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PubMed2006

International Life Sciences Institute North America Listeria monocytogenes strain collection: development of standard Listeria monocytogenes strain sets for research and validation studies.

Research and development efforts on bacterial foodborne pathogens, including the development of novel detection and subtyping methods, as well as validation studies for intervention strategies can greatly be enhanced through the availability and use of standardized strain collections. These types of strain collections are available for some foodborne pathogens, such as Salmonella and Escherichia coli. We have developed a standard Listeria monocytogenes strain collection that has not been previously available. The strain collection includes (i) a diversity set of 25 isolates chosen to represent a genetically diverse set of L. monocytogenes isolates as well as a single hemolytic Listeria innocua strain and (ii) an outbreak set, which includes 21 human and food isolates from nine major human listeriosis outbreaks that occurred between 1981 and 2002. The diversity set represents all three genetic L. monocytogenes lineages (I, n = 9; II, n = 9; and III, n = 6) as well as nine different serotypes. Molecular subtyping by EcoRI automated ribotyping and pulsed-field gel electrophoresis (PFGE) with AscI and ApaI separated the 25 isolates in the diversity set into 23 ribotypes and 25 PFGE types, confirming that this isolate set represents considerable genetic diversity. Molecular subtyping of isolates in the outbreak set confirmed that human and food isolates were identical by ribotype and PFGE, except for human and food isolates for two outbreaks, which displayed related but distinct PFGE patterns. Subtype and source data for all isolates in this strain collection are available on the Internet and are linked to the PathogenTracker database (www.pathogentracker.com), which allows the addition of new, relevant information on these isolates, including links to publications that have used isolates from this collection. We have thus developed a core L. monocytogenes strain collection, which will provide a resource for L. monocytogenes research and development efforts with centralized Internet-based data curation and integration.

Animals↗
PubMed2006

Molecular epidemiology of multidrug-resistant Shigella dysenteriae type 1 causing dysentery outbreaks in Central African Republic, 2003-2004.

Shigella dysenteriae type 1 (Sd1) represents a particular threat in developing countries because of the severity of the infection and its epidemic potential. Antimicrobial susceptibility testing and molecular subtyping by pulsed-field gel electrophoresis (PFGE) and plasmid profiling (PP) of Sd1 isolates collected during two dysentery outbreaks (2013 and 445 cases of bloody diarrhoea) in Central African Republic (CAR) during the period 2003-2004 were reported. Eleven Sd1 comparison strains (CS) acquired by travellers or residents of Africa (n=10) or Asia (n=1) between 1993 and 2003 were also analysed. The 19 Sd1 isolates recovered from CAR outbreaks were multidrug resistant, although susceptible to quinolones and fluoroquinolones. Molecular subtyping by PFGE was more discriminatory than PP. The PFGE using XbaI and NotI restriction enzymes indicated that the two outbreaks were due to two different clones and also revealed a genetic diversity among the CS recovered from outbreak or sporadic cases between 1993 and 2003. This study was the result of a fruitful collaboration between field physicians and microbiologists. The data collected will serve as the basis for establishing long-term monitoring of Sd1 in CAR.

Anti-Bacterial Agents↗
PubMed2026

Immunological Features of Neuroendocrine Neoplasms and Adrenal Tumors.

Neuroendocrine neoplasms, which occur throughout the human body, as well as adrenocortical carcinoma and pheochromocytoma, which originate in the adrenal gland, are primarily classified as rare malignancies. Immunotherapy, including immune checkpoint inhibitors (ICIs), is generally not incorporated into the standard care protocols for these tumors. The clinical efficacy of ICIs in these tumors has been modest. This may be due to the biological heterogeneity of these tumors. The tumor immune microenvironment profiles are heterogeneous among the molecular subtypes of pheochromocytoma/paraganglioma, suggesting a potential benefit observed in selected subgroups. Poorly differentiated neuroendocrine carcinoma (NEC) exhibits spontaneous activation of adaptive immunity, unlike well-differentiated neuroendocrine tumors. A delta-like ligand 3-directed T-cell-engaging bispecific antibody, tarlatamab, has recently demonstrated prolonged survival in small cell lung cancer, and investigations into its use in extrapulmonary NEC are underway. This review examines the immunological features of representative neuroendocrine and adrenal tumors (neuroendocrine tumor, neuroendocrine carcinoma, adrenocortical carcinoma, and pheochromocytoma/paraganglioma). In the future, elucidating the relationship between specific molecular subtypes and immunophenotypes may facilitate the development of personalized therapies and guide clinical investigations in promising patient subpopulations.

Humans↗
PubMed2005

A large outbreak of Clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use.

BACKGROUND AND OBJECTIVE: Fluoroquinolones have not been frequently implicated as a cause of Clostridium difficile outbreaks. Nosocomial C. difficile infections increased from 2.7 to 6.8 cases per 1000 discharges (P < .001). During the first 2 years of the outbreak, there were 253 nosocomial C. difficile infections; of these, 26 resulted in colectomy and 18 resulted in death. We conducted an investigation of a large C. difficile outbreak in our hospital to identify risk factors and characterize the outbreak. METHODS: A retrospective case-control study of case-patients with C. difficile infection from January 2000 through April 2001 and control-patients matched by date of hospital admission, type of medical service, and length of stay; an analysis of inpatient antibiotic use; and antibiotic susceptibility testing and molecular subtyping of isolates were performed. RESULTS: On logistic regression analysis, clindamycin (odds ratio [OR], 4.8; 95% confidence interval [CI95], 1.9-12.0), ceftriaxone (OR, 5.4; CI95, 1.8-15.8), and levofloxacin (OR, 2.0; CI95, 1.2-3.3) were independently associated with infection. The etiologic fractions for these three agents were 10.0%, 6.7%, and 30.8%, respectively. Fluoroquinolone use increased before the onset of the outbreak (P < .001); 59% of case-patients and 41% of control-patients had received this antibiotic class. The outbreak was polyclonal, although 52% of isolates belonged to two highly related molecular subtypes. CONCLUSIONS: Exposure to levofloxacin was an independent risk factor for C. difficile-associated diarrhea and appeared to contribute substantially to the outbreak. Restricted use of levofloxacin and the other implicated antibiotics may be required to control the outbreak

Anti-Bacterial Agents↗
PubMed2004

Eye infections due to Listeria monocytogenes in three cows and one horse.

A retrospective study was conducted to determine case histories, microbiological characteristics, and molecular subtypes associated with Listeria monocytogenes infections of the eye in large animals. For selected cases, environmental L. monocytogenes contamination patterns on case farms were also evaluated to probe for potential sources and spread of listerial eye infections. Records of 170 L. monocytogenes isolates from animal infections were reviewed to determine the fraction of isolates associated with eye infections (conjunctivitis, keratitis, and uveitis) of animals and to gather information on the clinical history of these cases. Overall, 4 of 170 Listeria monocytogenes isolates were associated with eye infections; 3 of these had occurred in cows and 1 in a horse. Molecular subtyping (by EcoRI ribotying) showed that 4 different L. monocytogenes subtypes were isolated from these 4 cases; the same ribotypes had previously been found among invasive animal listeriosis infections. Although a variety of L. monocytogenes subtypes were isolated from environmental sources, on 1 farm, the same ribotype associated with the eye infection was also isolated from a fecal sample of a healthy animal and from a soil sample. The data reported in this study further suggest that L. monocytogenes can be a cause of eye infections in several animal species. Listerial eye infections do not seem to require specific pathogen-related virulence characteristics but rather seem to be a function of environmental or host factors, such as direct exposure of the eyes of susceptible animals to high numbers of the pathogen. Although listerial eye infections are rarely diagnosed because of its ubiquitous nature, L. monocytogenes may have to be considered more commonly as a causative agent of eye infections in ruminants and horses.

Animals↗
PubMed2001

Evaluation of pulsed-field gel electrophoresis in epidemiological investigations of meningococcal disease outbreaks caused by Neisseria meningitidis serogroup C.

Since 1990, the frequency of Neisseria meningitidis serogroup C (NMSC) outbreaks in the United States has increased. Based on multilocus enzyme electrophoresis (MEE), the current molecular subtyping standard, most of the NMSC outbreaks have been caused by isolates of several closely related electrophoretic types (ETs) within the ET-37 complex. We chose 66 isolates from four well-described NMSC outbreaks that occurred in the United States from 1993 to 1995 to evaluate the potential of pulsed-field gel electrophoresis (PFGE) to identify outbreak-related isolates specific for each of the four outbreaks and to differentiate between them and 50 sporadic isolates collected during the outbreak investigations or through active laboratory-based surveillance from 1989 to 1996. We tested all isolates collected during the outbreak investigations by four other molecular subtyping methods: MEE, ribotyping (ClaI), random amplified polymorphic DNA assay (two primers), and serotyping and serosubtyping. Among the 116 isolates, we observed 11 clusters of 39 NheI PFGE patterns. Excellent correlation between the PFGE and the epidemiological data was observed, with an overall sensitivity of 85% and specificity of 71% at the 95% pattern relatedness breakpoint using either 1.5 or 1.0% tolerance. For all four analyzed outbreaks, PFGE would have given public health officials additional support in declaring an outbreak and making appropriate public health decisions.

Arizona↗
PubMed2005

Nationwide outbreak of listeriosis due to contaminated meat.

We used molecular subtyping to investigate an outbreak of listeriosis involving residents of 24 US states. We defined a case as infection with Listeria monocytogenes serotype 4b yielding one of several closely related patterns when subtyped by pulsed-field gel electrophoresis. Patients infected with strains yielding different patterns were used as controls. A total of 108 cases were identified with 14 associated deaths and four miscarriages or stillbirths. A case-control study implicated meat frankfurters as the likely source of infection (OR 17.3, 95% CI 2.4-160). The outbreak ended abruptly following a manufacturer-issued recall, and the outbreak strain was later detected in low levels in the recalled product. A second strain was recovered at higher levels but was not associated with human illness. Our findings suggest that L. monocytogenes strains vary widely in virulence and confirm that large outbreaks can occur even when only low levels of contamination are detected in sampled food. Standardized molecular subtyping and coordinated, multi-jurisdiction investigations can greatly facilitate detection and control of listeriosis outbreaks.

Adolescent↗
PubMed2004

Sporadic Creutzfeldt-Jakob disease: magnetic resonance imaging and clinical findings.

OBJECTIVE: To assess if clinical features, prion protein codon 129, and molecular subtype correlate with MRI basal ganglia hyperintensity in sporadic Creutzfeldt-Jakob disease (CJD). METHODS: The authors studied 219 patients including 153 confirmed CJD cases for their neurologic symptoms and MRI findings. The MRI was assessed by a blinded investigator for the presence of high signal intensity on T2-weighted images in the basal ganglia. RESULTS: Patients with basal ganglia high signal on T2-weighted images were more likely to present with rapid progressive dementia in an early stage and shorter disease duration (median 6.7 months and 8.6 months). Surprisingly, among the CJD cases, patients without signal increase of the basal ganglia were shown to have a higher frequency of extrapyramidal disturbances (82% vs 70%). More striking differences were found for symptoms such as depression and sensory disturbances, which were more frequent among cases without signal increase. MRI was more likely to be diagnostic in patients with MV2 molecular subtype. CONCLUSIONS: Selected clinical and pathologic features correlate with the presence of basal ganglia high signal on T2-weighted MRI in patients with definite or probable CJD.

Adult↗
PubMed2004

Effects of different experimental conditions on the PrPSc core generated by protease digestion: implications for strain typing and molecular classification of CJD.

The discovery of molecular subtypes of the pathological prion protein PrPSc has provided the basis for a novel classification of human transmissible spongiform encephalopathies (TSEs) and a potentially powerful method for strain typing. However, there is still a significant disparity regarding the understanding and nomenclature of PrPSc types. In addition, it is still unknown whether a specific PrPSc type is associated with each TSE phenotypic variant. In sporadic Creutzfeldt-Jakob disease (sCJD), five disease phenotypes are known, but only two major types of PrPSc, types 1 and 2, have been consistently reproduced. We further analyzed PrPSc properties in sCJD and variant CJD using a high resolution gel electrophoresis system and varying experimental conditions. We found that pH varies among CJD brain homogenates in standard buffers, thereby influencing the characteristics of protease-treated PrPSc. We also show that PrPSc type 1 and type 2 are heterogeneous species which can be further distinguished into five molecular subtypes that fit the current histopathological classification of sCJD variants. Our results shed light on previous disparities in PrPSc typing, provide a refined classification of human PrPSc types, and support the notion that the pathological TSE phenotype is related to PrPSc structure.

Animals↗
PubMed2006

Information systems in food safety management.

Information systems are concerned with data capture, storage, analysis and retrieval. In the context of food safety management they are vital to assist decision making in a short time frame, potentially allowing decisions to be made and practices to be actioned in real time. Databases with information on microorganisms pertinent to the identification of foodborne pathogens, response of microbial populations to the environment and characteristics of foods and processing conditions are the cornerstone of food safety management systems. Such databases find application in: Identifying pathogens in food at the genus or species level using applied systematics in automated ways. Identifying pathogens below the species level by molecular subtyping, an approach successfully applied in epidemiological investigations of foodborne disease and the basis for national surveillance programs. Predictive modelling software, such as the Pathogen Modeling Program and Growth Predictor (that took over the main functions of Food Micromodel) the raw data of which were combined as the genesis of an international web based searchable database (ComBase). Expert systems combining databases on microbial characteristics, food composition and processing information with the resulting "pattern match" indicating problems that may arise from changes in product formulation or processing conditions. Computer software packages to aid the practical application of HACCP and risk assessment and decision trees to bring logical sequences to establishing and modifying food safety management practices. In addition there are many other uses of information systems that benefit food safety more globally, including: Rapid dissemination of information on foodborne disease outbreaks via websites or list servers carrying commentary from many sources, including the press and interest groups, on the reasons for and consequences of foodborne disease incidents. Active surveillance networks allowing rapid dissemination of molecular subtyping information between public health agencies to detect foodborne outbreaks and limit the spread of human disease. Traceability of individual animals or crops from (or before) conception or germination to the consumer as an integral part of food supply chain management. Provision of high quality, online educational packages to food industry personnel otherwise precluded from access to such courses.

Consumer Product Safety↗
PubMed1999

A "case control" study on the rôle of HLA DR4 in severe periodontitis and rapidly progressive periodontitis. Identification of types and subtypes using molecular biology (PCR.SSO).

HLA DR4 antigens have been considered as a risk factor in periodontal disease. The aim of this "case control" study was to verify and to provide fuller clarification of such data. "Cases" or patients had to be aged between 20 and 48 years. They presented at least 5 sites spread over several teeth with an attachment loss equal or greater than 6 mm, and 10 sites spread over several teeth with periodontal pockets equal to or greater than 5 mm. Verification with a WHO probe showed an individual CPITN score of 4. Moreover, subjects whose average CPITN score for the 6 sextants was less than 3 were excluded from the study. Among these "severe periodontitis" patients, a subgroup was distinguished composed of subjects aged 20-35 years who presented, in accordance with the cases by Katz and co-workers, 5 or more teeth showing pocket depths of 6 mm or more. The dental chartings of these subjects showed an attachment loss of more than 3 mm on certain teeth over an inter-exam period of 1-3 years. They all displayed obvious loss of bony support in the affected sites. This constituted the "rapidly progressive periodontitis" subgroup. The "controls" were all over 20 years of age, and it was clinically verified that they were free of periodontal disease. There were 48 "cases" and 55 "controls". HLA typing of patients and controls was performed using "sequence oligoprobe hybridization after polymerase chain reaction" in accordance with the 11th International Workshop. This method allowed the detection of DR4 alleles as well as DR4 subtypes. The ethno-geographic origin of the subjects, considered as a confounding variable, was neutralized by stratified analysis. Subtypes 0401, 0404, 0405 and 0408 tended to be more frequent (p=0.08) in the cases (Severe Periodontitis). Focusing on analysis of "rapidly progressive periodontitis" in subjects aged 20-35 years, a very significant Mantel-Haenszel chi2 was obtained (p=0.0058) which led to a Mantel-Haenszel standardized odds ratio (OR) equal to 17. The 95% confidence interval was 1.03<0.R.<180.10. In conclusion, this supports previous reports and gives further clarification: in particular subtypes 0401, 0404, 0405 and 0408 can be considered as a risk factor for "rapidly progressive periodontitis". It should be noted that these determinants have been implicated in rheumatoid arthritis.

Adult↗
PubMed2001

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia.

Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL-AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients (n = 253 total) and healthy newborn controls (n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C-->T) and 1,298 (A-->C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations (MLL+, n = 37) when compared with controls [adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15-0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07--0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20--1.17) were observed for hyperdiploid leukemias (n = 138). No significant associations were evident for either polymorphism with TEL-AML1+ leukemias (n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia.

Adolescent↗
PubMed2005

Chicken RFamide-related peptide (GnIH) and two distinct receptor subtypes: identification, molecular characterization, and evolutionary considerations.

RFamide-related peptides (RFRPs) regulate the release of various pituitary hormones in vertebrates. It is completely unknown how the functions of RFRPs vary among animal classes and whether vertebrate RFRPs are orthologous to each other and belong to the same peptide family. This report concerns identification of avian RFRP (gonadotropin-inhibitory hormone, GnIH) from the chicken. Chromosome-wide synteny conservation demonstrated the orthologous relationships among vertebrate RFRPs. The consensus motif for RFRP was modified to Pro-Xaa-Arg-Phe-NH2. We also describe the first identification of two distinct types of receptors for non-mammalian RFRP (RFRPR and NPFFR) from the chicken. Amino acid comparison revealed substantial differences in both termini of receptors among classes of vertebrates. The 5'-flanking regions of chicken RFRPR and NPFFR suggested their expressions in the pituitary gland, and this was confirmed by the RT-PCR analysis. Localizations of both chicken RFRP and its receptors were distinct from those of mammals. These results indicated that avian RFRP, unlike the mammalian one, directly acts on the pituitary gland via receptors to regulate gonadotropin release. It was also suggested that functional differences, especially between avian and mammalian RFRPs, are substantially due to divergences in the structures and expression sites of their receptors.

Amino Acid Sequence↗
PubMed2004

Potassium channel subtypes as molecular targets for overactive bladder and other urological disorders.

Potassium channels have re-emerged as attractive targets for overactive bladder and other urological diseases in recent years, in part due to an enhanced understanding of their molecular heterogeneity, tissue distribution, functional roles and regulation in physiological and pathological states. Cloning and heterologous expression analysis, coupled with the advancement of improved high-throughput screening techniques, have enabled expeditious identification of selective small-molecule openers and blockers for ATP-sensitive K+ channels, Ca2+-activated K+ channels and voltage-dependent K+ channel-KQT-like subfamily (KCNQ) members, and has paved the way in the assessment of efficacy and adverse effects in preclinical models. This review focuses on the rationale for molecular targeting of K+ channels, the current status of target validation, including preclinical proof-of-concept studies, and provides perspectives on the limitations and hurdles to be overcome in realising the potential of these targets for diverse urological indications such as overactive bladder, erectile dysfunction and prostate diseases.

Aged↗
PubMed1998

The cryptic inv(2)(p23q35) defines a new molecular genetic subtype of ALK-positive anaplastic large-cell lymphoma.

Recently, a distinctive entity characterized by expression of the anaplastic lymphoma kinase (ALK) protein [most frequently due to the t(2;5)(p23;q35)-associated NPM-ALK fusion] has emerged within the heterogenous group of non-Hodgkin's lymphomas (NHL) classified as anaplastic large-cell lymphoma (ALCL). Sporadic variant 2p23/ALK abnormalities identified in ALK-positive ALCL indicate that genes other than NPM may also be involved in the deregulation of ALK and lymphomagenesis. We report here three cases with an inv(2)(p23q35) detected by fluorescence in situ hybridization (FISH) in young male patients with ALK-positive ALCL. In contrast to ALCL cases with the classical t(2;5)(p23;q35) that usually show both cytoplasmic and nuclear or predominantly nuclear alone localization of the NPM-ALK chimeric product, in all three cases with an inv(2)(p23q35) the ALK protein accumulated in the cytoplasm only, supporting the previous assumption that the oncogenic potential of ALK may not be dependent on its nuclear localization. As the first step to identify the ALK partner gene involved in the inv(2)(p23q35), we performed extensive FISH studies and demonstrated that the 2q35 breakpoint occurred within the 1,750-kb region contained within the 914E7 YAC. Moreover, a striking association of the inv(2)(p23q35) with a secondary chromosomal change, viz, ider(2)(q10)inv(2)(p23q35), carrying two additional copies of the putative ALK-related fusion gene, was found in all three patients, suggesting that, in contrast to the standard t(2;5)/NPM-ALK fusion, multiple copies of the putative 2q35-ALK chimeric gene may be required for efficient tumor development. In summary, we demonstrate that the inv(2)(p23q35), a variant of the t(2;5)(p23;q35), is a recurrent chromosomal abnormality in ALK-positive ALCL, the further characterization of which should provide new insight into the pathogenesis of these lymphomas.

Adult↗
PubMed2026

Meta-Merging the Transcriptomes of Gastric Tumors Redefines the Connections among Molecular and Clinical Subtypes.

INTRODUCTION: The availability of a large number of cancer expression profiles presents an excellent opportunity to re-investigate various biological and clinical questions. While several expression profiles have been established for different cancers, merging them may provide a more powerful platform for extensively extrapolating molecular and clinical features across multiple cohorts. MATERIALS AND METHODS: In this study, five gastric tumor expression profiles from the Gene Expression Omnibus [GEO] and one in-house cohort comprising a total of 1,060 samples were merged. The batch effect was removed using non-parametric ComBat analysis, and the seamless merging of datasets was confirmed through various parameters. RESULTS: Extrapolation of ACRG [Asian Cancer Research Group] and TCGA [The Cancer Genome Atlas] molecular subtypes in the merged cohort of 1,060 gastric tumors revealed nine distinct clusters. Notably, the following patterns were observed: [i] mutual exclusivity between Epithelial to Mesenchymal Transition [EMT] and Microsatellite Instability [MSI] subtypes in 90% of tumors; [ii] overlapping occurrence of EMT and MSI subtypes in the remaining tumors; [iii] overlap between MSI and Epstein-Barr Virus [EBV] subtype tumors; [iv] both commonalities and differences between EMT and Genomically Stable [GS] subtypes; and [v] an association between EBV positivity and PI3K mutation. CONCLUSION: The current study demonstrates that compiling a larger expression profile is valuable for revisiting the molecular features and epidemiology associated with molecular subtypes, thereby aiding in the development of novel diagnostics and targeted therapeutics.

Humans↗