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PubMed2001

Cytokine-induced sickness behavior: where do we stand?

Sickness behavior refers to the coordinated set of behavioral changes that develop in sick individuals during the course of an infection. At the molecular level, these changes are due to the effects of proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNFalpha), in the brain. Peripherally released cytokines act on the brain via a fast transmission pathway involving primary afferent nerves innervating the body site of inflammation and a slow transmission pathway involving cytokines originating from the choroid plexus and circumventricular organs and diffusing into the brain parenchyma by volume transmission. At the behavioral level, sickness behavior appears to be the expression of a central motivational state that reorganizes the organism's priorities to cope with infectious pathogens. There is clinical and experimental evidence that activation of the brain cytokine system is associated with depression, although the exact relationship between sickness behavior and depression is still elusive.

Brain↗

PubMed2026

Total Synthesis and Structural Revision of Rhabdobranin Reveals a Cryptic Gram-Negative Antibiotic.

Gram-negative bacteria present a major clinical challenge but also remain an underexplored source of antibacterial natural products. Resistance-guided genome mining of the entomopathogenic symbiont Xenorhabdus identified the rdb biosynthetic gene cluster, which encodes a putative prodrug antibiotic, pre-rhabdobranin. However, the inability to isolate the proposed active metabolite, rhabdobranin, has prevented direct functional evaluation. Here we report a convergent total synthesis of the proposed structure of pre-rhabdobranin B, which revealed a stereochemical misassignment at the N-terminal arginine residue. Synthesis of both rhabdobranin epimers showed that, although they are nearly indistinguishable by standard analytical methods, inversion at this single stereocenter has a pronounced effect on antibacterial activity. Biological evaluation of the revised rhabdobranin structure revealed potent antibacterial activity against Gram-negative pathogens, including WHO critical-priority carbapenem-resistant Klebsiella pneumoniae. Cellular and biochemical profiling implicated inhibition of protein biosynthesis as its principal antibacterial mechanism. We further show that the GNAT-family acetyltransferase RdbK N-acetylates rhabdobranin, attenuating its activity and establishing a secondary self-resistance mechanism. These findings validate resistance-gene-guided discovery in Gram-negative symbionts as a strategy for uncovering cryptic antibiotics and identify rhabdobranin as a promising scaffold for Gram-negative antibiotic development.

Anti-Bacterial Agents↗

PubMed2001

Cytokine-induced sickness behavior: mechanisms and implications.

Sickness behavior refers to a coordinated set of behavioral changes that develop in sick individuals during the course of an infection. At the molecular level, these changes are due to the brain effects of proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFalpha). Peripherally released cytokines act on the brain via a fast transmission pathway involving primary afferent nerves innervating the bodily site of inflammation and a slow transmission pathway involving cytokines originating from the choroid plexus and circumventricular organs and diffusing into the brain parenchyma by volume transmission. At the behavioral level, sickness behavior appears to be the expression of a central motivational state that reorganizes the organism priorities to cope with infectious pathogens. There is evidence that the sickness motivational state can interact with other motivational states and respond to nonimmune stimuli probably by way of sensitization and/or classical conditioning. However, the mechanisms that are involved in plasticity of the sickness motivational state are not yet understood.

Adaptation, Physiological↗

PubMed1999

Risk screening for exposure to groundwater pollution in a wastewater irrigation district of the Mexico City region.

Untreated wastewater from the Mexico City basin has been used for decades to irrigate cropland in the Mezquital Valley, State of Hidalgo, Mexico. Excess irrigation water recharges the near-surface aquifer that is used as a domestic water supply source. We assessed the groundwater quality of three key groundwater sources of domestic water by analyzing for 24 trace metals, 67 target base/neutral/acid (BNA) organic compounds, nontarget BNA organics, 23 chlorinated pesticides, 20 polychlorinated biphenyls, and nitrate, as well as microbiological contaminants--coliforms, Vibrio cholerae, and Salmonella. Study participants answered a questionnaire that estimated ingestion and dermal exposure to groundwater; 10% of the sample reported frequent diarrhea and 9% reported persistent skin irritations. Detection of V. cholerae non-01 in surface waters at all sites suggested a potential risk (surrogate indicator present) of diarrheal disease for canal and river bathers by accidental ingestion, as well as potential Vibrio contamination of near-surface groundwater and potential cholera risk, magnified by lapses in disinfection. High total coliform levels in surface water and lower levels in groundwater at all sites indicated fecal contamination and a potential risk of gastrointestinal disease in populations exposed to inadequately disinfected groundwater. Using chemical criteria, no significant risk from ingestion or dermal contact was identified at the method detection limits at any site, except from nitrate exposure: infants and young children are at risk from methemoglobinemia at all sites. Results suggest that pathogen risk interventions are a priority, whereas nitrate risk needs further characterization to determine if formal treatment is needed. The risks exist inside and outside the irrigation district. The method was highly cost-effective.

Humans↗

PubMed2002

The highest priority: what microbial genomes are telling us about immunity.

Study of microbial genomes has provided new insight into the functions that pathogens require for survival in the animal host. Small genome bacterial pathogens, defined as those < or = 1/3 the size of Escherichia coli, include chlamydiae, rickettsiae and ehrlichiae, mycoplasmas, and spirochetes. The small genome size is believed to result from reductive evolution, a process of initial mutation with loss of function followed by progressive accumulation of mutations and eventual gene deletion. This is most notable in the 1.1 Mb genome of Rickettsia prowazekki in which 24% of the genome is non-coding, as compared to approximately 10% in the 4.4 Mb E. coli. Consequently, these pathogens are thus presumed to retain only the most important functions for survival and propagation. There is consistent evidence from small genomes that the genetic deletion is primarily related to the loss of metabolic function and especially reduction of multiple overlapping pathways and duplicated genes. Thus, these pathogens undergo progressive reduction in their genomes yet maintain the ability to infect, survive within, and cause disease in animals. In the face of this reductive process, what genes and associated functions are maintained? Strikingly, these pathogens devote a high percentage of their genomes to paralogous families of polymorphic surface molecules. This retention suggests that evasion of the immune response is the highest priority of obligate microbial pathogens and provides a strategy for identifying protective antigens for vaccine development to control disease.

Adaptation, Physiological↗

PubMed2003

Cutting edge: class I presentation of host peptides following HIV infection.

Class I MHC molecules bind intracellular peptides for presentation to cytotoxic T lymphocytes. Identification of peptides presented by class I molecules during infection is therefore a priority for detecting and targeting intracellular pathogens. To understand which host-encoded peptides distinguish HIV-infected cells, we have developed a mass spectrometric approach to characterize HLA-B*0702 peptides unique to or up-regulated on infected T cells. In this study, we identify 15 host proteins that are differentially presented on infected human T cells. Peptides with increased expression on HIV-infected cells were derived from multiple categories of cellular proteins including RNA binding proteins and cell cycle regulatory proteins. Therefore, comprehensive analysis of the B*0702 peptide repertoire demonstrates that marked differences in host protein presentation occur after HIV infection.

Antigen Presentation↗

PubMed2001

[Microflora in ENT and CNS diseases in patients living in the Moscow region].

Patients with ENT and CNS inflammation living in the Moscow Region have been examined for pathogenic contamination of relevant clinical samples. The microflora changes were followed up, pathogenic agents of high and moderate priority were identified. It is shown that for Moscow Region, ENT and CNS purulent inflammation is associated primarily with coagulase-negative staphylococci, E. coli, meningococci, S. viridans and yeast fungi.

Bacterial Infections↗

PubMedDate not supplied

[Monitoring of etiological agents of acute enteric infections in the Moscow region].

The fecal microflora of patients with acute enteric infections (AEI) has been examined on the territory of the Moscow region. The pathogens of high, moderate and low priority levels have been detected. As revealed in this study, shigellae, salmonellae, enteropathogenic and enteroinvasive Escherichia are the etiological agents of bacterial diarrheas on the territory of the Moscow region. The dynamics of the etiological agents of AEI in the region has been established.

Acute Disease↗

PubMed2001

Design of a novel mammalian screening system for the detection of bioavailable, non-cytotoxic streptogramin antibiotics.

Screening and development of new antibiotic activities to counteract the increasing prevalence of multidrug-resistant (MDR) human pathogenic bacteria has once again become a priority in human chemotherapy. Here we describe a novel mammalian cell culture-based screening platform for the detection of streptogramin antibiotics. Quinupristin-dalfopristin (Synercid), a synthetically modified streptogramin, is presently the sole effective agent in the treatment of some MDR nosocomial infections. A Streptomyces coelicolor transcriptional regulator (Pip) has been adapted to modulate reporter gene expression (SEAP, secreted alkaline phosphatase) in Chinese hamster ovary cells (CHO) in response to streptogramin antibiotics. This CHO cell-based technology was more sensitive in detecting the production of the model streptogramin pristinamycin, from Streptomyces pristinaespiralis, than antibiogram tests using a variety of human pathogenic bacteria as indicator strains. The reporter system was able to detect pristinamycin compound produced by a single S. pristinaespiralis colony. The assay was rapid (17 hours) and could be carried out in a high-throughput 96-well plate assay format or a 24-well transwell set-up. This novel mammalian cell-based antibiotic screening concept enables detection of bioavailable and non-cytotoxic representatives of a particular class of antibiotics in a single assay and represents a promising alternative to traditional antibiogram-based screening programs.

Alkaline Phosphatase↗

PubMed2003

Health and environmental policy issues in Canada: the role of watershed management in sustaining clean drinking water quality at surface sources.

Sustaining clean and safe drinking water sources is increasingly becoming a priority because of global pollution. The means of attaining and maintaining clean drinking water sources requires effective policies that identify, document, and reduce watershed risks. These risks are defined by their potential impact to human health. Health and risk are, therefore, indelibly linked because they are in part defined by each other. Understanding pathogen ecology and identifying watershed sources remains a priority because of the associated acute risks. Surface water quality changes resulting from inputs of human waste, nutrients and chemicals are associated with higher drinking water risks. Nutrient input can increase primary production and the resulting increase of organic matter results in greater disinfection by-product formation or requires greater treatment intensity. Many drinking water disease outbreaks have resulted from breaches in treatment facilities, therefore, even with greater treatment intensity poor source water quality intrinsically has greater associated health risks. Government and international agencies play a critical role in developing policy. The goal of maintaining water supplies whose availability is maximized and risks are minimized (i.e. sustainable) should be a vital part of such policy. Health risks are discussed in the context of a multi-barrier perspective and it is concluded that both passive (protection) and active (prescriptive management) management is necessary for sustainability. Canadian aboriginal water systems, British Columbian water policy and US EPA policies are given as examples. The basis for developing effective policies includes a strong reliance on sound science and effective instrumentation with careful consideration of stakeholders' interests. Only with such directed policies can the future availability of clean drinking water sources be ensured.

Canada↗

PubMed2002

Ticks and tick-borne diseases in Asia with special emphasis on China.

An international conference on the control of ticks and tick-borne diseases sponsored by the European Commission was held in Shanghai between 11 and 15 September 2000. Participants from China, Europe, Australia, India, Iran, Israel, Japan and Thailand attended the meeting. The main objectives were: (1) determining the current situation concerning the epidemiology, economics, diagnosis and integrated control measures of ticks and tick-borne diseases caused by protozoan and rickettsial pathogens; (2) the creation of regional and international research networks and priority settings; (3) the creation of training possibilities for young scientists; (4) the identification of new research directions and priority settings in relation to vaccine development and diagnostics. The papers presented during this meeting focused on parasite characterisation and the description of yet unidentified Theileria and Babesia species pathogenic for large and small ruminants in China. In addition, progress made in immunity and vaccine development against the pathogens mentioned above and their vector ticks was also discussed.

Animals↗

PubMed1996

Burkholderia cepacia: medical, taxonomic and ecological issues.

The increasing challenge posed by multiresistant saprophytes in medical microbiology is strikingly demonstrated by the emergence of Burkholderia (formerly Pseudomonas) cepacia as an opportunist pathogen in immunocompromised patients, particularly individuals with chronic granulomatous disease and cystic fibrosis (CF). Best known previously as a phytopathogen and the cause of soft rot of onions, B. cepacia presents three major problems for the CF community: innate multiresistance to antimicrobial agents; person-to-person transmission of epidemic strains through nosocomial or social contacts; and 'cepacia syndrome', a fulminating fatal pneumonia, sometimes associated with septicaemia, that occurs in approximately 20% of colonised patients, including those with previously mild disease. Accumulated evidence to dispel earlier suggestions that the organism is avirulent and merely a marker of existing lung disease includes: case-controlled studies in CF patients; reports of serious infections in non-CF patients; in-vitro and in-vivo evidence that B. cepacia induces production of pro-inflammatory markers, including the major cytokine TNFalpha; and histopathological evidence that exposure of transgenic CF mice to B. cepacia results in pneumonia. By the early 1990s, the use of selective culture media and DNA-based bacterial fingerprinting confirmed suspicions of epidemic person-to-person spread of B. cepacia. This evidence provided scientific justification for draconian and controversial measures for infection control, in particular, segregation of B. cepacia-colonised patients during treatment at CF centres and their exclusion from social gatherings and national conferences. Recently, molecular analyses of type strains and clinical isolates have revealed that isolates identified previously as B. cepacia belong to at least three distinct species and have increased concern regarding the reliability of current laboratory detection and identification systems. Clarification of the taxonomy of B. cepacia-like organisms and the pathogenic potential of environmental isolates remains a high priority, particularly when the organism's antifungal and degradative properties have created interest in its potential use as a biological control agent to improve crop yields and its use for the bioremediation of contaminated soils.

Allium↗

PubMed2003

Cultural and genetic approaches to managing mycotoxins in maize.

Infection of maize kernels by toxigenic fungi remains a challenging problem despite decades of research progress. Cultural practices, including crop rotation, tillage, planting date, and management of irrigation and fertilization, have limited effects on infection and subsequent mycotoxin accumulation. Current infrastructure and grain storage practices in developed countries can prevent postharvest development of mycotoxins, but this aspect remains a threat in developing countries, especially in tropical areas. Because most mycotoxin problems develop in the field, strategies are needed to prevent infection of growing plants by toxigenic fungi. Developing genetic resistance to Aspergillus flavus, Gibberella zeae, and Fusarium spp. (particularly F. verticillioides) in maize is a high priority. Sources of resistance to each of these pathogens have been identified and have been incorporated into public and private breeding programs. However, few, if any, commercial cultivars have adequate levels of resistance. Efforts to control infection or mycotoxin development through conventional breeding and genetic engineering are reviewed. The role of transgenic insect control in the prevention of mycotoxins in maize is discussed.

Mycotoxins↗

PubMed2000

[The state of vector-borne diseases in Indonesia].

From epidemiological point of view, Indonesia is an extremely interesting area owing its insular structure and ecological, anthropological, cultural and economical diversity. As everywhere, vector-borne diseases are the result of complex and variable epidemiological systems, subject both to biogeographical rules and human activity. Two main arboviroses are present in Indonesia: dengue and Japanese encephalitis. Dengue appears as an endemoepidemic disease and is mostly circumscribed to urban areas. Haemorrhagic cases were first observed in 1968; since then, the incidence has been constantly increasing and the disease is now one of the principal causes of child lethality. Japanese encephalitis is a rural endemic disease transmitted by rice-field mosquitoes; its incidence remains relatively low since pigs, which are usual link-hosts for the virus, are uncommon in this mainly Muslem country. Human clinical cases are recorded from non-Muslem islands such as Bali or Irian Jaya which raises the question of immunisation for travellers. Recently, Japanese encephalitis was observed on east of the Wallace line which had been considered as the eastern cut-off line. Malaria is common throughout the country, Plasmodium vivax being the most frequent species. Some of the Anopheline vectors are related to brackish water as are coastal species; others have been favoured by rice growing. Several species bite and rest outdoors, rendering control measures complex. Moreover, chloroquine resistance is increasing in both P. falciparum and P. vivax. All three filaria species responsible for human lymphatic filariasis exist in Indonesia. Bancroft filariasis is present in rather limited foci on most of the islands; malayan filariasis is very prevalent on many islands, mostly in coastal areas, and Timor filariasis exist only on a few small islands. These parasitic diseases are cumulative and do not practically endanger the health of travellers. In the past, plague was common on Java island, but today, human cases are very rare. Scrub typhus is prevalent everywhere, as is murine typhus, being very frequent in harbour cities and one of the main causes of hospitalisation for febrile syndromes.. On the whole, the situation of several of these diseases has been worsening in Indonesia for about thirty years. Although epidemiological situations constantly evolve, two recent occurrences should be paid particular attention: -transmigration which is now a national priority and greatly facilitates the spread of many pathogens, arboviroses or chloroquine-resistant plasmodia, but also of rats, mosquitoes, etc. -deforestation due either to land-farming by Javanese transmigrants or to sudden climatic changes such as El Niño in 1997. Such deep ecological transformations may have considerable and unforeseeable consequences on the epidemiology of vector-borne diseases in Indonesia.

Animals↗

PubMed1990

[Group B streptococci in neonatal pathology: pathogenetic mechanism, diagnosis and prevention].

Group B streptococci have recently attracted the attention of researchers as the causative agents of human neonatal disease. They are currently encountered much more frequently than it was believed previously. Various types of adult pathogen carriers have been described; this accounts for the numerous sources and pathways of infection transmission, both vertical and horizontal. The transmission risk depends on many factors, vaginal colonization in the parturient being of special import. The level of the pathogen adhesion to the barrier epithelium is reflective of the tissue sensitivity to infection. Increased sensitivity of the vaginal epithelium to B streptococci adhesion in association with the intake of some contraceptives has been found. The adhesive activity of avirulent streptococci B strains is shown to be higher than in the virulent strains, which is especially important in mixed virus bacterial infections. The streptococcal infection of high mortality is underlain by activation of persisting avirulent streptococci B that manifest their pathogenicity as a result of the virus-specific modifications in the host cell membrane. During 1985-1987, in Leningrad Institute of Gynecology and Obstetrics over 80 strains of streptococci B were isolated, the leading serotypes being Ia/C, Ib/C, II/C, III/R. Only 54% of the studied pregnancies attended with the streptococcus carriage had a favourable neonatal outcome. The strain serotypes from maternal isolates and abortuses fully correlated. Further improvement of the laboratory diagnosis and means of the pathogen and its carriers identification is a current priority.

Bacterial Adhesion↗

PubMed1987

Setting priorities: nationwide nosocomial infection prevention and control programs in the USA.

Approximately two million nosocomial infections occur annually in patients admitted to acute-care hospitals in the USA. Factors that should be considered in setting national priorities for nosocomial infection prevention and control efforts include incidence, mortality, prolongation of stay, cost of treatment, and potential for prevention of infections at different sites. National nosocomial infection priorities in the USA cover infections caused by emerging pathogens, infections at selected sites including the bloodstream, infections in intensive-care units, infections resulting from contaminated devices and products, development of the capability to analyze surveillance data in a timely fashion, dissemination of information on effective prevention strategies to infection control personnel, and training of infection control personnel, including physicians. The mechanism used to disseminate information on effective prevention strategies is the series of CDC 'Guidelines for the Prevention and Control of Nosocomial Infections'. These guidelines address prevention of nosocomial infections at the four major sites, handwashing and environmental control issues, infection control in personnel health, and isolation precautions.

Cross Infection↗

PubMed1998

Clinical implications of nosocomial gram-positive bacteremia and superimposed antimicrobial resistance.

The coexistence of a pathogen population with an ever-increasing resistance to many antibiotics and a patient population characterized by increasingly complex clinical problems has contributed to an increase in the bloodstream infections associated with gram-positive bacteria. This serious therapeutic challenge has already been associated with an increase in infection-related morbidity and mortality, a prolongation of hospital stays, and an escalation of healthcare costs. Vancomycin resistance, long prevalent among the enterococci, has emerged in strains of Staphylococcus aureus. Several cases of infection caused by S. aureus strains with intermediate-level resistance to vancomycin (MIC=8 microg/mL) have recently been reported. As glycopeptide resistance accelerates among the gram-positive bacteria, so does the potential for adverse clinical consequences associated with bloodstream infections caused by these pathogens. The patients least able to tolerate the effects of uncontrolled bloodstream infections are also those at the highest risk for the development of infections caused by glycopeptide-resistant pathogens. In this at-risk population, a poor outcome may be anticipated if effective antibiotic therapy is unavailable. Appropriate rationing of vancomycin and other antimicrobial agents that increase the selection of antibiotic-resistant strains of gram-positive bacteria and the rapid development of novel antimicrobial agents with reliable gram-positive activity must be immediate priorities if the threat posed by glycopeptide-resistant gram-positive pathogens is to be countered.

Anti-Bacterial Agents↗

PubMed2003

Coronary atherosclerosis and somatic mutations: an overview of the contributive factors for oxidative DNA damage.

Coronary artery disease (CAD) is a multifactorial process that appears to be caused by the interaction of environmental risk factors with multiple predisposing genes. Genetic research on CAD has traditionally focused on investigation aimed at identifying disease-susceptibility genes. Recent evidence suggests that somatically acquired DNA mutations may also contribute significantly to the pathogenesis of the disease, underlining the similarity between atherosclerotic and carcinogenic processes. The generation of oxidative stress has been emphasized as an important cause of DNA damage in atherosclerosis. This review highlights some of the major atherogenic risk factors as likely mediators in the oxidative modification of DNA. It also examines the hypothesis that an increase in oxidative stress may derive from "oxidatively" damaged mitochondria. Accordingly, further research in this field should be given high priority, since increased somatic DNA damage could be an important pathogenic factor and an additional prognostic predictor, as well as a potential target for therapeutic strategies in coronary artery disease.

Aging↗