Infections in children with cancer-old approaches and new.
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Child↗
Biomedical subjects
A Reilly
Publications and source records attributed to A Reilly.
Investigation of chromosome 2q in osteoarthritis of the hand: no significant linkage in a Tasmanian population.
BACKGROUND: Previous studies have suggested a strong genetic component to osteoarthritis (OA), especially that of the hand, and three linkage studies have suggested the existence of susceptibility loci in disparate regions of chromosome 2q. OBJECTIVE: To examine for linkage to 2q in a Tasmanian population of women and men with familial hand OA. METHODS: Hand OA (distal interphalangeal, carpometacarpal, and Heberden's nodes) was assessed by a combination of hand photographs and radiographs. A non-parametric linkage (NPL) analysis was performed on chromosome 2q of 69 members in 22 families with severe distal interphalangeal joint OA using Genehunter. A quantitative trait linkage analysis of a larger group of 456 members in 68 families was also performed using SOLAR. RESULTS: The maximum non-parametric linkage score was 1.05 (p=0.15) at marker IL1R1, close to the centromere. All components of hand OA scores had significant heritability in this dataset (28%-35%, all p<0.001). Despite this, the quantitative trait analysis (after adjustment for age and, where appropriate, sex) yielded maximum LOD scores of 0.90 for Heberden's nodes (both sexes combined), and 1.19 for carpometacarpal OA score (women only). CONCLUSIONS: These results do not provide confirmation of linkage on chromosome 2q in the larger white population with hand OA. They suggest that there are regional variations in the genetic cause of hand OA and that other loci not on 2q may be important in this disease.
Adult↗
Relationships between IFNgamma, IL-6, corticosterone, and Listeria monocytogenes pathogenesis in BALB/c mice.
The relationships between Listeria monocytogenes (LM) pathogenesis, based on bacterial load, and serum levels of IL-6, IFNgamma, and corticosterone (CORT) were quantified. Serum IFNgamma levels increased along with the LM burden; however, with LM burdens > or =3 x 10(6) CFU per spleen, the serum IFNgamma level decreased along with a decrease in splenic weight. Serum IL-6 levels exponentially increased with increases of LM, and the CORT level positively correlated with the increase in IL-6 and LM. The serum level of IFNgamma appeared to be a good biomarker of the host's ability to combat the infection only when the LM burden did not exceed a critical level (>3 x 10(6) CFU per spleen). Interestingly, the LM load at which the IFNgamma level began to decline was near the dose at which the IL-6 concentration exponentially increased, suggesting a transition point shift from stress (assessed as CORT level) being immunoenhancing to becoming immunosuppressive. The IL-6:IFNgamma ratio may be a good indicator of disease severity and/or the ability to cope with an infection.
Animals↗
Evidence for functionally significant polymorphism of human glutamate cysteine ligase catalytic subunit: association with glutathione levels and drug resistance in the National Cancer Institute tumor cell line panel.
Glutamate-cysteine ligase (GCL) is the first and rate-limiting enzyme involved in the biosynthesis of glutathione (GSH). The GCL heterodimer is encoded by two genes: GLCLC, which directs synthesis of the catalytic subunit, and GLCLR, which encodes the regulatory subunit. We have previously identified a polymorphic GAG/CTC trinucleotide repeat within the 5' untranslated region of GLCLC. Here we report the further characterization of GLCLC polymorphism and the existence of five GLCLC alleles as defined by the trinucleotide repeat, which exhibits a range of 4 to 10 uninterrupted repeats. Significant variation in GLCLC allele frequencies was observed in four different ethnic populations examined. Interindividual variation in the capacity to produce GSH due to GLCLC polymorphism is hypothesized to influence the cellular response to environmental toxicants and chemotherapeutic agents. To test this hypothesis, the 60 tumor cell lines of the National Cancer Institute drug screening panel were genotyped for the GLCLC trinucleotide repeat, and the association of GLCLC genotype with GSH levels and drug sensitivity/resistance data was examined. Here we demonstrate an association between certain GLCLC alleles and GSH levels and/or drug sensitivity, providing evidence that suggests polymorphism of human GLCLC is functionally significant.
Antineoplastic Agents↗
Epidemiology of human listeriosis and seafoods.
While rarely diagnosed prior to 1960, more than 10,000 cases of listeriosis were recorded in the medical literature between 1960 and 1982, and thousands more have been reported annually world-wide [Rocourt J., 1991. Human listeriosis, 1989. WHO/HPP/FOS/91.3, World Health Organization, Geneva, Switzerland; Rocourt, J., Brosch, R., 1992. Human listeriosis, 1990. WHO/HPP/FOS/92.3, World Health Organization, Geneva, Switzerland; Rocourt, J., Jacquet, Ch., Bille, J., 1997. Human listeriosis, 1991/1992. WHO/FNU/FOS/97.1, World Health Organization, Geneva, Switzerland]. This widespread increase in reporting is most likely due to demographic trends and changes in food production, processing and storage, especially the extended cold food chain and the ability of Listeria monocytogenes to grow at low temperatures: L. monocytogenes is a bacterium responsible for opportunistic infections, preferentially affecting individuals whose immune system is perturbed, including pregnant women, newborns, people over 65 years, immunocompromised patients, such as cancer victims, transplant recipients, people on hemodialysis and AIDS patients. Thus, the increasing lifespan and medical progress allowing immunodeficient individuals to survive, partially explains the increasing incidence of listeriosis. Moreover, L. monocytogenes is ubiquitous and can grow at temperatures as low as 0 degrees C. At this temperature growth is very slow. The expansion of the agro-food industry, the widespread use of systems of cold storage and changes in consumers demands have led to a large increase in the pool of Listeria that can cause foodborne infections.
Animals↗
Antibody-mediated elimination of the obligate intracellular bacterial pathogen Ehrlichia chaffeensis during active infection.
It is generally accepted that cellular, but not humoral immunity, plays an important role in host defense against intracellular bacteria. However, studies of some of these pathogens have provided evidence that antibodies can provide immunity if present during the initiation of infection. Here, we examined immunity against infection by Ehrlichia chaffeensis, an obligate intracellular bacterium that causes human monocytic ehrlichiosis. Studies with mice have demonstrated that immunocompetent strains are resistant to persistent infection but that SCID mice become persistently and fatally infected. Transfer of immune serum or antibodies obtained from immunocompetent C57BL/6 mice to C57BL/6 scid mice provided significant although transient protection from infection. Bacterial clearance was observed when administration occurred at the time of inoculation or well after infection was established. The effect was dose dependent, occurred within 2 days, and persisted for as long as 2 weeks. Weekly serum administration prolonged the survival of susceptible mice. Although cellular immunity is required for complete bacterial clearance, the data show that antibodies can play a significant role in the elimination of this obligate intracellular bacterium during active infection and thus challenge the paradigm that humoral responses are unimportant for immunity to such organisms.
Animals↗
Microsatellite loci to determine population structure of the Patagonian toothfish Dissostichus eleginoides.
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Alleles↗
Autonomic nerve function in adolescents with Type 1 diabetes mellitus: relationship to microalbuminuria.
AIMS: Thirty adolescent patients with Type 1 diabetes mellitus and microalbuminuria were studied for evidence of early autonomic neuropathy. METHODS: Using tests involving cardiovascular and pupillary reflexes, the adolescents were compared with a normoalbuminuric group of patients with diabetes, who were matched for age, sex, puberty and duration of diabetes. RESULTS: There was an increased prevalence of autonomic nerve dysfunction in the patients with microalbuminuria. These patients had higher resting heart rates (86 beats/min in the microalbuminuric group vs. 77 beats/min in normoalbuminuric controls, P = 0.002), and impaired pupillary dilatation in darkness (pupillary diameter % 56.5% vs. 62.5%, P = 0.003). Patients with microalbuminuria also had poorer long term glycaemic control (mean HbA1C 8.7% vs. 7.8%, P = 0.002) and higher blood pressures (systolic 125 vs. 116 mmHg, P = 0.001; diastolic 69 vs. 62 mmHg, P = 0.0001; mean arterial pressure 90 vs. 83 mmHg, P = 0.002) than those with normal urinary albumin excretion. CONCLUSIONS: Microalbuminuria and autonomic nerve dysfunction co-exist in patients with Type 1 DM. Longitudinal studies will determine whether these findings have implications for the identification of patients at higher risk of progression of early renal complications.
Adolescent↗
Crystallization and preliminary X-ray crystallographic analysis of a periplasmic tetrahaem flavocytochrome c3 from Shewanella frigidimarina NCIMB400 which has fumarate reductase activity.
The fumarate reductase of Escherichia coli and other bacteria is a membrane-bound enzyme consisting of four subunits. A soluble periplasmic 64 kDa tetrahaem flavocytochrome c3 from Shewanella frigidimarina NCIMB400 which possesses a catalytic fumarate reductase activity has been crystallized. The crystals belong to space group P212121 with unit-cell parameters a = 72.4, b = 110.1, c = 230.2 A. Assuming a molecular dimer in the asymmetric unit, the crystals contain 65% solvent and, when cryocooled to 100 K, the crystals diffract to at least 3.0 A resolution. The crystals, however, display an inherent lack of isomorphism and the plausibility of a MAD phasing experiment has therefore been investigated by measuring the iron K absorption edge from a single crystal.
Crystallization↗
NMR detection of slow conformational dynamics in an endonuclease toxin.
The cytotoxic activity of the secreted bacterial toxin colicin E9 is due to a non-specific DNase housed in the C-terminus of the protein. Double-resonance and triple-resonance NMR studies of the 134-amino acid 15N- and 13C/15N-labelled DNase domain are presented. Extensive conformational heterogeneity was evident from the presence of far more resonances than expected based on the amino acid sequence of the DNase, and from the appearance of chemical exchange cross-peaks in TOCSY and NOESY spectra. EXSY spectra were recorded to confirm that slow chemical exchange was occurring. Unambiguous sequence-specific resonance assignments are presented for one region of the protein, Pro65-Asn72, which exists in two slowly exchanging conformers based on the identification of chemical exchange cross-peaks in 3D 1H-1H-15N EXSY-HSQC, NOESY-HSQC and TOCSY-HSQC spectra, together with C alpha and C beta chemical shifts measured in triple-resonance spectra and sequential NH NOEs. The rates of conformational exchange for backbone amide resonances in this stretch of amino acids, and for the indole NH of either Trp22 or Trp58, were determined from the intensity variation of the appropriate diagonal and chemical exchange cross-peaks recorded in 3D 1H-1H-15N NOESY-HSQC spectra. The data fitted a model in which this region of the DNase has two conformers, NA and NB, which interchange at 15 degrees C with a forward rate constant of 1.61 +/- 0.5 s-1 and a backward rate constant of 1.05 +/- 0.5 s-1. Demonstration of this conformational equilibrium has led to a reappraisal of a previously proposed kinetic scheme describing the interaction of E9 DNase with immunity proteins [Wallis et al. (1995) Biochemistry, 34, 13743-13750 and 13751-13759]. The revised scheme is consistent with the specific inhibitor protein for the E9 DNase, Im9, associating with both the NA and NB conformers of the DNase and with binding only to the NB conformer detected because the rate of dissociation of the complex of Im9 and the NA conformer, NAI. is extremely rapid. In this model stoichiometric amounts of Im9 convert, the E9 DNase is converted wholly into the NBI form. The possibility that cis-trans isomerisation of peptide bonds preceding proline residues is the cause of the conformational heterogeneity is discussed. E9 DNase contains 10 prolines, with two bracketing the stretch of amino acids that have allowed the NA [symbol: see text] NB interconversion to be identified, Pro65 and Pro73. The model assumes that one or both of these can exist in either the cis or trans form with strong Im9 binding possible to only one form.
Amino Acid Sequence↗
The diversity of redox proteins involved in bacterial heterotrophic nitrification and aerobic denitrification.
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Aerobiosis↗
Prevention and control of enterohaemorrhagic Escherichia coli (EHEC) infections: memorandum from a WHO meeting. WHO Consultation on Prevention and Control of Enterohaemorrhagic Escherichia coli (EHEC) Infections.
Escherichia coli is a commonly occurring inhabitant of the intestine of humans and other animals, but there are several pathogenic types of E. coli which cause a variety of human diseases. One of these pathogenic types, E. coli O157:H7, belongs to the group of enterohaemorrhagic E. coli (EHEC) which produce potent toxins and cause a particularly severe form of disease, haemorrhagic colitis (HC). About 10% of patients with HC can go on to develop haemolytic uraemic syndrome (HUS), a life-threatening complication of E. coli O157:H7 infection that is characterized by acute renal failure, haemolytic anaemia, and thrombocytopenia. These sequelae are particularly serious in young children and older people. On average, 2-7% of patients with HUS die, but in some outbreaks among the elderly the mortality rate has been as high as 50%. This Memorandum reviews the growing importance of E. coli O157:H7 as a foodborne pathogen and reports on the issues of surveillance, outbreak investigation, and control strategies with respect to EHEC infections that were discussed at the WHO Consultation on Prevention and Control of EHEC Infections, held in Geneva on 28 April to 1 May 1997. Recommended measures for prevention and control include the following: use of potable water in food production; presentation of clean animals at slaughter; improved hygiene throughout the slaughter process; appropriate use of food processing measures; thorough cooking of foods; and the education of food handlers, abattoir workers, and farm workers on the principles and application of food hygiene.
Child↗
Effects of AMPA and D1 receptor activation on striatal and nigral GABA efflux.
The ability of locally-administered AMPA and D1 receptor ligands to modulate in vivo striatal and nigral GABA efflux was determined in awake, intact male rats using a dual-probe microdialysis technique. Intrastriatal perfusion of AMPA (100 microM) produced a 50-100% increase in striatal GABA efflux that was totally blocked by co-perfusion with TTX (10.0 microM). This AMPA-stimulated, TTX-sensitive GABA efflux was similar across repeated dialsysis perfusions. The effects of intrastriatal perfusion of the full D1-like agonist SKF 81297 were complex. Perfusion of the higher dose (100 microM) of SKF 81297 enhanced GABA efflux, whereas perfusion of the lower dose (10 microM) decreased GABA efflux. Both of these effects were blocked by co-perfusion with the D1-like antagonist SCH 23390 (10 microM). Intrastriatal perfusion of AMPA (100 microM), SKF 81297 (100 microM), or AMPA + SKF 81297 did not stimulate GABA efflux in the substantia nigra. These bidirectional effects of D1 agonists and the apparent dissociation, under certain conditions, between striatal and nigral GABA efflux highlight the complexities of DA- and Glu-modulated striatonigral activity in situ.
Animals↗
Aging, physical activity, insulin-like growth factor I, and body composition in Guatemalan women.
Aging is associated with diminished secretion of growth hormone and the major endogenous mediator of growth hormone action, insulin-like growth factor I (IGF-I). Aging is also associated with decreased physical activity. Alterations in body composition characteristic of the aging process (increased fat mass and decreased lean body mass) may be related to the decline in anabolic effects of IGF-I with aging, decreased physical activity, or both. Guatemalan women often maintain a high level of physical activity during aging. The purpose of this study was to determine whether IGF-I concentrations correlated with physical activity level (determined by standardized scoring of a self-report questionnaire) and body composition (determined by bioelectrical impedance analysis) in elderly Guatemalan women. In 112 women aged 20-87 y, we found a progressively lower serum IGF-I with age (r = -0.732). In subjects > 60 y of age, the self-reported activity level was associated with a lower percentage body fat (P < 0.001) but there was no significant relation between physical activity level and either lean body mass or IGF-I. We conclude that there is a significant age-related decline in serum IGF-I concentrations in Guatemalan women, similar to that observed in both men and women in the United States. An increased level of physical activity in the elderly Guatemalan population was associated with reduced body fat but did not modify the expected reduction in circulating IGF-I concentrations that occurs with aging.
Adult↗
Three-dimensional solution structure and 13C nuclear magnetic resonance assignments of the colicin E9 immunity protein Im9.
The 86-amino acid colicin E9 immunity protein (Im9), which inhibits the DNase activity of colicin E9, has been overexpressed in Escherichia coli and isotopically enriched with 15N and 13C. Using the 3D CBCANH and CBCA(CO)NH experiments, we have almost completely assigned the backbone 13C resonances and extended previously reported 15N/1H backbone assignments [Osborne et al. (1994), Biochemistry 33, 12347-12355]. Side chain assignments for almost all residues were made using the 3D 13C HCCH-TOCSY experiment allied to previous 1H assignments. Sixty solution structures of Im9 were determined using the DIANA program on the basis of 1210 distance restraints and 56 dihedral angle restraints. The 30 lowest-energy structures were then subjected to a slow-cooling simulated annealing protocol using XPLOR and the 21 lowest-energy structures, satisfying the geometric restraints chosen for further analysis. The Im9 structure is well-defined except for the termini and two solvent-exposed loops between residues 28-32 and 57-64. The average RMSD about the average structure of residues 4-84 was 0.94 A for all heavy atoms and 0.53 A for backbone C alpha, C = O, and N atoms. The Im9 fold is novel and can be considered a distorted antiparallel four-helix bundle, in which the third helix is rather short, being terminated close to its N-terminal end by a proline at its C-terminus. The structure fits in well with available kinetic and biochemical data concerning the interaction between Im9 and its target DNase. Important residues of Im9 that govern specificity are located on the molecular surface in a region rich in negatively charged groups, consistent with the proposed electrostatically steered association [Wallis et al. (1995a), Biochemistry 34, 13743-13750].
Bacterial Proteins↗
Four of eleven loci required for transient complementation of human cytomegalovirus DNA replication cooperate to activate expression of replication genes.
As previously shown, 11 loci are required to complement human cytomegalovirus (HCMV) DNA replication in a transient-transfection assay (G. S. Pari and D. G. Anders, J. Virol. 67:6979-6988, 1993). Six of these loci encode known or candidate replication fork proteins, as judged by sequence and biochemical similarities to herpes simplex virus homologs of known function; three encode known immediate early regulatory proteins (UL36-38, IRS1/TRS1, and the major immediate early region spanning UL122-123); and two encode early, nucleus-localized proteins of unknown functions (UL84 and UL112-113). We speculated that proteins of the latter five loci might cooperate to promote and regulate expression of the six replication fork proteins. To test this hypothesis we made luciferase reporter plasmids for each of the replication fork gene promoters and measured their activation by the candidate effectors, expressed under the control of their respective native promoters, using a transient-cooperativity assay in which the candidate effectors were subtracted individually from a transfection mixture containing all five loci. The combination of UL36-38, UL112-113, IRS1, or TRS1 and the major immediate early region produced as much as 100-fold-higher expression than the major immediate early region alone; omitting any one of these four loci from complementing mixtures produced a significant reduction in expression. In contrast, omitting UL84 had insignificant (less than twofold), promoter-dependent effects on reporter activity, and these data do not implicate UL84 in regulating HCMV early-gene expression. Most of the effector interactions showed significant positive cooperativity, producing synergistic enhancement of expression. Similar responses to these effectors were observed for the each of the promoters controlling expression of replication fork proteins. However, subtracting UL112-113 had little if any effect on expression by the UL112-113 promoter or by the simian virus 40 promoter-enhancer under the same conditions. Several lines of evidence argue that the cooperative interactions observed in our transient-transfection assays are important to viral replication in permissive cells. Therefore, the data suggest a model in which coordinate expression of multiple essential replication proteins during permissive infection is vitally dependent upon the cooperative regulatory interactions of proteins encoded by multiple loci and thus have broad implications for our understanding of HCMV biology.
Base Sequence↗
Healthy Marketplaces.
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Conservation of Natural Resources↗
The napEDABC gene cluster encoding the periplasmic nitrate reductase system of Thiosphaera pantotropha.
The napEDABC locus coding for the periplasmic nitrate reductase of Thiosphaera pantotropha has been cloned and sequenced. The large and small subunits of the enzyme are coded by napA and napB. The sequence of NapA indicates that this protein binds the GMP-conjugated form of the molybdopterin cofactor. Cysteine-181 is proposed to ligate the molybdenum atom. It is inferred that the active site of the periplasmic nitrate reductase is structurally related to those of the molybdenum-dependent formate dehydrogenases and bacterial assimilatory nitrate reductases, but is distinct from that of the membrane-bound respiratory nitrate reductases. A four-cysteine motif at the N-terminus of NapA binds a [4Fe-4S] cluster. The DNA- and protein-derived primary sequence of NapB confirm that this protein is a dihaem c-type cytochrome and, together with spectroscopic data, indicate that both NapB haems have bis-histidine ligation. napC is predicted to code for a membrane-anchored tetrahaem c-type cytochrome that shows sequence similarity to the NirT cytochrome c family. NapC may be the direct electron donor to the NapAB complex. napD is predicted to encode a soluble cytoplasmic protein and napE a monotopic integral membrane protein, napDABC genes can be discerned at the aeg-46.5 locus of Escherichia coli K-12, suggesting that this operon encodes a periplasmic nitrate reductase system, while napD and napC are identified adjacent to the napAB genes of Alcaligenes eutrophus H16.
Amino Acid Sequence↗