk samples were inoculated on diverse culture media. Seventy isolates were selected and identified by 16S rDNA PCR sequencing. Parallel, PCR-DGGE and quantitative real-time PCR were used to assess the presence of bacterial DNA in the samples. Neither bacteria nor yeasts could be detected in the milk samples provided by the women suffering from Raynaud’s syndrome. In contrast, large numbers of bacteria were isolated from those with infectious lactational mastitis. Globally, the levels of bacterial DNA were significantly higher in the milk of mastitis-suffering women. Bacteriological analysis of milk can be an useful tool to facilitate the differential diagnosis between the infectious mastitis and Raynaud’s syndrome during lactation.     

Prion domains: sequences, structures and interactions

Mammalian and most fungal infectious proteins (also known as prions) are self-propagating amyloid, a filamentous beta-sheet structure. A prion domain determines the infectious properties of a protein by forming the core of the amyloid. We compare the properties of known prion domains and their interactions with the remainder of the protein and with chaperones. Ure2p and Sup35p, two yeast prion proteins, can still form prions when the prion domains are shuffled, indicating a parallel in-register beta-sheet structure.     

The Prion Challenge to the `Central Dogma' of Molecular Biology, 1965–1991: Part I: Prelude to Prions

Since the 1930s, scientists studying the neurological disease scrapie had assumed that the infectious agent was a virus. By the mid 1960s, however, several unconventional properties had arisen that were difficult to reconcile with the standard viral model. Evidence for nucleic acid within the pathogen was lacking, and some researchers considered the possibility that the infectious agent consisted solely of protein. In 1982, Stanley Prusiner coined the term `prion' to emphasize the agent's proteinaceous nature. This infectious protein hypothesis was denounced by many scientists as `heretical'.This essay asks why the concept of an infectious protein was considered controversial. Some biologists justified their evaluation of this hypothesis on the grounds that an infectious protein contradicted the `central dogma of molecular biology'. Others referred to vague theoretical constraints such as molecular biology's `theoretical structure' or `framework'. Examination of the objections raised by researchers reveals exactly what generalizations were being challenged by a protein model of infection.This two-part survey of scrapie and prion research reaches several conclusions: (1) A theoretical framework is present in molecular biology, exerting its influence in hypothesis formation and evaluation; (2) This framework consists of several related, yet separable, generalizations or `elements', including Francis Crick's Central Dogma and Sequence Hypothesis, plus notions concerning infection, replication, protein synthesis, and protein folding; (3) The term `central dogma' has stretched beyond Crick's original 1958 definition to encompass at least two other `framework elements': replication and protein synthesis; and (4) From the study of scrapie and related diseases, biological information has been delineated into at least two classes: sequential and what I call `conformational'.In Part I of this essay, a brief review of the central dogma, as outlined by both Francis Crick and James Watson, will be given. The developments in scrapie research from 1965 to 1972 will then be traced. This section will summarize many of the puzzling, non-viral-like properties of the scrapie agent. Alternative hypotheses to the viral explanation will also be presented, including early versions of a protein-only hypothesis. Part II of this essay will follow the developments in scrapie and prion research from the mid 1970s through 1991. The growing prominence of a protein-only model of infection will be balanced by continued objections from many researchers to a pathogen devoid of nucleic acid. These objections will help illuminate those generalizations in molecular biology that were indeed challenged by a protein-only model of infection.     

Modelling fungus dispersal scenarios using cellular automata

This study focused on representing spatio-temporal patterns of fungal dispersal using cellular automata. Square lattices were used, with each site representing a host for a hypothetical fungus population. Four possible host states were allowed: resistant, permissive, latent or infectious. In this model, the probability of infection for each of the healthy states (permissive or resistant) in a time step was determined as a function of the host's susceptibility, seasonality, and the number of infectious sites and the distance between them. It was also assumed that infected sites become infectious after a pre-specified latency period, and that recovery is not possible. Several scenarios were simulated to understand the contribution of the model's parameters and the spatial structure on the dynamic behaviour of the modelling system. The model showed good capability for representing the spatio-temporal pattern of fungus dispersal over planar surfaces. With a specific problem in mind, the model can be easily modified and used to describe field behaviour, which can contribute to the conservation and development of management strategies for both natural and agricultural systems.     

Non-infectious aggregates of the prion protein react with several PrPSc-directed antibodies

The key event in the pathogenesis of prion diseases is the conformational conversion of the normal prion protein (PrP) (PrP^C) into an infectious, aggregated isoform (PrP^Sc) that has a high content of β-sheet. Historically, a great deal of effort has been devoted to developing antibodies that specifically recognize PrP^Sc but not PrP^C, as such antibodies would have enormous diagnostic and experimental value. A mouse monoclonal IgM antibody (designated 15B3) and three PrP motif-grafted monoclonal antibodies (referred to as IgG 19–33, 89–112, and 136–158) have been previously reported to react specifically with infectious PrP^Sc but not PrP^C. In this study, we extend the characterization of these four antibodies by testing their ability to immunoprecipitate and immunostain infectious and non-infectious aggregates of wild-type, mutant, and recombinant PrP. We find that 15B3 as well as the motif-grafted antibodies recognize multiple types of aggregated PrP, both infectious and non-infectious, including forms found in brain, in transfected cells, and induced in vitro from purified recombinant protein. These antibodies are exquisitely selective for aggregated PrP, and do not react with soluble PrP even when present in vast excess. Our results suggest that 15B3 and the motif-grafted antibodies recognize structural features common to both infectious and non-infectious aggregates of PrP. Our study extends the utility of these antibodies for diagnostic and experimental purposes, and it provides new insight into the structural changes that accompany PrP oligomerization and prion propagation.