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PubMed1990

Importance of salmonellae and Campylobacter jejuni in the etiology of diarrheal disease among children less than 5 years of age in a community in Bangkok, Thailand.

The etiology of diarrhea in children less than 5 years of age in a low-income housing project in Bangkok, Thailand, was determined over 1 year. Nontyphoidal salmonellae (13%), Campylobacter jejuni (12%), rotavirus (12%), enterotoxigenic Escherichia coli (7%), shigellae (6%), E. coli that hybridized with the enteropathogenic E. coli adherence factor probe (3%), and enteroinvasive E. coli (1%) were identified in 345 episodes of diarrhea in children less than 5 years of age. Salmonellae were identified in 17% and C. jejuni was identified in 15% of 54 children less than 6 months of age with diarrhea. Shigellae, enteroinvasive E. coli, enteropathogenic E. coli adherence factor, and enterotoxigenic E. coli were not isolated from children less than 6 months of age. Since salmonellae and C. jejuni were the most common bacterial pathogens identified in children less than 6 months of age, efforts to prevent transmission of salmonellae and campylobacter to young children should be a public health priority in Bangkok.

Campylobacter Infections↗

PubMed2006

Microbial exposure assessment of an urban recreational lake: a case study of the application of new risk-based guidelines.

New WHO and Australian guidelines promote a risk-management approach for minimising exposure to pathogens in recreational waters. Between 2003 and 2005, they were applied to Lake Parramatta (10 ha, 450 ML), a potential recreation site in Sydney, Australia. A three stage approach was developed involving (1) initial suitability assessment using historic data, (2) revised suitability assessment based on new data and (3) characterisation of hazardous (especially wet weather) events. Contrary to the stage 1 suitability classification, stage 2 baseline data indicated that during dry weather the lake had water quality sufficient for primary contact recreation (95th percentiles for enterococci = 19 MPN/100, n = 50) and the major pathogen source was wildfowl. Guideline principles provided a rationale for collecting microbiological and geographic data needed to understand local cycles of lake contamination/recovery. The concept of hazardous events was particularly useful. Studies of stormwater events led us to identify a transition point (> 10 mm rainfall in 24 h) where human-faecal pathogen risks increased and access needed to be controlled. Together baseline and event data yielded operational tools (i.e. event detection methods, action triggers, auditing criteria, remediation priorities) for minimising bather exposure.

Clostridium perfringens↗

PubMed2003

Vaccines for children: policies, politics and poverty.

The dawn of the 21st century ushered in spectacular advances in vaccine production technology. However, the benefits of these developments have been largely confined to the world's most affluent and least afflicted. Of the 14 million deaths that occur world-wide in children aged less than 5 years, over 95% of these occur in developing countries and at least 70% are caused by infections for which vaccines are already available in other countries. While impoverished countries do not have a right to be assisted with the provision of funds or vaccines by affluent developed countries, an initiative for the global eradication of a vaccine preventable disease, requires a global effort. Assisting developing countries to achieve such goals should be a high priority for wealthy nations, even if only to protect their own populations. With improved international travel, not only can newly emerging diseases spread across the globe, but pathogens eliminated from one population can be re-imported by travellers or immigrants. In contrast, the recent decline in acceptance of immunisation programmes in developed countries are secondary to strong anti-vaccine movements attributing unproven adverse reactions to vaccines, placing these life-saving vaccines into disrepute. A fertile ground for propagation of these ideologies is created by parents who in their lifetime may not have seen a child killed or maimed from bacterial meningitis or measles and therefore have little understanding of the risk-benefit of vaccination. The development and deployment of vaccines must be a global effort as are the treaties for global disarmament for weapons of mass destruction.

Child↗

PubMed2005

Nature X nurture: genetic vulnerabilities interact with physical maltreatment to promote conduct problems.

Maltreatment places children at risk for psychiatric morbidity, especially conduct problems. However, not all maltreated children develop conduct problems. We tested whether the effect of physical maltreatment on risk for conduct problems was strongest among those who were at high genetic risk for these problems using data from the E-risk Study, a representative cohort of 1,116 5-year-old British twin pairs and their families. Children's conduct problems were ascertained via parent and teacher interviews. Physical maltreatment was ascertained via parent report. Children's genetic risk for conduct problems was estimated as a function of their co-twin's conduct disorder status and the pair's zygosity. The effect of maltreatment on risk for conduct problems was strongest among those at high genetic risk. The experience of maltreatment was associated with an increase of 2% in the probability of a conduct disorder diagnosis among children at low genetic risk for conduct disorder but an increase of 24% among children at high genetic risk. Prediction of behavioral pathology can attain greater accuracy if both pathogenic environments and genetic risk are ascertained. Certain genotypes may promote resistance to trauma. Physically maltreated children whose first-degree relatives engage in antisocial behavior warrant priority for therapeutic intervention.

Adolescent↗

PubMed2025

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.

BACKGROUND: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. METHODS: To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. RESULTS: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. CONCLUSION: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Humans↗

PubMed1995

Current approaches to the development of vaccines against disease caused by respiratory syncytial virus (RSV) and parainfluenza virus (PIV). A meeting report of the WHO Programme for Vaccine Development.

The paramyxoviruses respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) are the two most common agents of severe lower respiratory tract disease in infants and children throughout the world. RSV causes yearly epidemics of bronchiolitis and pneumonia in infants and young children, while PIV3 is a common cause of bronchiolitis, pneumonia and croup. Together these two agents account for up to 30% of all hospitalizations of infants and young children for respiratory tract disease. A licensed vaccine is not currently available for either of these viruses. Development of vaccines against diseases caused by RSV and PIV3 is one of the priorities of the Global Programme for Vaccines (GPV). On 27 March 1994, GPV sponsored a workshop in Nyon, Switzerland, to review the status of vaccine development for these pathogens and to explore new methods of immunization that might be applied to the prevention of diseases caused by RSV and PIV. Furthermore, the World Health Organization (WHO) wished to assess progress in the development of methodologies to rescue infectious virus from cDNA clones of RSV and PIV3. This technology, when developed, will be extremely valuable in developing new vaccine candidates and in unravelling the genetic basis of attenuation of existing vaccines. This paper summarizes the findings presented at this one-day meeting.

Animals↗

PubMed2004

Recent progress on the cytokine regulation of intestinal immune responses to Eimeria.

A variety of methods are available to combat avian diseases in the commercial setting, including improved farm management practices, use of antibiotic drugs, selection of disease resistant chicken strains, and manipulation of the chicken immune system. In the latter category, development of vaccines against the major avian diseases has become a priority for the poultry industry. With increasing demands for developing alternative control programs for many poultry diseases, it is important to understand the basic immunobiology of host-pathogen interactions in order to develop novel vaccination strategies. From studies carried out in many mammalian species, it is evident that host immune responses to intracellular pathogens are complex and involve many components of the host immune system. For enteric pathogens such as Eimeria and Salmonella, understanding cell-mediated immunity is most important because antibodies, although abundantly produced locally, can not access and act on these intracellular pathogens. In poultry, slow but increasing understanding of various components of host immune system mediating cellular immunity is opening new opportunities for thorough investigation of the role of thymus-derived lymphocyte subpopulations and cytokines in normal and disease states. This paper will review recent progress with chicken cytokines that have been characterized, and discuss various experimental strategies to enhance host immunity to pathogens using chicken cytokines.

Animals↗

PubMed2002

Cloning and expression of the haloalkane dehalogenase gene dhmA from Mycobacterium avium N85 and preliminary characterization of DhmA.

Haloalkane dehalogenases are microbial enzymes that catalyze cleavage of the carbon-halogen bond by a hydrolytic mechanism. Until recently, these enzymes have been isolated only from bacteria living in contaminated environments. In this report we describe cloning of the dehalogenase gene dhmA from Mycobacterium avium subsp. avium N85 isolated from swine mesenteric lymph nodes. The dhmA gene has a G+C content of 68.21% and codes for a polypeptide that is 301 amino acids long and has a calculated molecular mass of 34.7 kDa. The molecular masses of DhmA determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by gel permeation chromatography are 34.0 and 35.4 kDa, respectively. Many residues essential for the dehalogenation reaction are conserved in DhmA; the putative catalytic triad consists of Asp123, His279, and Asp250, and the putative oxyanion hole consists of Glu55 and Trp124. Trp124 should be involved in substrate binding and product (halide) stabilization, while the second halide-stabilizing residue cannot be identified from a comparison of the DhmA sequence with the sequences of three dehalogenases with known tertiary structures. The haloalkane dehalogenase DhmA shows broad substrate specificity and good activity with the priority pollutant 1,2-dichloroethane. DhmA is significantly less stable than other currently known haloalkane dehalogenases. This study confirms that a hydrolytic dehalogenase is present in the facultative pathogen M. avium. The presence of dehalogenase-like genes in the genomes of other mycobacteria, including the obligate pathogens Mycobacterium tuberculosis and Mycobacterium bovis, as well as in other bacterial species, including Mesorhizobium loti, Xylella fastidiosa, Photobacterium profundum, and Caulobacter crescentus, led us to speculate that haloalkane dehalogenases have some other function besides catalysis of hydrolytic dehalogenation of halogenated substances.

Alkanes↗

PubMed2000

Kids first?

Nearly 20 years afer the licensure of a vaccine against the hepatitis B virus, an estimated 300,000 U.S. residents still become infected with the potentially fatal liver virus every year. One major reason for the persistence of hepatitis B is that few adolescents and adults whose sexual and drug-using behavior places them in danger of infection are able to obtain the vaccine. Public health authorities and legislators have spent hundreds of millions of dollars to vaccinate low-risk but politically popular babies, while largely ignoring high-risk older siblings, parents, aunts, and uncles. Now this strategy, chosen in part for political reasons, is unwittingly fueling anti-vaccine efforts. The United States' poor use of the hepatitis B vaccine will surely cast a shadow over efforts to prevent HIV, a disease with remarkably similar transmission patterns.

Adolescent↗

PubMed2005

Rhizobacteria and their potential to control Fusarium verticillioides: effect of maize bacterisation and inoculum density.

Fusarium verticillioides is the most important seed transmitted pathogen that infects maize. It produces fumonisins, toxins that have potential toxicity for humans and animals. Control of F. verticillioides colonisation and systemic contamination of maize has become a priority area in food safety research. The aims of this research were (1) to characterise the maize endorhizosphere and rhizoplane inhabitant bacteria and Fusarium spp., (2) to select bacterial strains with impact on F. verticillioides growth and fumonisin B1 production in vitro, (3) to examine the effects of bacterial inoculum levels on F. verticillioides root colonisation under greenhouse conditions. Arthrobacter spp. and Azotobacter spp. were the predominant genera isolated from maize endorhizosphere and rhizoplane at the first sampling period, whilst F. verticillioides strains showed the greatest counts at the same isolation period. All F. verticillioides strains were able to produce fumonisin B1 in maize cultures. Arthrobacter globiformis RC5 and Azotobacter armeniacus RC2, used alone or in a mix, demonstrated important effects on F. verticillioides growth and fumonisin B1 suppression in vitro. Only Azotobacter armeniacus RC2 significantly reduced the F. verticillioides root colonisation at 10(6) and 10(7) CFU g(-1) levels under greenhouse conditions.

Antibiosis↗

PubMed2003

Genes for schizophrenia? Recent findings and their pathophysiological implications.

CONTEXT: Schizophrenia is highly heritable, but the genes have remained elusive. Identifying the genes is essential if the pathogenesis and pathophysiology of schizophrenia is finally to be understood, and to give the prospect of more effective treatment. STARTING POINT: H Stefansson and colleagues (Am J Hum Genet 2002; 71: 877-92) showed association of the neuregulin (NRG1) gene with schizophrenia. Other recent papers describe six additional susceptibility genes. Replications are already being reported for some of them. The genes are biologically plausible, and may have convergent effects on glutamatergic and other synapses. We review the evidence for each gene, the possible pathogenic mechanisms, and the implications of the findings. WHERE NEXT? Given earlier failures to replicate apparent breakthroughs, the results should be viewed with caution. Unequivocal replications remain the top priority. The respective contributions of each gene, epistatic effects, and functional interactions between the gene products, all need investigation. Confirmation that any of the genes is a true susceptibility gene for schizophrenia could trigger the same rapid therapeutic progress as has occurred recently in Alzheimer's disease.

Animals↗

PubMed2026

Deep DNA and protein level feature integration for robust clinical variant interpretation using probabilistic gradient boosting.

A major challenge in clinical genomics is to classify genetic variations correctly, since it directly affects disease diagnosis and personal care. The existing methods tend to be based on the combination of different factors, such as protein structure, population frequencies, phenotypic annotations, and sequence conservation. Nevertheless, these methods often cannot be used to achieve the necessary interpretability, quantify uncertainty, and address rare cases. This paper presents a probabilistic gradient boosting model on variant pathogenicity prediction. The suggested framework applies biological characteristics at both level of DNA and protein levels while also scaling the level of uncertainty in clinical decision making. Our machine learning aims to solve the issues of variant interpretation by managing the features and through probability-based pathogenicity prediction. The framework formulation is aimed at generalizing over various datasets and minimizing overfitting. At the same time, it can ensure reasonable performance to facilitate clinical experiments. The model has also been tested on three standard datasets and demonstrated to be more predictive of the pathogenic effect of variants, in comparison with a variety of existing tools. The probabilistic gradient boosting model proposed had ROC AUC values of 0.9293, 0.9610, and 0.9646 on ClinVar variants, GRCh37, and GRCh38 human genome respectively. Furthermore, the dataset was ensured to include both exonic and intronic variants, and Variants of Uncertain Significance were also taken into consideration for Performance Testing. Through this it also aims to provide better clinical significance which will lead to a good interpretable tool for priority of variants for a large variety of disease conditions.

ClinVar↗

PubMed2002

DNA vaccines against cytomegalovirus: current progress.

The development of a vaccine for the prevention of primary cytomegalovirus (CMV) infection is a major public health priority. Live attenuated virus, recombinant viral vector, recombinant protein and peptide vaccines have been studied as potential vaccine candidates. In recent years, DNA vaccination strategies have been developed for many pathogens, including CMV. This review aims to bring together many aspects of this relatively new vaccine technology as applied to current research into the development of vaccines against CMV.

Animals↗

PubMed2004

Protein kinases as targets for anti-parasitic chemotherapy.

Parasitic protozoa infecting humans have a staggering impact on public health, especially in the developing world. Furthermore, several protozoan species are major pathogens of domestic animals and have a considerable impact on food production. In many instances, the parasites have developed resistance against available chemotherapeutic agents, making the search for alternative drugs a priority. In line with the current interest in protein kinases inhibitors as potential drugs against a variety of diseases, the possibility that protein kinases may represent targets for novel anti-parasitic agents is being explored. Research into parasite protein kinases has benefited greatly from genome and EST sequencing projects, with the genomes of a few species fully sequenced (notably that of the human malaria parasite Plasmodium falciparum) and several more under way. The overall picture that emerged from research in this area shows that the phylogenetic isolation of parasitic protozoa is reflected by atypical structural and functional properties of many of their protein kinase homologues. Likewise, evidence is emerging, which suggests that the organisation of some otherwise well-conserved signal transduction pathways is divergent in some parasitic species. The differences between protein kinases of a parasite and their homologues in its host cell suggest that specific inhibition of the former can be achieved. The development of anti-parasitic drugs based on protein kinase inhibition is being pursued following two avenues: one consists of screening chemical libraries on recombinant enzymes; several protein kinases from parasitic protozoa are now available for this approach. The second approach relies on the identification of the molecular targets of kinase inhibitors which display anti-parasitic properties. This has led to promising developments in a few instances, in particular regarding PKG as a drug target against Eimeria and Toxoplasma, and purvalanol B, a purine-based CDK inhibitor which appears to affect unexpected targets in several protozoan parasites. The recent resolution of the structure of a Plasmodium protein kinase complexed with small inhibitory molecules opens the way to a rational approach towards the design of anti-parasitic drugs based on kinase inhibition.

Animals↗

PubMed2000

Tuberculosis vaccine design: influence of the completed genome sequence.

Tuberculosis continues to be a major health problem, with more adults dying from Mycobacterium tuberculosis than any other pathogen world-wide. With the onset of the HIV epidemic and an increase in drug-resistant M. tuberculosis strains, the need for an improved vaccine has become an international priority. The recent completion of the genome sequences for two M. tuberculosis strains provides a wealth of information that can be used to design new strategies for vaccine development. The challenge comes in making rational choices from among the 4,000 genes of the most probable candidate immunogens or virulence genes.Thus, a well-designed screen is needed to reduce the number of candidates that must be tested. Presently, the most valuable role that bioinformatics can play is to provide such a screen.

Animals↗

PubMed2003

[Transfusion-transmitted bacterial infection: residual risk and perspectives of prevention].

Bacterial contamination of blood components represents today the highest infectious risk of blood transfusion, the risk is particularly high when it affects platelet concentrates. The residual risk of transfusion reaction due to bacterial contamination of platelets concentrates remains stable. For all severity 1 case occurs with 25,000 distributed platelets concentrates and 1 death occurs with 200,000 distributed units. In France, efforts have focused on the prevention of contamination during donation--involving measures such as rejecting the first few millilitres of donated blood and improving skin disinfection--and the prevention of bacterial proliferation in platelets concentrates--notably by removing leukocytes and ensuring high-quality storage of donated blood. Improving strategies for reducing the risks of bacterial contamination is one of the priorities of the French National Blood Transfusion Service (l'Etablissement français du sang-EFS). There is currently considerable debate about the relative importance of bacterial screening methods and methods for inactivating pathogens present in PC. Automated culture (Biomérieux) and the ScanSystem (Hemosystem) and BDS (Pall) method are the most advanced detection systems available, to our knowledge. In term of pathogen inactivation system for platelets, Intercept (Baxter) is nearing the commercial market. These new prevention have logistic and/or functional consequences that will require close scrutiny methods. A national study group is currently considering the consequences of each of these methods and should give its opinion at the end of the first half of 2003.

Bacterial Infections↗

PubMed2005

[Towards bacterial detection in labile blood products].

Bacterial contamination of blood components represents today the highest infectious risk in blood transfusion, the risk is particularly high when it affects platelet concentrates. The prevention methods developed over the past ten years (donor selection, phlebotomy site preparation, first 30 ml diversion, systematic leuko-reduction...) which aimed at limiting the introduction of bacteria in donations and bacterial proliferation, has reduced the risk of transfusion reaction due to the bacterial contamination. Improving strategies for reducing the risks of bacterial contamination is one of the priorities of the French National Blood Transfusion Service (l'Etablissement français du sang - EFS). It is essential to improve existent prevention methods and develop the implication of all the actors (from donation to transfusion) involved in the prevention of this risk. Bacterial detection or pathogens inactivation are now available and are able to reduce (for detection) or prevent (for inactivation) the occurrence of reaction due to bacterial contamination of PC. Up to now, the choice is in favour of bacterial detection. Three methods (BacT/Alert, BioMerieux; eBDS, Pall; ScanSystem, Hemosystem) of detection of bacterial contamination in PC can be generalised now. Adaptations, need for their implementation are acceptable, especially concerning PC availability.

Automation↗

PubMed1981

Nosocomial infections--a 1980 view: progress, priorities and prognosis.

Following a brief historic perspective, this review highlights the progress that has been made in the field of nosocomial infections in the past decade. Scientific progress has been made in a few efficacy studies, the determinative role of the host, concepts of immunoincompetence, emerging pathogens, such as Legionnella pneumophila, the epidemiology of antimicrobial drug resistance and concepts of chemoprophylaxis. Major advances have been made in preventing a few specific nosocomial infections such as hepatitis B. The evolving roles of infection control practitioners and hospital epidemiologists represent important progress in meeting manpower needs. Major failures of the past decade include the continuing absence of an acceptable scientific basis for infection control, the lack of standards for hospital infection control and the consequent inability to carry out effective education. Major challenges in the 1980s will be to determine what is effective and what is not in infection control activities, and to focus control activities and recommendations more sharply.

Cross Infection↗