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Biomedical subjects

John Thompson

Publications and source records attributed to John Thompson.

At least 19 recordsLinked to original sources
PubMed2007

HLA mismatching within or outside of cross-reactive groups (CREGs) is associated with similar outcomes after unrelated hematopoietic stem cell transplantation.

The National Marrow Donor Program maintains a registry of volunteer donors for patients in need of a hematopoietic stem cell transplantation. Strategies for selecting a partially HLA-mismatched donor vary when a full match cannot be identified. Some transplantation centers limit the selection of mismatched donors to those sharing mismatched antigens within HLA-A and HLA-B cross-reactive groups (CREGs). To assess whether an HLA mismatch within a CREG group ("minor") may result in better outcome than a mismatch outside CREG groups ("major"), we analyzed validated outcomes data from 2709 bone marrow and peripheral blood stem cell transplantations. Three-hundred and ninety-six pairs (15%) were HLA-DRB1 allele matched but had an antigen-level mismatch at HLA-A or HLA-B. Univariate and multivariate analyses of engraftment, graft-versus-host disease, and survival showed that outcome is not significantly different between minor and major mismatches (P = .47, from the log-rank test for Kaplan-Meier survival). However, HLA-A, HLA-B, and HLA-DRB1 allele-matched cases had significantly better outcome than mismatched cases (P < .001). For patients without an HLA match, the selection of a CREG-compatible donor as tested does not improve outcome.

Alleles↗
PubMed2006

Dietary patterns of New Zealand European preschool children.

AIMS: To record and describe the dietary patterns of a large group of New Zealand (NZ) European preschool children and to compare these with NZ Ministry of Health (MOH) food and nutrition guidelines. METHODS: Mothers were interviewed when children enrolled in the Auckland Birthweight Collaborative (ABC) study were seen at 3.5 years of age. Approximately half of the children in the study were born small for gestational age (SGA =10th percentile) and the remaining were born appropriate for gestational age (AGA >10th percentile). Food frequency information was collected on 549 New Zealand European children. The analysis utilised weighting to allow for the disproportionate sampling of children born SGA. RESULTS: Compared with nutritional guidelines, 27% and 54% of preschool children did not eat the recommended two or more servings of fruit per day or two or more servings of vegetables per day, respectively; 93% of children did not eat breads and cereals the recommended four or more times a day. CONCLUSION: A notable proportion of children were not eating fruit and vegetables at levels recommended by the MOH. Preschool children's food frequency patterns were, however, similar to patterns reported for school-aged children in the National Children's Nutrition Survey.

Child Nutritional Physiological Phenomena↗
PubMed2006

Genetic requirements for growth of Escherichia coli K12 on methyl-alpha-D-glucopyranoside and the five alpha-D-glucosyl-D-fructose isomers of sucrose.

Strains of Escherichia coli K12, including MG-1655, accumulate methyl-alpha-D-glucopyranoside via the phosphoenolpyruvate-dependent glucose:phosphotransferase system (IICB(Glc)/IIA(Glc)). High concentrations of intracellular methyl-alpha-D-glucopyranoside 6-phosphate are toxic, and cell growth is prevented. However, transformation of E. coli MG-1655 with a plasmid (pAP1) encoding the gene aglB from Klebsiella pneumoniae resulted in excellent growth of the transformant MG-1655 (pAP1) on the glucose analog. AglB is an unusual NAD+/Mn2+-dependent phospho-alpha-glucosidase that promotes growth of MG-1655 (pAP1) by catalyzing the in vivo hydrolysis of methyl-alpha-D-glucopyranoside 6-phosphate to yield glucose 6-phosphate and methanol. When transformed with plasmid pAP2 encoding the K. pneumoniae genes aglB and aglA (an alpha-glucoside-specific transporter AglA (IICB(Agl))), strain MG-1655 (pAP2) metabolized a variety of other alpha-linked glucosides, including maltitol, isomaltose, and the following five isomers of sucrose: trehalulose alpha(1-->1), turanose alpha(1-->3), maltulose alpha(1-->4), leucrose alpha(1-->5), and palatinose alpha(1-->6). Remarkably, MG-1655 (pAP2) failed to metabolize sucrose alpha(1-->2). The E. coli K12 strain ZSC112L (ptsG::cat manXYZ nagE glk lac) can neither grow on glucose nor transport methyl-alpha-D-glucopyranoside. However, when transformed with pTSGH11 (encoding ptsG) or pAP2, this organism provided membranes that contained either the PtsG or AglA transporters, respectively. In vitro complementation of transporter-specific membranes with purified general phosphotransferase components showed that although PtsG and AglA recognized glucose and methyl-alpha-D-glucopyranoside, only AglA accepted other alpha-D-glucosides as substrates. Complementation experiments also revealed that IIA(Glc) was required for functional activity of both PtsG and AglA transporters. We conclude that AglA, AglB, and IIA(Glc) are necessary and sufficient for growth of E. coli K12 on methyl-alpha-D-glucoside and related alpha-D-glucopyranosides.

Amino Acid Sequence↗
PubMed2006

Safe restraint of the child passenger.

AIM: The aim of this study was to understand the need for, and use of, booster seats in the 4-12 years age group and to identify risk factors for booster seat-non-use. METHOD: A cross-sectional sample of 1101 children aged 4-12 years travelling in 663 privately owned vehicles was taken from the Auckland region. Auckland is New Zealand's largest population centre, with a population of over 1.5 million. Information was gathered using a short questionnaire followed by direct inspection to identify those children using booster seats. The SafetyBeltSafe USA '5-step rule' was used to look at those children not using a booster seat to determine whether one was still required. RESULTS: While booster seat use has improved significantly in younger children since a similar study in 1992, only 40% of sampled children requiring a booster seat were using one. Booster seat use by children requiring them declined sharply as age increased. While 93% of 5- to 8-year-olds required a booster, only 30% were using one. The requirement for booster seats fell dramatically to 34% of 9- to 12-year-olds, but only 3% were using one. CONCLUSION: The high rate of need for booster seats and the lack of use of booster seats in children aged 5-8 years is a strong argument for legislation and education programmes targeting this age group. While the proportion of 9- to 12-year-olds needing a booster drops sharply, there would likely be benefits from educating parents on the '5-step rule' or similar method to help identify the 30% of these older children that would continue to benefit from a booster seat. Rear seating should be promoted alongside booster seat use in the age group 4-12 years.

Automobile Driving↗
PubMed2005

Which progestogen is more likely to increase the risk of fatal myocardial infarction: a combination of epidemiological and trial evidence.

OBJECTIVES: To evaluate the impact of metabolic effects of different progestogens on the risk of fatal myocardial infarction is evaluated. METHODS: The changes in (apo)lipoproteins obtained from a randomized trial of three hormone therapy regimens were applied to three models for predicting fatal myocardial infarction derived from the apolipoprotein-related mortality risk (AMORIS) study. In our trial, 487 postmenopausal women were randomized to oral estradiol, with sequential addition of two trimegestone (TMG) doses or norethisterone acetate (NETA), and studied at baseline and after 3, 6, and 12 months. RESULTS: The change from baseline in risk of fatal myocardial infarction, using AMORIS model 3, containing total cholesterol, triglycerides, and apolipoprotein AI, was a 10% reduction for the two TMG doses; NETA had no apparent impact. The differences between treatments were significant at all three time points. When apoB was added in AMORIS model 4, the difference between treatments (5% reduction in the two doses of TMG, compared to NETA) decreased over time, probably due to the effect of dropouts in the NETA group. CONCLUSIONS: This analysis shows different metabolic responses to progestogens in terms of risk of fatal myocardial infarction. Generalization of health benefits or adverse effects seen in trials of hormone therapy to other progestogens could be misleading.

Aged↗
PubMed2005

Systematic review and meta-analysis of the association between {beta}2-adrenoceptor polymorphisms and asthma: a HuGE review.

A number of studies have investigated two common polymorphisms in the beta(2)-adrenoceptor gene, Arg/Gly16 and Gln/Glu27, in relation to asthma susceptibility. The authors performed a meta-analysis of each polymorphism, as well as haplotype analysis, for adult and pediatric populations separately, using published data, supplemented by additional data requested from the original authors. Individual analysis detected no effect of Arg/Gly16 in adults but did suggest a recessive protective effect of Gly16 for children, with an odds ratio of 0.71 (95% confidence interval (CI): 0.53, 0.96) compared with the other genotypes. Results for Gln/Glu27 in adults seem to indicate that heterozygotes are at decreased risk of asthma than either homozygote (odds ratio = 0.73, 95% CI: 0.62, 0.87), although the studies are heterogeneous; in children, the Glu/Glu genotype has a decreased risk of asthma (odds ratio = 0.60, 95% CI: 0.35, 0.99) compared with the other genotypes. Despite the proximity of these two polymorphic sites, the linkage disequilibrium coefficient of 0.41 was not high (p < 0.001). Haplotype analysis suggests that there may be an interaction between the two sites, with a lower risk of asthma associated with the Glu27 allele (compared with Gln27), and that this risk is modified by the allele at position 16.

Alleles↗
PubMed2005

NAD+ and metal-ion dependent hydrolysis by family 4 glycosidases: structural insight into specificity for phospho-beta-D-glucosides.

The import of disaccharides by many bacteria is achieved through their simultaneous translocation and phosphorylation by the phosphoenolpyruvate-dependent phosphotransferase system (PEP-PTS). The imported phospho-disaccharides are, in some cases, subsequently hydrolyzed by members of the unusual glycoside hydrolase family GH4. The GH4 enzymes, occasionally found also in bacteria such as Thermotoga maritima that do not utilise a PEP-PTS system, require both NAD(+) and Mn(2+) for catalysis. A further curiosity of this family is that closely related enzymes may show specificity for either alpha-d- or beta-d-glycosides. Here, we present, for the first time, the three-dimensional structure (using single-wavelength anomalous dispersion methods, harnessing extensive non-crystallographic symmetry) of the 6-phospho-beta-glycosidase, BglT, from T.maritima in native and complexed (NAD(+) and Glc6P) forms. Comparison of the active-center structure with that of the 6-phospho-alpha-glucosidase GlvA from Bacillus subtilis reveals a striking degree of structural similarity that, in light of previous kinetic isotope effect data, allows the postulation of a common reaction mechanism for both alpha and beta-glycosidases. Given that the "chemistry" occurs primarily on the glycone sugar and features no nucleophilic attack on the intact disaccharide substrate, modulation of anomeric specificity for alpha and beta-linkages is accommodated through comparatively minor structural changes.

Bacterial Proteins↗
PubMed2005

Intestinal transplantation in children: a summary of clinical outcomes and prognostic factors in 108 patients from a single center.

We performed 124 intestinal transplants on 108 children (median age, 1.5 years) since 1994. Initial graft types included isolated intestine (I) (n=26), liver and intestine (LI) (n=26), multivisceral (MV) (n=50), and multivisceral without liver (MMV) (n=6). Four groups were defined by type of induction therapy: none, OKT3, or cyclophosphamide (August 1994-December 1997, n=25), early experience with daclizumab (January 1998-December 2000, n=26), recent experience with daclizumab (January 2001-April 2004, n=40), and Campath-1H (January 2001-April 2004, n=17). Actuarial patient survival at 1 year for groups 1-4 was 44%+/-10%, 54%+/-10%, 83%+/-6%, and 41%+/-12%, respectively, with group 3 having the most favorable survival (P=0.0004). Using Cox stepwise regression, the hazard rate of developing severe rejection was significantly higher in patients with transplant type I or LI (P=0.0002), with no difference between these groups (P=0.24) but a significantly higher rate for LI versus MV (P=0.005). Three factors associated with improved patient survival were recipient of MV or MMV (P=0.008), age at transplantation greater than 1 year (P=0.01), and use of daclizumab (P=0.0006). Cause-specific hazard analysis revealed a decreased rate of rejection-related mortality for recipients of MV or MMV (P=0.0007), whereas age greater than 1 year indicated a lower rate of infection-related mortality (P=0.0009). Pediatric intestinal transplantation provides an increasingly realistic chance of survival, particularly with the more recent use of daclizumab and multivisceral transplantation. A protective effect of multivisceral transplantation appears to exist with respect to the development of severe rejection.

Antibodies, Monoclonal↗
PubMed2005

Intratracheal pulmonary ventilation improves gas exchange during laparoscopy in a pediatric lung injury model.

BACKGROUND/PURPOSE: This study was aimed at determining whether intraoperative intratracheal pulmonary ventilation (ITPV) could prevent/treat respiratory complications of laparoscopy in a model of pediatric pulmonary insufficiency. METHODS: Severe lung injury was induced in 0- to 2-month-old lambs (n = 5) by endotracheal saline lavage. Animals then underwent establishment of CO2 pneumoperitoneum. Intraperitoneal pressures were progressively raised from 0 to 15 mm Hg, at intervals of 5 mm Hg. At each interval, blood gas and hemodynamic data were recorded, 20 minutes after initiation of both conventional ventilation and pure ITPV. All ventilatory parameters were constant and identical on both modes of ventilation. RESULTS: On conventional ventilation, severe respiratory acidosis and hypoxemia ensued at intraperitoneal pressures of 5 mm Hg and 10 mm Hg or more, respectively. Compared with conventional ventilation, ITPV led to statistically significant decreases in PCO2 at intraperitoneal pressures of 5 mm Hg (43.2 +/- 5.2 vs 56.1 +/- 6.6 mm Hg) and 10 mm Hg (45.1 +/- 3.2 vs 61 +/- 6.3 mm Hg) and to significant increases in PO2 at 10 mm Hg (92 +/- 10.2 vs 61 +/- 8.1 mm Hg), resolving the acidosis and hypoxemia at those pressure levels. CONCLUSIONS: Compared with conventional ventilation, ITPV improves both CO2 removal and oxygenation during CO2 pneumoperitoneum in a pediatric lung injury model. Intratracheal pulmonary ventilation may be a safer intraoperative mode of ventilation for neonates and children with respiratory failure who require laparoscopy.

Acidosis, Respiratory↗
PubMed2005

100 multivisceral transplants at a single center.

OBJECTIVE: The objective of this study was to summarize the evolution of multivisceral transplantation over a decade of experience and evaluate its current status. SUMMARY BACKGROUND DATA: Multivisceral transplantation can be valuable for the treatment of patients with massive abdominal catastrophes. Its major limitations have been technical and rejection of the intestinal graft. METHODS: This study consisted of an outcome analysis of 98 consecutive patients who received multivisceral transplantation at our institution. This represents the largest single center experience to date. RESULTS: The most common diseases in our population before transplant were intestinal gastroschisis and intestinal dysmotility syndromes in children, and mesenteric thrombosis and trauma in adults. Kaplan Meier estimated patient and graft survivals for all cases were 65% and 63% at 1 year, 49% and 47% at 3 years, and 49% and 47% at 5 years. Factors that adversely influenced patient survival included transplant before 1998 (P = 0.01), being hospitalized at the time of transplant (P = 0.05), and being a child who received Campath-1H induction (P = 0.03). Among 37 patients who had none of these 3 factors (15 adults and 22 children), estimated 1- and 3-year survivals were 89% and 71%, respectively. Patients transplanted since 2001 had significantly less moderate and severe rejections (31.6% vs 67.6%, P = 0.0005) with almost half of these patients never developing rejection. CONCLUSIONS: Multivisceral transplantation is now an effective treatment of patients with complex abdominal pathology. The incidences of serious acute rejection and patient survival have improved in the most recent experience. Our results show that the multivisceral graft seems to facilitate engraftment of transplanted organs and raises the possibility that there is a degree of immunologic protection afforded by this procedure.

Adolescent↗
PubMed2005

Pharmacogenomics: integration into drug discovery and development.

To deliver on the promise of personalized medicine requires the integration of pharmacogenomics into the discovery and development of medicines. Over the last few years the pharmaceutical industry has been building considerable resources to achieve that. However, this requires new skill sets, capabilities and infrastructures which have not been a traditional part of the industry's efforts. In this article we describe how the integration of genetics and pharmacogenomics data has begun to deliver success and illustrate the challenges that the new science and technologies bring and how these challenges can be addressed in order to deliver on the promise.

Drug Design↗
PubMed2004

Targeted alpha therapy for cancer.

Targeted alpha therapy (TAT) offers the potential to inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The practicality and efficacy of TAT is tested by in vitro and in vivo studies in melanoma, leukaemia, colorectal, breast and prostate cancers, and by a phase 1 trial of intralesional TAT for melanoma. The alpha-emitting radioisotope used is Bi-213, which is eluted from the Ac-225 generator and chelated to a cancer specific monoclonal antibody (mab) or protein (e.g. plasminogen activator inhibitor-2 PAI2) to form the alpha-conjugate (AC). Stable alpha-ACs have been produced which have been tested for specificity and cytotoxicity in vitro against melanoma (9.2.27 mab), leukaemia (WM60), colorectal (C30.6), breast (PAI2, herceptin), ovarian (PAI2, herceptin, C595), prostate (PAI2, J591) and pancreatic (PAI2, C595) cancers. Subcutaneous inoculation of 1-1.5 million human cancer cells into the flanks of nude mice causes tumours to grow in all mice. Tumour growth is compared for untreated controls, nonspecific AC and specific AC, for local (subcutaneous) and systemic (tail vein or intraperitoneal) injection models. The 213Bi-9.2.27 AC is injected into secondary skin melanomas in stage 4 patients in a dose escalation study to determine the effective tolerance dose, and to measure kinematics to obtain the equivalent dose to organs. In vitro studies show that TAT is one to two orders of magnitude more cytotoxic to targeted cells than non-specific ACs, specific beta emitting conjugates or free isotopes. In vivo local TAT at 2 days post-inoculation completely prevents tumour formation for all cancers tested so far. Intra-lesional TAT can completely regress advanced sc melanoma but is less successful for breast and prostate cancers. Systemic TAT inhibits the growth of sc melanoma xenografts and gives almost complete control of breast and prostate cancer tumour growth. Intralesional doses up to 450 microCi in human patients are effective in regressing melanomas, with no concomitant complications. These results point to the application of local and systemic TAT in the management of secondary cancer. Results of the phase 1 clinical trial of TAT of subcutaneous, secondary melanoma indicate proof of the principle that TAT can make tumours in patients regress.

Alpha Particles↗
PubMed2004

Do co-occurring plant species adapt to one another? The response of Bromus erectus to the presence of different Thymus vulgaris chemotypes.

Local modification of the soil environment by individual plants may affect the performance and composition of associated plant species. The aromatic plant Thymus vulgaris has the potential to modify the soil through leaching of water-soluble compounds from leaves and litter decomposition. In southern France, six different thyme chemotypes can be distinguished based on the dominant monoterpene in the essential oil, which is either phenolic or non-phenolic in structure. We examine how soils from within and away from thyme patches in sites dominated by either phenolic or non-phenolic chemotypes affect germination, growth and reproduction of the associated grass species Bromus erectus. To do so, we collected seeds of B. erectus from three phenolic and three non-phenolic sites. Seeds and seedlings were grown on soils from these sites in a reciprocal transplant type experiment in the glasshouse. Brome of non-phenolic origin performed significantly better on its home soil than on soil from a different non-phenolic or a phenolic site. This response to local chemotypes was only observed on soil collected directly underneath thyme plants and not on soil in the same site (<5 m away) but where no thyme plants were present. This is preliminary evidence that brome plants show an adaptive response to soil modifications mediated by the local thyme chemotypes. Reproductive effort was consistently higher in brome of phenolic origin than in brome of non-phenolic origin (on both thyme- and grass-soil), indicating that life-history variation may be related to environmental factors which also contribute to the spatial differentiation of thyme chemotypes. Moreover, we found that brome growing on thyme-soil in general was heavier than when growing on grass-soil, regardless of the origin of the brome plants. This is concordant with thyme-soil containing higher amounts of organic matter and nitrogen than grass-soil. Our results indicate that patterns of genetic differentiation and local adaptation may modify competitive interactions and possible facilitation effects in natural communities.

Adaptation, Physiological↗
PubMed2004

An unusual mechanism of glycoside hydrolysis involving redox and elimination steps by a family 4 beta-glycosidase from Thermotoga maritima.

Among the numerous well-characterized families of glycosidases, family 4 appears to be the anomaly, requiring both catalytic NAD+ and a divalent metal for activity. The unusual cofactor requirement prompted the proposal of a mechanism involving key NAD+-mediated redox steps as well as elimination of the glycosidic oxygen. Primary kinetic isotope effects for the 2- and 3-deutero substrate analogues, isotopic exchange with solvent, and structural analysis of a 6-phospho-beta-glucosidase, BglT (E.C. 3.2.1.6), provided evidence in support of the proposed mechanism, which has striking resemblances to that of the sugar dehydratases. Furthermore, analysis of the stereochemical outcome indicated that family 4 enzymes are retaining glycosidases.

Glucosidases↗
PubMed2004

Characterization of an ultraviolet B-induced lipase in Arabidopsis.

An Arabidopsis expressed sequence tag clone, 221D24, encoding a lipase has been characterized using an antisense approach. The lipase gene is expressed during normal growth and development of Arabidopsis rosette leaves but is down-regulated as the leaves senesce. When plants are exposed to sublethal levels of UV-B radiation, expression of the lipase is strongly up-regulated. The lipase protein is localized in the cell cytosol and is present in all organs of Arabidopsis plants. Recombinant lipase protein produced in Escherichia coli preferentially hydrolyzed phospholipids, indicating that the gene encodes a phospholipase. Transgenic plants in which lipase expression is suppressed showed enhanced tolerance to UV-B stress but not osmotic stress and were unable to up-regulate PR-1 expression when irradiated with UV-B. The observations collectively indicate that the lipase is capable of deesterifying membrane phospholipids and is up-regulated in response to UV-B irradiation.

Amino Acid Sequence↗
PubMed2004

Changes in gonadal steroid receptors in the cardinal ligaments of prolapsed uteri: immunohistomorphometric data.

BACKGROUND: The precise mechanism of uterine prolapse is poorly understood. This immunohistochemical study was performed on paraffin-embedded sections of the cardinal ligaments in an attempt to evaluate the differential expression of gonadal steroid receptors in human cardinal ligaments of prolapsed uteri compared with non-prolapsed controls. METHODS: Specimens from women with pelvic organ prolapse (POP) stage III (n = 33), together with the appropriate controls (n = 25), were stained for estrogen receptor alpha (ERalpha), ERbeta, progesterone receptor (PR), androgen receptor (AR) and Ki-67. The control materials were samples of the cardinal ligaments obtained from pre- and post-menopausal women with no prolapse, who were not using hormonal therapy. RESULTS The prolapsed ligaments expressed 1.5-2.5 times more ERalpha-positive cells (statistically significant in post-menopausal women not taking HRT, P < 0.001), a 3-4 times greater percentage of AR-positive cells (P = 0.004 and P = 0.008 in pre-menopausal and post-menopausal women not taking HRT, respectively) and twice the percentage of PR-positive cells (statistically significant in the pre-menopausal group, P = 0.03) compared with the no prolapse group. Expression of ERbeta was twice as high in the ligaments of pre-menopausal women with no prolapse compared with those with prolapse (P = 0.02), and no significant difference was found in the post-menopausal groups. The use of HRT was significantly associated with low AR and high PR expression. Ki-67 expression was not detected in these specimens. CONCLUSIONS: The clearly discernible levels of expression of ERalpha, ERbeta, AR and PR in the prolapsed cardinal ligaments may suggest a relationship to the process of tissue stretch 'trauma', rather than an effect of the menopausal status, HRT use or cell proliferation. The use of HRT in post-menopausal women appears to offset some of the changes observed with the prolapse.

Adult↗
PubMed2004

Novel catalytic mechanism of glycoside hydrolysis based on the structure of an NAD+/Mn2+ -dependent phospho-alpha-glucosidase from Bacillus subtilis.

GlvA, a 6-phospho-alpha-glucosidase from Bacillus subtilis, catalyzes the hydrolysis of maltose-6'-phosphate and belongs to glycoside hydrolase family GH4. GH4 enzymes are unique in their requirement for NAD(H) and a divalent metal for activity. We have determined the crystal structure of GlvA in complex with its ligands to 2.05 A resolution. Analyses of the active site architecture, in conjunction with mechanistic studies and precedent from the nucleotide diphosphate hexose dehydratases and other systems, suggest a novel mechanism of glycoside hydrolysis by GlvA that involves both the NAD(H) and the metal.

Amino Acid Sequence↗