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D R Jones

Publications and source records attributed to D R Jones.

At least 55 records · Page 3Linked to original sources
PubMed2001

Evidence for the involvement of diacylglycerol kinase in the activation of hypoxia-inducible transcription factor 1 by low oxygen tension.

Hypoxia-inducible factor 1 (HIF-1) induces a gene expression program essential for the cellular adaptation to lowered oxygen environments. The intracellular mechanisms by which hypoxia induces HIF-1 remain poorly understood. Here we show that exposure of various cell types to hypoxia raises the intracellular level of phosphatidic acid primarily through the action of diacylglycerol kinase (DGK). Pharmacological inhibition of DGK activity through use of the specific DGK inhibitors and abrogated specifically HIF-1-dependent transcription analyzed with a HIF-1-responsive reporter plasmid. A more detailed analysis revealed that pharmacological inhibition of DGK activity prevented the hypoxia-dependent accumulation of the HIF-1alpha subunit and the subsequent HIF-1-DNA complex formation as well as hypoxia-induced activity of the HIF-1 transactivation domains localized to amino acids 530-582 and 775-826 of the HIF-1alpha subunit. Our results demonstrate for the first time that accumulation of phosphatidic acid through DGK underlines oxygen sensing and provide evidence for the involvement of this lipid kinase in the intracellular signaling that leads to HIF-1 activation.

Cell Nucleus↗
PubMed2001

Abiotic hydrolysis of the detergent builder tripolyphosphate by hydrous manganese dioxide.

The hydrolysis of tripolyphosphate to orthophosphate is facilitated by suspensions of amorphous manganese dioxide. Pyrophosphate is observed as an intermediate. The rate enhancement decreases with increasing pH. The weak sorption of orthophosphate on the oxide also decreases with increasing pH, indicating that the orthophosphate product would be bioavailable. The presence of calcium ions in natural waters increases both the rate of hydrolysis of tripolyphosphate and the extent of sorption of orthophosphate. Under some circumstances this abiotic mechanism could play a significant role in the hydrolysis of tripolyphosphate in the aquatic environment.

Detergents↗
PubMed2001

Influence of graft ischemic time on outcomes following lung transplantation.

BACKGROUND: Reperfusion injury is the most common cause of early mortality following lung transplantation. Although cold graft ischemic time has been reported to influence this injury, some lung grafts with short ischemic times develop significant reperfusion injury, whereas other grafts with more prolonged ischemic times do not develop injury. Our hypothesis was that ischemic time did not significantly influence reperfusion injury or other outcomes following lung transplantation. METHODS: Data on 136 patients who had lung transplantation over a 10 year period was used for analysis. RESULTS: Cold graft ischemic time > or = 6 hours did not increase the risk of reperfusion injury, acute rejection, cytomegalovirus infection, bacterial or fungal pneumonia, bronchiolitis obliterans syndrome, 1-month mortality, 1-year mortality, or 5-year mortality compared with ischemic times of either < 4 hours or 4 to 6 hours. The incidence of reperfusion injury was at least 20% for each time group. CONCLUSIONS: At least 20% of all patients will develop reperfusion injury regardless of cold graft ischemic time. Prolonged ischemic times up to 8 hours do not result in a significant increase in adverse short-term, intermediate, or long-term outcomes. Cautious extension of ischemic time beyond the current target of 4 to 6 hours may be warranted for geographic expansion of the donor lung pool.

Adolescent↗
PubMed2001

An illustrated guide to the methods of meta-analysis.

Meta-analysis is now accepted as a necessary tool for the evaluation of health care. Such analyses have been carried out in virtually every area of medicine to evaluate a wide spectrum of health care interventions and policies. This paper has three broad aims: (1) to describe the basic principles of meta-analysis, using a meta-analysis of interventions intended to reduce hospital re-admission rates for illustration; (2) to consider threats to the internal validity of meta-analysis, and the measures which can be taken to minimize their impact; and (3) to present an overview of more specialist and developing methods for synthesizing data, with the intention of outlining the directions meta-analysis may take in the future. The methods used to synthesize studies, which take 'weighted averages' of effect sizes have been refined to a high degree, while the methods for dealing with threats to the validity of meta-analyses such as publication bias, and variations in quality of the primary studies, are at a less advanced stage. However, many consider this standard 'weighted average' approach to meta-analysis not to be 'state of the art' in at least some situations, where the use of more sophisticated methods, generally to explain variation in estimates from different studies and synthesize a broader base of evidence, would be advantageous. Currently, approaches which attempt to do this are mainly still in the experimental stage and, unfortunately, ideas which sound natural and appealing are often difficult to implement in practice. Clearly, it will be some time before they are used routinely, but significant steps have been made.

Bayes Theorem↗
PubMed2001

Genetic differences between adenocarcinomas arising in Barrett's esophagus and gastric mucosa.

BACKGROUND & AIMS: Barrett adenocarcinoma (BA+) and gastric adenocarcinoma comprise a related group of neoplasms that nevertheless have some distinct clinicopathologic characteristics. This study aimed at defining critical molecular abnormalities that may underlie differences between BA+ and gastric adenocarcinomas. METHODS: We used comparative genomic hybridization for the analyses of 34 xenografts of adenocarcinomas that arose from esophageal or gastric origin. RESULTS: All tumors, except one, exhibited DNA copy number alterations. Losses in 4q and 14q and gains at 2p and 17q were more frequent in proximal (esophageal, gastroesophageal junction [GEJ], and cardia) tumors than in distal (body and antrum) tumors (P <or= 0.050). These changes were significantly higher in BA+ compared with distal tumors (P <or= 0.040). In addition, losses in 5q and gains at 20q were significantly higher in BA+ than in distal cancers (P <or= 0.040). Losses in 5q and 8p and gains at 2q, 6p, 12p, and 20q were significantly more frequent in BA+ tumors (P <or= 0.050) than in GEJ and cardiac tumors without associated Barrett's esophagus. Additionally, losses in 14q, which were common in proximal tumors, were more often seen in BA+ (P = 0.100) than in other proximal tumors. CONCLUSIONS: Although these adenocarcinomas share some common genetic alterations, the differences in the DNA copy numbers in BA+ cases suggest that unique genetic alterations may be involved in these cancers' development.

Adenocarcinoma↗
PubMed2001

The effects of genetic selection on production parameters of single comb White Leghorn hens.

Four commercial table egg genetic stocks consisting of the Ottawa Control Strains 5, 7, and 10 (CS5, CS7, and CS10) and the 1993 H&N "Nick Chick" (CCS) were housed in the same environment and compared for production characteristics. These birds were housed in an environmentally controlled laying facility with trideck cages. Feed consumption, egg production, and mortality were monitored daily and compiled every 28 d. The study was conducted for two egg production cycles, including the molt period. Body weight was progressively lower for the more modern strains with CS5 being the heaviest and CCS maintaining the smallest body weight throughout the production periods. The CCS had the highest (P < 0.0001) hen-day production rate, which resulted in the greatest daily egg mass among the strains. The CCS consumed the greatest amount of feed and exhibited the highest gross egg income among the strains. We concluded that genetic selection has improved production parameters in commercial layers as determined by measurements in this study.

Animals↗
PubMed2001

Effect of ABO blood group mismatching on corneal epithelial cells: an in vitro study.

AIM: To determine, in vitro, the effects of blood group ABO mismatching on corneal epithelial cells. METHODS: Corneal epithelial cell cultures were established from 32 human cadaver donor eyes. Epithelial cells (100 microl of 4 x 10(2) cells per microl) were incubated for 4 hours with antibodies against blood group antigens A, B, and AB, with and without complement. Cell lysis was assayed by a chemiluminescent assay using Cytolite reagent. Live cells, remaining after incubation, were counted in a scintillation counter. The blood group of the donors was determined retrospectively, in a blinded manner. RESULTS: Retrospective tracing of donor blood groups was possible for 20 donors. In all cases the blood group corresponded with that suggested by the cell lysis assay. Significant cell lysis was observed when known A group cells were incubated with anti-A and anti-AB antibody, B group cells were incubated with anti-B and AB antibody, and AB group cells were incubated with anti-AB antibody. Lysis occurred only in the presence of complement. No lysis of O group cells was observed with any of the antibodies. In all cases, lysis was observed only with neat (serum) antibody concentrations. CONCLUSIONS: Blood group ABO mismatching results in significant lysis of corneal epithelial cells. The antibody concentration required for lysis equals that found in serum. Such levels of antibody are unlikely to be achieved in tears and/or aqueous. This may offer an explanation for the conflicting reports of the studies on the effect of blood group matching on corneal grafts. The variability in the outcome may reflect the levels of antibodies gaining access to the corneal cells and not the mismatching alone.

ABO Blood-Group System↗
PubMed2001

Maintenance of cAMP in non-heart-beating donor lungs reduces ischemia-reperfusion injury.

Studies suggest that pulmonary vascular ischemia-reperfusion injury (IRI) can be attenuated by increasing intracellular cAMP concentrations. The purpose of this study was to determine the effect of IRI on capillary permeability, assessed by capillary filtration coeficient (Kfc), in lungs retrieved from non-heart-beating donors (NHBDs) and reperfused with the addition of the beta(2)-adrenergic receptor agonist isoproterenol (iso), and rolipram (roli), a phosphodiesterase (type IV) inhibitor. Using an in situ isolated perfused lung model, lungs were retrieved from NHBD rats at varying intervals after death and either ventilated with O(2) or not ventilated. The lungs were reperfused with Earle's solution with or without a combination of iso (10 microM) and roli (2 microM). Kfc, lung viability, and pulmonary hemodynamics were measured. Lung tissue levels of adenine nucleotides and cAMP were measured by HPLC. Combined iso and roli (iso/roli) reperfusion decreased Kfc significantly (p < 0.05) compared with non-iso/roli-reperfused groups after 2 h of postmortem ischemia. Total adenine nucleotide (TAN) levels correlated with Kfc in non-iso/roli-reperfused (r = 0.89) and iso/roli-reperfused (r = 0.97) lungs. cAMP levels correlated with Kfc (r = 0.93) in iso/roli-reperfused lungs. Pharmacologic augmentation of tissue TAN and cAMP levels might ameliorate the increased capillary permeability observed in lungs retrieved from NHBDs.

Adenine Nucleotides↗
PubMed2001

Methods for exploring heterogeneity in meta-analysis.

In meta-analysis, when the difference in results between studies is greater than would be expected by chance, one needs to investigate whether the observed variation in results across studies is associated with clinical and/or methodological differences between studies. This article reviews methods used in meta-analysis for exploring heterogeneity, including statistical tests for homogeneity, methods for visually displaying results of primary studies, methods for reducing heterogeneity, methods for investigating sources of heterogeneity, and identification of moderator variables or effect modifiers. The investigation of sources of heterogeneity in meta-analysis is by nature exploratory, and therefore its results should always be interpreted with caution. However, careful investigation of heterogeneity may provide an important second level of evidence that can be useful in suggesting direction of future research. Sometimes, it may provide clinically important results by indicating who might benefit more or less from a treatment or how an intervention should be applied.

Data Interpretation, Statistical↗
PubMed2001

The effects of depth on the cardiac and behavioural responses of double-crested cormorants (Phalacrocorax auritus) during voluntary diving.

Heart rate and dive behaviour were monitored in double-crested cormorants (Phalacrocorax auritus) during shallow (1 m) and deep diving (12 m), after breathing different gas mixtures, to investigate the role of depth and the accompanying changes in blood gas levels in cardiac and behavioural control during voluntary diving. Pre-dive heart rate in both shallow- and deep-diving birds was approximately three times the resting heart rate (137.9+/-17.5 beats min(-1); mean +/- S.D., N=5), falling abruptly upon submersion to around 200-250 beats min(-1). During shallow diving, the initial reduction in heart rate was followed by a secondary, more gradual decline, to around the resting level. In contrast, during deep diving, heart rate stabilised at 200-250 beats min(-1). In dives of similar duration, mean dive heart rate was significantly lower during shallow diving (163.2+/-14.0 beats min(-1)) than during deep diving (216.4+/-7.7 beats min(-1)), but in both cases was significantly above the resting value. The difference in cardiac response is probably due to an increase in arterial oxygen tension (Pa(O(2))) during the descent phase of deep dives (compression hyperoxia). Exposure to a hyperoxic gas mixture before shallow diving significantly increased mean dive heart rate, while exposure to a hypoxic gas mixture in both the shallow and deep dive tanks significantly reduced mean dive heart rate. In contrast, breathing hypercapnic gas before diving had no significant effect on dive heart rate. We suggest that the cardiac response to voluntary diving in double-crested cormorants is strongly influenced by changes in blood oxygen levels throughout the dive. Dive duration was unaffected by alterations in inspired gas composition, but surface interval duration decreased during hyperoxic gas exposure and increased during hypoxic gas exposure. The most efficient dive pattern (highest dive/pause ratio) was observed after hyperoxic exposure. Our study suggests that blood oxygen level is a powerful stimulus that facilitates the cardiac and behavioural adjustments during foraging that are important components of a strategy allowing double-crested cormorants to maximise the time spent under water and, hence, potential foraging time.

Animals↗
PubMed2001

In utero stem cell transplantation: two steps forward but one step back?

The concept of in utero stem cell transplantation has provided hope that at least some of the genetic disorders which can be diagnosed prenatally can be treated before the pathological sequelae become manifested. Our increasing knowledge of haematopoietic stem cell biology has provided further possibilities for optimising this transplant procedure. However, the relatively poor success rate achieved using this procedure has prompted some to suggest that there may be fetal rejection of donor cells via an immune mechanism. However, the prevailing evidence from both animal models and from human cases, suggest that there may be other mechanisms which are preventing successful engraftment in some disorders and these must be addressed if the procedure is to receive further attention. The ability to achieve sustained engraftment after in utero transplantation will have relevance for those seeking to use gene therapy as an alternative therapeutic stratagem.

Animals↗
PubMed2001

Psychiatric considerations in military aerospace medicine.

Military aerospace medicine requires a psychiatric selection and certification process that determines not only the absence of significant mental disorders, but also the presence of positive qualities in the realms of motivation, ability and stability: not all normal people are fit to fly. Other issues of aerospace psychiatry involve maintenance of mental resilience and hardiness during a flying career, aeromedical decisions about when to remove from flight duties and when to return, criteria for waivers for psychiatric conditions, use of medications for treatment of psychiatric symptoms, questions of substance abuse, and research in such areas as genetics. This report reviews the basis for military aerospace psychiatry, primarily as practiced in the United States Air Force (USAF), and presents some of its underlying principles as they apply to clinical situations.

Accidents, Aviation↗
PubMed2001

Purification and characterization of insulin-mimetic inositol phosphoglycan-like molecules from grass pea (Lathyrus sativus) seeds.

BACKGROUND: Signal transduction through the hydrolysis of glycosyl-phosphatidylinositol (GPI) leading to the release of the water-soluble inositol phosphoglycan (IPG) molecules has been demonstrated to be important for mediating some of the actions of insulin and insulin-like growth factor-I (IGF-I). MATERIALS AND METHODS: In the present study, GPI from grass pea (Lathyrus sativus) seeds has been purified and partially characterized on the basis of its chromatographic properties and its compositional analysis. RESULTS: The results indicate that it shows similarities to GPI previously isolated from other sources such as rat liver. IPG was generated from L. sativus seed GPI by hydrolysis with a GPI-specific phospholipase D (GPI-PLD). This IPG inhibited protein kinase A (PKA) in an in vitro assay, caused cell proliferation in explanted cochleovestibular ganglia (CVG), and decreased 8-Br-cAMP-induced phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression in cultured hepatoma cells. CONCLUSIONS: Our data indicate that L. sativus seed IPG possess insulin-mimetic activities. This may explain why L. sativus seeds have been used in some traditional medicines to ameliorate diabetic symptoms.

Animals↗
PubMed2001

Aeromedical management of U.S. air force aviators who attempt suicide.

BACKGROUND: Little has been published about the aeromedical management and disposition of aviators who attempt suicide, and almost no such information about military aviators exists in the open literature. The few available data are scattered and frequently anecdotal. METHODS: The authors reviewed all case reports of fliers evaluated at the USAF School of Aerospace Medicine's Aeromedical Consultation Service (ACS) between 1981-96 for possible return to flying duties after a suicide attempt, and prepared a representative case report. RESULTS: Between 1981 and 1996, the ACS evaluated 14 trained aviators (pilots and other aircrew members, excluding flight surgeons) who had attempted suicide. Of these, 11 (79%) ultimately received a recommendation for return to flying duties. CONCLUSIONS: In most instances the underlying stressors included failed intimate interpersonal relationships, administrative or legal problems, psychiatric disorders, death of spouse, or job conflicts. Evidence of abuse of alcoholor other substances was found in 54% of an earlier, larger data set of attempters. Some data on aircrew suicide completion were available and are reported. The top medical priorities after such attempts should be to diagnose what is wrong, and to treat it. In spite of the common assumption that a suicide attempt inevitably ends a military flying career, some attempters can return to safe and effective flying duty after appropriate psychotherapy. If the flier regains physical and mental health and maintains them for at least 6 mo after treatment, then that flier may be evaluated by an outside aeromedical psychiatric consultant such as the ACS (to avoid transference issues between flier and therapist) for possible return to flying duties. Waiver action should be based on the underlying psychiatric diagnosis, not the suicidal attempt itself. Follow-up may be accomplished through periodic mental health evaluations in conjunction with routine physical examination procedures. Issues involving substance abuse and security clearances must be handled through the appropriate channels.

Adult↗
PubMed2001

Involvement of the nuclear matrix in the control of skeletal genes: the NMP1 (YY1), NMP2 (Cbfa1), and NMP4 (Nmp4/CIZ) transcription factors.

The functional role of the osteoblast nuclear matrix has been a matter of supposition. Its presumed function as an architectural agent of transcription derives primarily from the low solubility of nuclear matrix proteins and their typical localization into discrete subnuclear domains. In addressing how the nuclear matrix regulates skeletal genes, the authors compare Nmp4, Cbfal, and YY1 for the purpose of profiling osteoblast nuclear matrix transcription factors. All three proteins contribute to the transcription of ECM genes and partition into the osteoblast nuclear matrix via a nuclear matrix targeting domain. The authors propose that osteoblast nuclear matrix transcription factors involved in ECM regulation generally have the capacity to alter DNA geometry and reciprocally respond to DNA as an allosteric ligand. This may allow these proteins to adapt to the local nuclear architecture and generate the pattern of regulation specified by that architecture via unmasking of the appropriate transactivation domains. Osteoblast nuclear matrix transcription factors may also act as transcriptional adaptor molecules by supporting the formation of higher order protein complexes along target gene promoters. The genes encoding all three proteins considered here have trinucleotide repeat domains, although the significance of this is unclear. There is no canonical nuclear matrix binding motif, but finger-like structures may be suited for anchoring proteins to discrete subnuclear domains. Finally, the ability to leave the osteoblast nuclear matrix may be as important to the function of some nuclear matrix transcription factors as their association with this subcompartment.

Animals↗
PubMed2000

Hierarchical models in generalized synthesis of evidence: an example based on studies of breast cancer screening.

Evidence regarding the potential benefits of a particular health care intervention is often available from a variety of disparate sources. However, formal synthesis of such evidence has traditionally concentrated almost exclusively on that derived from randomized studies, although for a range of conditions the randomized evidence will be less than adequate due to economic, organizational or ethical considerations. In such situations a formal synthesis of the evidence that is available from observational studies can be valuable whilst awaiting higher quality evidence from randomized trials. Consideration of randomized studies alone may be appropriate when assessing the efficacy of an intervention, but assessment of the effectiveness of such an intervention within a more general target population may be improved by consideration of evidence from non-randomized studies as well. Standard meta-analysis methods may allow for both within- and between-study heterogeneity; however when multiple sources of evidence are considered an extra level of complexity is introduced, namely study type. One possible solution to the problem of making inferences, particularly regarding an overall population effect, in such situations is to model the heterogeneity, both quantitative and qualitative, using a Bayesian hierarchical model. The hierarchical nature of such models specifically allows for the quantitative within and between sources of heterogeneity, whilst the Bayesian approach can accommodate a priori beliefs regarding qualitative differences between the various sources of evidence. The use of such methods in practice is illustrated in the context of screening for breast cancer; in this example evidence is available from both randomized clinical trials and observational studies. A particular appeal of a Bayesian approach for this type of problem lies in the prediction of future benefits likely to be observed in a target population. This approach to health service monitoring in general is discussed.

Aged↗
PubMed2000

Type Ialpha phosphatidylinositol 4-phosphate 5-kinase is a putative target for increased intracellular phosphatidic acid.

Despite the fact that phosphatidic acid (PtdOH) has been implicated as a lipid second messenger for nearly a decade, its intracellular targets have remained unclear. We sought to investigate how an increase in the level of PtdOH could modulate phosphatidylinositol 4-phosphate 5-kinase (PIPkin), an enzyme involved in phosphatidylinositol 4,5-bisphosphate synthesis. Transfection of porcine aortic endothelial (PAE) cells with haemagglutinin (HA)-tagged type Ialpha PIPkin followed by immunofluorescence confocal microscopy revealed the enzyme to be localised to the plasma membrane. When the transfected PAE cells were stimulated with lyso-PtdOH, increased PIPkin activity was found to be associated with HA immunoprecipitates in an in vitro assay. This PIPkin activation was found to be greatly reduced by prior treatment of the cells with 1-butanol, thereby implicating phospholipase D (PLD) as the in vivo generator of PtdOH. In order to determine if the PtdOH-dependent activation of type Ialpha PIPkin was dictated by a specific molecular composition of PtdOH, the wild type murine and porcine alpha isoforms of diacylglycerol kinase (DGK) were individually co-transfected along with type Ialpha PIPkin. Under these conditions an increase in type Ialpha PIPkin lipid kinase activity was found in HA immunoprecipitates in an in vitro assay. No increases in lipid kinase activity were observed when type Ialpha PIPkin was co-transfected with either the human DGKepsilon isoform or a kinase-dead mutant of the murine DGKalpha isoform. These results provide the first direct evidence for the unification of the production of saturated/monounsaturated PtdOH (through two different routes, PLD and DGK) and the in vivo activation of type Ialpha PIPkin by this lipid second messenger.

Animals↗