The basis of the alloimmune response.
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Animals↗
Biomedical subjects
J Barrett
Publications and source records attributed to J Barrett.
Characterising doctor-parent communication in counselling for impending preterm delivery.
OBJECTIVE: To examine the counselling of women admitted to hospital in preterm labour. Such women and their partners are often asked to participate in difficult decisions including mode of delivery, fetal monitoring, and resuscitation. STUDY DESIGN: Questionnaire based descriptive study. STUDY SETTING: A tertiary level perinatal referral centre. PATIENTS: Forty-nine women in preterm labour at 22-30 weeks gestation, admitted in two separate periods between March 1997 and May 1999. INTERVENTION AND OUTCOME MEASURE: Within 24 hours of counselling, parents were asked to complete a questionnaire assessing recall of the management plan, desire for involvement in decision making, anxiety, and feelings of control over their health. A parallel questionnaire was completed by the clinicians. RESULTS: Parents and clinicians on recall agreed well about obstetric issues but poorly about neonatal issues. Overall 27% of parents felt: "I would prefer to have the doctors advise me, rather than asking me to decide". In 79% of cases, clinicians believed parents preferred advice rather than to make decisions, but in 45% of these, they misidentified those who wished to make their decisions. Anxiety levels for one third of the mothers were high, and associated with poorer concordance of recall between parents and clinicians. CONCLUSIONS: Serious deficiencies exist in parent-clinician encounters during extremely preterm labour. Concordance between parents and clinicians is poor and anxiety very high. A quarter of parents appear to prefer to relinquish decision making autonomy, but clinicians cannot correctly identify this subgroup. Standardised counselling in the perinatal period, using formal decision aids, should be investigated.
Communication↗
Across the interface: the hastings heart function clinic.
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Aged↗
A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4.
Substantial evidence supports the familial aggregation of exceptional longevity. The existence of rare families demonstrating clustering for this phenotype suggests that a genetic etiology may be an important component. Previous attempts at localizing loci predisposing for exceptional longevity have been limited to association studies of candidate gene polymorphisms. In this study, a genome-wide scan for such predisposing loci was conducted by using 308 individuals belonging to 137 sibships demonstrating exceptional longevity. By using nonparametric analysis, significant evidence for linkage was noted for chromosome 4 at D4S1564 with a MLS of 3.65 (P = 0.044). The analysis was corroborated by a parametric analysis (P = 0.052). These linkage results indicate the likelihood that there exists a gene, or genes, that exerts a substantial influence on the ability to achieve exceptional old age. Identification of the genes in humans that allow certain individuals to live to extreme old age should lead to insights on cellular pathways that are important to the aging process.
Aged↗
Isolation and expansion of cytomegalovirus-specific cytotoxic T lymphocytes to clinical scale from a single blood draw using dendritic cells and HLA-tetramers.
Cytomegalovirus (CMV) reactivation in immunocompromised recipients of allogeneic stem cell transplantation is a cause of morbidity and mortality from viral pneumonitis. Antiviral drugs given to reactivating patients have reduced the mortality from CMV but have toxic side effects and do not always prevent late CMV disease. Cellular immunotherapy to prevent CMV disease is less toxic and could provide prolonged protection. However, a practical approach to generating sufficient quantities of CMV-specific cytotoxic T cells (CTLs) is required. This study describes a system for generating sufficient CMV-specific CTLs for adoptive immunotherapy of HLA-A*0201 bone marrow transplant recipients from 200 mL donor blood. Donor monocytes are used to generate dendritic cells (DCs) in medium with autologous plasma, interleukin 4, granulocyte-macrophage colony-stimulating factor, and CD40 ligand. The DCs are pulsed with the immunodominant HLA-A*0201-restricted CMV peptide pp65(495-503), and incubated with donor T cells. These cultures are restimulated twice with peptide-pulsed lymphoblastoid cell lines (LCLs) or CD40-ligated B cells and purified with phycoerythrin (PE)-labeled pp65(495-503)/HLA-A*0201 tetramers by flow sorting, or with anti-PE paramagnetic beads. The pure tetramer-positive population is then rapidly expanded to obtain sufficient cells for clinical immunotherapy. The expanded CTLs are more than 80% pure, of memory phenotype, with a Tc1 cytokine profile. They efficiently kill CMV-infected fibroblasts and express the integrin VLA-4, suggesting that the CTLs could cross endothelial barriers. This technique is reproducible and could be used for generating CMV-specific CTLs to prevent CMV disease after allogeneic blood and marrow transplantation. (Blood. 2001;98:505-512)
Antigen-Presenting Cells↗
Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus.
Dopamine is implicated in movement, learning, and motivation, and in illnesses such as Parkinson's disease, schizophrenia, and drug addiction. Little is known about the control of dopamine release in humans, but research in experimental animals suggests that the prefrontal cortex plays an important role in regulating the release of dopamine in subcortical structures. Here we used [(11)C]raclopride and positron emission tomography to measure changes in extracellular dopamine concentration in vivo after repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in healthy human subjects. Repetitive TMS of the left dorsolateral prefrontal cortex caused a reduction in [(11)C]raclopride binding in the left dorsal caudate nucleus compared with rTMS of the left occipital cortex. There were no changes in binding in the putamen, nucleus accumbens, or right caudate. This shows that rTMS of the prefrontal cortex induces the release of endogenous dopamine in the ipsilateral caudate nucleus. This finding has implications for the therapeutic and research use of rTMS in neurological and psychiatric disorders.
Adult↗
Lower-than-expected linkage disequilibrium between tightly linked markers in humans suggests a role for gene conversion.
Understanding the pattern of linkage disequilibrium (LD) in the human genome is important both for successful implementation of disease-gene mapping approaches and for inferences about human demographic histories. Previous studies have examined LD between loci within single genes or confined genomic regions, which may not be representative of the genome; between loci separated by large distances, where little LD is seen; or in population groups that differ from one study to the next. We measured LD in a large set of locus pairs distributed throughout the genome, with loci within each pair separated by short distances (average 124 bp). Given current models of the history of the human population, nearly all pairs of loci at such short distances would be expected to show complete LD as a consequence of lack of recombination in the short interval. Contrary to this expectation, a significant fraction of pairs showed incomplete LD. A standard model of recombination applied to these data leads to an estimate of effective human population size of 110,000. This estimate is an order of magnitude higher than most estimates based on nucleotide diversity. The most likely explanation of this discrepancy is that gene conversion increases the apparent rate of recombination between nearby loci.
Computer Simulation↗
Glycosaminoglycan binding properties of the myxoma virus CC-chemokine inhibitor, M-T1.
Poxviruses encode a number of secreted virulence factors that function to mitigate or modulate the host immune response. M-T1 is a secreted 43-kDa glycoprotein produced by the myxoma virus, a poxvirus pathogen of rabbits, that binds CC-chemokines with high affinity, blocks binding to their cognate G-protein coupled receptors, and thereby inhibits chemokine-induced leukocyte chemotaxis. The present study indicates that M-T1, but not the related vaccinia virus 35-kDa CC-chemokine-binding protein, can localize to cell surfaces through an interaction with glycosaminoglycan molecules. In addition to biochemically characterizing the nature of this interaction, we demonstrate that M-T1 can also simultaneously interact with CC-chemokines while bound to heparin, suggesting that the binding sites on M-T1 for chemokines and heparin are distinct. Furthermore, using recombinant baculovirus-expressed M-T1 truncation and internal deletion mutants, we localize the heparin-binding region of M-T1 to the C terminus of the protein, a region that contains a high abundance of basic residues and includes two clusters of basic amino acid residues that resemble Cardin and Weintraub heparin-binding consensus sequences. The ability of M-T1 to simultaneously interact with chemokines and glycosaminoglycans may enable M-T1 to tether to endothelial surfaces or extracellular matrix and capture host chemokines that are expressed close to sites of virus infection.
Amino Acid Sequence↗
Biochemical characterisation of a hydrophobic ligand binding protein from the tapeworm Hymenolepis diminuta.
The cestode Hymenolepis diminuta contains an abundant, cytoplasmic, hydrophobic ligand, binding protein (H-HLBP). Studies with polarity sensitive probes suggest a single hydrophobic binding site, the results also indicate that the single tryptophan in the molecule (Trp41) is involved in ligand binding. Of the possible physiological ligands tested, only haematin and retinoids (retinol and retinoic acid) show appreciable binding in addition to fatty acids. H-HLBP also binds a range of anthelmintics, again with K(D) values in the nM range. The interaction of anthelmintics with hydrophobic binding proteins may be important in determining drug specificity and site of action and could have a role in the development of drug resistance.
Animals↗
Laboratory evaluation of the molluscicidal properties of some Saudi Arabian euphorbiales against Biomphalaria pfeifferi.
Laboratory studies were conducted to evaluate the molluscicidal properties of three Saudi Arabian Euphorbiales. The results showed that the methanol extract of Euphorbia schimperiana has a high molluscicidal potency. The activity remains stable over a wide range of temperature and pH values, in the presence of organic and inorganic substrates and after exposure of the solutions to ultraviolet radiation.
Aluminum Silicates↗
Proteomic analysis of Fasciola hepatica excretory-secretory products.
This paper describes a global investigation of the components of Fasciola hepatica excretory-secretory (ES) products by a proteomic approach. Despite the absence of a F. hepatica genome sequencing project we have shown that it was possible to identify 29 of the 60 prominent proteins found using two-dimensional gel electrophoresis. As well as cathepsin L proteases, a number of enzymes implicated in parasite protection from the host immune system were also found to be present in relatively large abundance. These included superoxide dismutase, thioredoxin peroxidase, glutathione S-transferases and fatty acid binding proteins, all of which may play a part in the detoxification of reactive oxygen intermediates. Interestingly, ovine superoxide dismutase was the only protein from the host identified on the gel. We suggest that the relative abundance and protective nature of the components of the ES products of this organism play an important role in its survival within the host. The precise identification, to individual NCBI database entries, of a number of glutathione S-transferases and cathepsin Ls from F. hepatica, by peptide mass fingerprinting, was hampered by multi-database submissions of the two protein superfamilies from this organism.
Amino Acid Sequence↗
Proteomic identification of glutathione S-transferases from the model nematode Caenorhabditis elegans.
Glutathione affinity chromatography and two-dimensional electrophoresis (2-DE) were used to purify glutathione binding proteins from Caenorhabditis elegans. All proteins identified after peptide mass fingerprinting using matrix-assisted laser desorption/ionization-time of flight were found to belong to the glutathione S-transferase (GST) superfamily. From the 26 individual spots identified, 12 different GSTs were isolated. Of these, five were found on the gel only once, whilst the remaining seven were represented by 21 separate spots. Most of the GSTs identified were of the nematode specific class, however, three Alpha class GSTs, a Pi and a Sigma class GST were also isolated.
Animals↗
Enhancing patient safety through teamwork training.
The effective reduction of medical errors depends on an environment of safety for patients in both clinically-based and systems-oriented arenas. Formal teamwork training is proposed as a systems approach that will achieve these ends. In a study conducted by Dynamics Research Corporation, weaknesses and error patterns in Emergency Department teamwork were assessed, and a prospective evaluation of a formal teamwork training intervention was conducted. Improvements were obtained in five key teamwork measures, and most importantly, clinical errors were significantly reduced.
Aviation↗
Role of amniotic fluid interphase fluorescence in situ hybridization (FISH) analysis in patient management.
We retrospectively reviewed 309 amniotic fluid interphase fluorescence in situ hybridization (FISH) analyses performed from October 1995 to June 1999 to assess the role of interphase FISH in the management of patients at increased risk for fetal aneuploidies. Gestational age and indications for amniocentesis, clinical interventions after FISH results, as well as interventions after final culture reports were analyzed. There were 244 (79%) normal, 50 (16%) abnormal and 15 (5%) inconclusive FISH results. There were no false-positive or false-negative results, but there were nine (3%) clinically significant chromosomal abnormalities not detectable by FISH. Of the 50 women with abnormal FISH results, 26 (52%) elected to terminate the pregnancy prior to the availability of the standard chromosome analysis. In two of the fetuses with trisomy 21 no abnormalities were reported by ultrasound examination. Our experience indicates that interphase FISH results played an important role in decision making, especially for pregnancies close to 24 weeks' gestation. Standard karyotype analysis is still required for detection of chromosome abnormalities not detectable by interphase FISH techniques and for clarification of unusual or inconclusive FISH results.
Amniotic Fluid↗
Determining which patients require evaluation for blunt cardiac injury following blunt chest trauma.
The objective of this study was to determine prospectively which risk factors require cardiac monitoring for blunt cardiac injury (BCI) following blunt chest trauma. All patients who sustained blunt chest trauma had an electrocardiogram (ECG) on admission to our urban level I trauma center. Those with ST segment changes, dysrhythmias, hemodynamic instability, history of cardiac disease, age > 55 years, or a need for general anesthesia within 24 hours (group 1) were admitted to the intensive care unit (ICU) for 24 hours where they were subjected to serial ECGs, creatinine phosphokinase (CPK) assays, and echocardiography (ECHO). Those with only mechanism for BCI, i.e., none of the above risk factors (group 2), were admitted to a nonmonitored bed and had a follow-up ECG 24 hours later. A series of 315 patients were admitted with blunt chest trauma during a 17-month period; 144 patients were in group 1 and 171 in group 2. Overall, 22 patients were diagnosed as BCI (+BCI), defined as evolving ST segment changes, dysrhythmias, a CPK-MB index of > 2.5, or hemodynamic instability. Of the 18 +BCI patients in group 1, all were symptomatic (i.e., none was included solely for a cardiac history, age, or need for general anesthesia). Six of these patients required treatment for dysrhythmias, hypotension, or pulmonary edema; one of whom died. Four patients with +BCI were in group 2 and had ECG changes at 24 hours; none of these four had any sequelae from their +BCI. None of the ECHOs demonstrated abnormal wall motion. Patients who sustain blunt chest trauma with a normal ECG, normal blood pressure, and no dysrhythmias on admission require no further intervention for BCI. Patients with ST segment changes, dysrhythmias, or hypotension following blunt chest trauma should be monitored for 24 hours, as this subgroup occasionally requires further treatment for complications of BCI. ECHO adds nothing as a screening test.
Adult↗
Long term modulation of the HPA axis by the hippocampus. Behavioral, biochemical and immunological endpoints in rats exposed to chronic mild stress.
Mature rats were given lesions of the hippocampus (HIPPO), subiculum (SUBIC) or fimbria-fornix (FIFO) and then received the mild chronic stressors of food deprivation and isolation housing for ten months prior to testing. Group differences in circadian activity were investigated along with locomotion elicited by amphetamine (AMP 1.0-2.0 mg/kg i.p.) alone, and following the corticosterone (CORT) synthesis inhibitor, metyrapone (MET 10.0-25.0 mg/kg i.p.). Basal levels of plasma CORT, (ng/ml), plasma glucose (GLUC, mmol/l), thymic and splenic wet weights were subsequently determined along with complete blood counts (CBC). In comparison to age matched, unoperated controls, selective SUBIC lesions altered the circadian periodicity of locomotion, while rats with FIFO lesions were spontaneously hyperactive. Both HIPPO and FIFO animals showed significantly higher levels of amphetamine-induced locomotion. In all groups metyrapone significantly enhanced locomotion elicited by amphetamine, probably due to a pharmacokinetic interaction between these drugs. In comparison to controls, animals in the HIPPO group showed significant reductions in plasma glucose levels, decreased thymic wet weights and reductions in lymphocyte numbers, indicating lesion-related immuno-suppression. These findings highlight a functional difference among the effects of these specific hippocampal lesions on neural regulation of the HPA axis, under conditions of chronic mild stress, suggesting that the modulatory influence of the hippocampus on the stress axis is dependent on the neuroanatomical location and total extent of cell loss within this structure. They further suggest that the heightened response to amphetamine occurs independently of any lesion-induced changes in modulation of the HPA axis.
Animals↗
A common class of nematode glutathione S-transferase (GST) revealed by the theoretical proteome of the model organism Caenorhabditis elegans.
The genome verified C. elegans free-living nematode model is a new tool for investigating gene expression in human and animal nematode parasites. There is limited information on designating glutathione S-transferase (GST) to specific classes in lower invertebrates such as nematodes. Following cloning, amino acid sequence alignment, recombinant expression and Western blotting we provide evidence of a new GST class in nematodes or lower invertebrates.
Amino Acid Sequence↗
Thermal hysteresis proteins.
Extreme environments present a wealth of biochemical adaptations. Thermal hysteresis proteins (THPs) have been found in vertebrates, invertebrates, plants, bacteria and fungi and are able to depress the freezing point of water (in the presence of ice crystals) in a non-colligative manner by binding to the surface of nascent ice crystals. The THPs comprise a disparate group of proteins with a variety of tertiary structures and often no common sequence similarities or structural motifs. Different THPs bind to different faces of the ice crystal, and no single mechanism has been proposed to account for THP ice binding affinity and specificity. Experimentally THPs have been used in the cryopreservation of tissues and cells and to induce cold tolerance in freeze susceptible organisms. THPs represent a remarkable example of parallel and convergent evolution with different proteins being adapted for an anti-freeze role.
Adaptation, Biological↗