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Biomedical subjects

D T Jones

Publications and source records attributed to D T Jones.

At least 19 recordsLinked to original sources
PubMed2001

Endoscopic sinus surgery in cystic fibrosis: do patients benefit from surgery?

OBJECTIVE: To examine the effects of endoscopic sinus surgery on the pulmonary status of cystic fibrosis (CF) patients through the objective parameters of steroid use, pulmonary function tests (PFTs), and inpatient hospital days (IHDs). METHODS: Retrospective chart review of all patients with CF who underwent endoscopic sinus surgery from 1993 to 1999 at a tertiary care children's hospital. Preoperative pulmonary function, inhaler and steroid use, and IHDs were compared to postoperative parameters within a 1-year period. RESULTS: Sixty-six patients, including eight lung transplant patients, underwent a total of 112 endoscopic sinus surgery procedures; 25 patients underwent more than one procedure. Patients were taking oral steroids preoperatively in 28% of procedures and inhaled steroids in 40%. Postoperatively, there was no statistically significant change in oral or inhaled steroid use, or in postoperative pulmonary function. If the index hospitalization, which was often for reasons not related to sinus disease, was considered part of the preoperative time period, endoscopic sinus surgery (ESS) was noted to result in a marked reduction (9.5 days (adjusted), P=0.001) in hospital days during the subsequent 6 months. If the date of the procedure alone was used to define pre- and postoperative time periods, the reduction in postoperative days was more modest and not statistically significant (3.5 days (adjusted), P=0.21). CONCLUSIONS: Although we found no statistically significant difference in PFTs, or steroid requirements following ESS, ESS may have resulted in a reduced need for hospitalization in the 6 months following the procedure. Future prospective studies in a larger number of patients and using more detailed outcome measures are needed to better evaluate the effects of endoscopic sinus surgery in pediatric patients with CF.

Adolescent↗
PubMed2001

Caspase 8 activation independent of Fas (CD95/APO-1) signaling may mediate killing of B-chronic lymphocytic leukemia cells by cytotoxic drugs or gamma radiation.

Ligation of the cell-surface Fas molecule by its ligand (Fas-L) or agonistic anti-Fas monoclonal antibodies results in the cleavage and activation of the cysteine protease procaspase 8 followed by the activation of procaspase 3 and by apoptosis. In some leukemia cell lines, cytotoxic drugs induce expression of Fas-L, which may contribute to cell killing through the ligation of Fas. The involvement of Fas, Fas-L, and caspase 8 was studied in the killing of B-cell chronic lymphocytic leukemia (B-CLL) cells by chlorambucil, fludarabine, or gamma radiation. Spontaneous apoptosis was observed at 24-hour incubation, with additional apoptosis induced by each of the cytotoxic treatments. Although Fas mRNA expression was elevated after exposure to chlorambucil, fludarabine, or gamma radiation, Fas protein levels only increased after irradiation. Therefore, Fas expression may be regulated by multiple mechanisms that allow the translation of Fas mRNA only in response to restricted cytotoxic stimuli. None of the cytotoxic stimuli studied here induced Fas-L expression. An agonistic anti-Fas monoclonal antibody (CH-11) did not significantly augment apoptosis induction by any of the death stimuli. A Fas-blocking antibody (ZB4) did not inhibit spontaneous, chlorambucil-, fludarabine-, or radiation-induced apoptosis. However, procaspase 8 processing was induced by all cytotoxic stimuli. These data suggest that the Fas/Fas-L signaling system does not play a major role in the induction of apoptosis in B-CLL cells treated with cytotoxic drugs or radiation. However, Fas-independent activation of caspase 8 may play a crucial role in the regulation of apoptosis in these cells.

Antibodies, Monoclonal↗
PubMed2001

Evaluating the potential of using fold-recognition models for molecular replacement.

Here, the proposal is investigated that protein tertiary structure prediction methods and threading methods in particular might be applied to the problem of solving a protein structure by X-ray crystallography, thus reducing the need for the more traditional experimental intensity methods of data phasing, such as heavy-metal isomorphous replacement and anomalous scattering methods, and without reference to a very closely related protein of known structure. If this kind of approach were to become successful and reliable, this would represent a significant advance in protein structure determination, offering an easy and accessible method for the initial data phasing for proteins' crystal structures, utilizing the vast amount of structural data, deposited in the Brookhaven PDB, that has been accumulated over the past 30 years of crystallographic structural studies. In the light of the ongoing structural genomics initiatives, the successful development of this kind of approach would be of enormous benefit.

Crystallography, X-Ray↗
PubMed2001

Organ motion and its management.

PURPOSE: To compile and review data on the topic of organ motion and its management. METHODS AND MATERIALS: Data were classified into three categories: (a) patient position-related organ motion, (b) interfraction organ motion, and (c) intrafraction organ motion. Data on interfraction motion of gynecological tumors, the prostate, bladder, and rectum are reviewed. Literature pertaining to the intrafraction movement of the liver, diaphragm, kidneys, pancreas, lung tumors, and prostate is compiled. Methods for managing interfraction and intrafraction organ motion in radiation therapy are also reviewed.

Female↗
PubMed2001

The effects of carbon dioxide on exercise-induced asthma: an unlikely explanation for the effects of Buteyko breathing training.

OBJECTIVES: To examine the effect of breathing 3% CO2 on exercise-induced asthma (EIA), as a raised airway CO2 level is suggested to mediate the effects of Buteyko breathing training (BBT). DESIGN: Double-blind crossover study, using a standard laboratory-based exercise challenge, with EIA defined as a fall of 15% or greater in the forced expiratory volume in one second (FEV1) within 30 minutes of completing a standard exercise protocol. SUBJECTS: 10 adults with confirmed EIA. INTERVENTION: Air enriched with 3% CO2 during and for 10 minutes after exercise. OUTCOME MEASURES: Maximum percentage fall in FEV1 after exercise. Area under curve (AUC) of the decrease in FEV1 with time. RESULTS: Mean maximum fall in FEV1 was similar: 19.9% with air, and 26.9% with 3% CO2 (P = 0.12). The mean AUC for the total 30-minute post-exercise period was 355 for air and 520 for 3% CO2 (P = 0.07). After discontinuing the 3% CO2 at 10 minutes after exercise, there was a further and sustained fall in FEV1. Mean AUC for the period 10-30 minutes post-exercise was significantly greater for CO2 than air (275 and 137, respectively [P = 0.02]). Mean minute ventilation was increased when subjects exercised breathing 3% CO2: 77.5 L/min for 3% CO2, compared with 68.7 L/min for air (P = 0.02). CONCLUSION: Breathing 3% CO2 during exercise does not prevent EIA. The shape of the FEV1 response curve after 3% CO2 suggests that a greater degree of EIA (because of increased minute ventilation during exercise) was opposed by a direct relaxant effect of CO2 on the airway. Increased airway CO2 alone is an unlikely mechanism for the reported benefits of BBT; nevertheless, further study of the effects of voluntary hypoventilation in asthma is warranted.

Administration, Inhalation↗
PubMed2001

Predicting novel protein folds by using FRAGFOLD.

The results of applying a fragment-based protein tertiary structure prediction method to the prediction of 8 CASP4 targets are described. The method is based on the assembly of supersecondary structural fragments taken from highly resolved protein structures using a simulated annealing algorithm. Despite the significant degree of success in this case, there is clearly much more developmental work required before predictions with the accuracy of a good homology model, or even a good fold recognition model, can be made with use of this kind of approach.

Bacteriocins↗
PubMed2001

Proton RBE for early intestinal tolerance in mice after fractionated irradiation.

BACKGROUND AND PURPOSE: To determine the influence of the number of fractions (or the dose per fraction) on the proton relative biological effectiveness (RBE). MATERIALS AND METHODS: Intestinal crypt regeneration in mice was used as the biological endpoint. RBE was determined relative to cobalt-60 gamma rays for irradiations in one, three and ten fractions separated by a time interval of 3.5h. Proton irradiations were performed at the middle of a 7-cm Spread Out Bragg Peak (SOBP). RESULTS: Proton RBEs (and corresponding gamma dose per fraction) at the level of 20 regenerated crypts per circumference were found equal to 1.15+/-0.04 (10.0 Gy), 1.15+/-0.05 (4.8 Gy) and 1.14+/-0.07 (1.7 Gy) for irradiations in one, three and ten fractions, respectively. Alpha/beta ratios as derived from direct analysis of the 'quantal radiation response data' were found to be 7.6 Gy for gamma rays and 8.2 Gy for protons. Additional proton irradiations in ten fractions at the end of the SOBP were found to be more effective than at the middle of the SOBP by a factor of 1.14 (1.05-1.23). CONCLUSION: Proton RBE for crypt regeneration was found to be independent of fractionation up to ten fractions. One can expect that it remains unchanged for higher number of fractions as the lethalities for doses smaller than 3 Gy are exclusively due to direct lethal events. As a tendency for increased effectiveness at the end of the SOBP is reported in the majority of the studies, for clinical applications it would be advisable to allow for by arranging a sloping depth dose curve in the deeper part of the target volume. Finally, it must be noticed that most of in vitro and in vivo RBE values for protons are larger than the current clinical RBE (RBE=1.10).

Animals↗
PubMed2001

Critically assessing the state-of-the-art in protein structure prediction.

One of the most tantalising 'grand challenges' in structural biology is to solve the problem of predicting the structure of a protein from its amino acid sequence alone. Although this problem appeals to many researchers on a purely academic level, the practical importance of protein structure prediction has become particularly clear with the release of the first draft of the complete human genome sequence last year. This moved modern biology into the new so-called 'post genome' era, and for the foreseeable future, one of the main issues in modern biology will be the characterisation of the many 'unknown' gene sequences which are now sitting waiting in DNA and protein data banks. Protein structure can provide a great deal of insight into the evolutionary origins, function and mechanism of a protein, and so any means for determining the 3-D structure of a novel protein will likely be of critical importance.

Animals↗
PubMed2001

Autologous plasma activates Akt/protein kinase B and enhances basal survival and resistance to DNA damage-induced apoptosis in B-chronic lymphocytic leukaemia cells.

We have studied the actions of autologous plasma on both basal and DNA damage-induced apoptosis in B-chronic lymphocytic leukaemia (B-CLL) cells. Apoptosis was quantified using morphological criteria and Western blot analysis for the apoptosis-specific p85 fragment of poly(ADP ribose) polymerase. Cell viability was estimated using the methyl thiazol tetrazolium bromide dye reduction assay. Plasma cultures showed lower rates of basal apoptosis as well as a decreased cytotoxic response to chlorambucil and gamma-radiation compared with cultures in fetal calf serum. Experiments using neutralizing antibodies suggested that the protective actions of plasma could not be accounted for by interleukin 4, the interferons alpha or gamma or stromal cell-derived factor 1, each of which have been shown to protect B-CLL cells from apoptosis in vitro. Plasma addition to B-CLL cells resulted in rapid activation of the Akt protein kinase, a key signalling enzyme that has been implicated in anti-apoptotic signalling. LY294002, an inhibitor of phosphatidylinositol 3'-kinase, blocked Akt activation by plasma. To the best of our knowledge, this is the first report to show that factors present in plasma promote basal survival of B-CLL cells and resistance to cytotoxic drugs via stimulation of the Akt cytoprotective-signalling pathway. Pharmacological blockade of this pathway may have potential in the development of novel therapeutic strategies for B-CLL treatment.

Antineoplastic Agents, Alkylating↗
PubMed2001

Endoscopic dacryocystorhinostomy in children.

BACKGROUND: Persistent nasolacrimal duct obstruction (NLDO) often requires treatment by probing, intubation, or balloon dacryoplasty. Refractory cases have been managed by external dacryocystorhinostomy (DCR), which leaves a scar; however, this procedure is generally avoided in young children. Endoscopic DCR has been successfully performed in adults and described in children. We report the success of this procedure in a series of pediatric patients. METHODS: A retrospective review of all endoscopic lacrimal procedures performed in a 3-year period was undertaken. Seventeen children (22 ducts) with persistent NLDO after at least one failed probing, with or without silicone tube placement, underwent endoscopic DCR. Follow-up ranged from 6 to 36 months, and success was defined as resolution of tearing and discharge by follow-up clinical evaluation and by parental history. RESULTS: All but 2 patients (88%) with NLDO showed complete resolution of tearing and discharge. These 2 patients had recurrent symptoms after the Crawford tubes were removed and required revision endoscopic DCR. No complications from this procedure were noted. CONCLUSIONS: Endoscopic DCR is a safe and effective means of treating persistent NLDO in infants and young children when simple probing, intubation, or balloon procedures have failed. The team ophthalmology-otolaryngology endoscopic approach provides a highly successful alternative for patients with a persistent distal obstruction that might otherwise require an external procedure.

Adolescent↗
PubMed2001

Protein structure prediction in genomics.

As the number of completely sequenced genomes rapidly increases, including now the complete Human Genome sequence, the post-genomic problems of genome-scale protein structure determination and the issue of gene function identification become ever more pressing. In fact, these problems can be seen as interrelated in that experimentally determining or predicting or the structure of proteins encoded by genes of interest is one possible means to glean subtle hints as to the functions of these genes. The applicability of this approach to gene characterisation is reviewed, along with a brief survey of the reliability of large-scale protein structure prediction methods and the prospects for the development of new prediction methods.

Animals↗
PubMed2001

What are the baselines for protein fold recognition?

MOTIVATION: What constitutes a baseline level of success for protein fold recognition methods? As fold recognition benchmarks are often presented without any thought to the results that might be expected from a purely random set of predictions, an analysis of fold recognition baselines is long overdue. Given varying amounts of basic information about a protein-ranging from the length of the sequence to a knowledge of its secondary structure-to what extent can the fold be determined by intelligent guesswork? Can simple methods that make use of secondary structure information assign folds more accurately than purely random methods and could these methods be used to construct viable hierarchical classifications? EXPERIMENTS PERFORMED: A number of rapid automatic methods which score similarities between protein domains were devised and tested. These methods ranged from those that incorporated no secondary structure information, such as measuring absolute differences in sequence lengths, to more complex alignments of secondary structure elements. Each method was assessed for accuracy by comparison with the Class Architecture Topology Homology (CATH) classification. Methods were rated against both a random baseline fold assignment method as a lower control and FSSP as an upper control. Similarity trees were constructed in order to evaluate the accuracy of optimum methods at producing a classification of structure. RESULTS: Using a rigorous comparison of methods with CATH, the random fold assignment method set a lower baseline of 11% true positives allowing for 3% false positives and FSSP set an upper benchmark of 47% true positives at 3% false positives. The optimum secondary structure alignment method used here achieved 27% true positives at 3% false positives. Using a less rigorous Critical Assessment of Structure Prediction (CASP)-like sensitivity measurement the random assignment achieved 6%, FSSP-59% and the optimum secondary structure alignment method-32%. Similarity trees produced by the optimum method illustrate that these methods cannot be used alone to produce a viable protein structural classification system. CONCLUSIONS: Simple methods that use perfect secondary structure information to assign folds cannot produce an accurate protein taxonomy, however they do provide useful baselines for fold recognition. In terms of a typical CASP assessment our results suggest that approximately 6% of targets with folds in the databases could be assigned correctly by randomly guessing, and as many as 32% could be recognised by trivial secondary structure comparison methods, given knowledge of their correct secondary structures.

Computational Biology↗
PubMed2001

Emended descriptions of Clostridium acetobutylicum and Clostridium beijerinckii, and descriptions of Clostridium saccharoperbutylacetonicum sp. nov. and Clostridium saccharobutylicum sp. nov.

On the basis of 16S rRNA gene sequencing and DNA-DNA reassociation, industrial solvent-producing clostridia have been assigned to four species. In this study, the phenotypic characteristics of Clostridium acetobutylicum, Clostridium beijerinckii, 'Clostridium saccharoperbutylacetonicum', and an unnamed Clostridium sp. represented by the strains NCP 262T and NRRL B643 are compared. In addition, a further 40 strains of solvent-producing clostridia have been classified by biotyping, DNA fingerprinting and 16S rRNA gene sequencing. These included 14 C. beijerinckii strains, two strains currently designated as 'Clostridium kaneboi' and 'Clostridium butanologenum', and 24 production strains used in the commercial acetone-butanol fermentation. All of the C. beijerinckii strains were confirmed to have been classified correctly. The 'C. kaneboi' and 'C. butanologenum' strains require reclassification as C. acetobutylicum and C. beijerinckii, respectively. The commercial production strains were found to belong either to C. beijerinckii or to the unnamed Clostridium sp. For the comparative phenotypic studies of the four species, representative strains were selected from each of the DNA-fingerprint subgroups within each species. These strains were analysed for their ability to utilize different carbohydrates, hydrolyse gelatin or aesculin, and produce indole, and were tested for the presence of catalase and urease. On the basis of these results, several phenotypic traits were found to be useful for differentiating between the four species. The descriptions of C. acetobutylicum and C. beijerinckii have been emended. The names Clostridium saccharoperbutylacetonicum sp. nov. [type strain = N1-4 (HMT) = ATCC 27021T] and Clostridium saccharobutylicum sp. nov. (type strain = DSM 13864T = ATCC BAA-117T) are proposed for the two new species.

Acetone↗
PubMed2001

Integrated web-based viewing and secure remote access to a clinical data repository and diverse clinical systems.

The advent of the World-Wide-Web protocols and client-server technology has made it easy to build low-cost, user-friendly, platform-independent graphical user interfaces to health information systems and to integrate the presentation of data from multiple systems. The authors describe a Web interface for a clinical data repository (CDR) that was moved from concept to production status in less than six months using a rapid prototyping approach, multi-disciplinary development team, and off-the-shelf hardware and software. The system has since been expanded to provide an integrated display of clinical data from nearly 20 disparate information systems.

Computer Graphics↗
PubMed2000

Proton relative biological effectiveness (RBE) for survival in mice after thoracic irradiation with fractionated doses.

PURPOSE: This study aims at providing relative biological effectiveness (RBE) data under reference conditions accounting for the determination of the "clinical RBE" of protons. METHODS AND MATERIALS: RBE (ref. (60)Co gamma-rays) of the 200 MeV clinical proton beam produced at the National Accelerator Centre (South Africa) was determined for lung tolerance assessed by survival after selective irradiation of the thorax in mice. Irradiations were performed in 1, 3, or 10 fractions separated by 12 h. Proton irradiations were performed at the middle of a 7-cm spread out Bragg peak (SOBP). Control gamma irradiations were randomized with proton irradiations and performed simultaneously. A total of 1008 mice was used, of which 96 were assessed for histopathology. RESULTS: RBEs derived from LD50 ratios were found not to vary significantly with fractionation (corresponding dose range, approximately 2-20 Gy). They, however, tend to increase with time and reach (mean of the RBEs for 1, 3 and 10 fractions) 1.00, 1.08, 1.14, and 1.25 for LD50 at 180, 210, 240, and 270 days, respectively (confidence interval approximately 20%). alpha/beta ratios for protons and gamma are very similar and average 2.3 (0.6-4.8) for the different endpoints. Additional irradiations in 10 fractions at the end of the SOBP were found slightly more effective ( approximately 6%) than at the middle of the SOBP. A control experiment for intestinal crypt regeneration in mice was randomized with the lung experiment and yielded an RBE of 1.14 +/- 0.03, i.e., the same value as obtained previously, which vouches for the reliability of the experimental procedure. CONCLUSION: There is no need to raise the clinical RBE of protons in consideration of the late tolerance of healthy tissues in the extent that RBE for lung tolerance was found not to vary with fractionation nor to differ significantly from those of the majority of early- and late-responding tissues.

Animals↗
PubMed2000

Protein structure prediction in the postgenomic era.

As the number of completely sequenced genomes rapidly increases, the postgenomic problem of gene function identification becomes ever more pressing. Predicting the structures of proteins encoded by genes of interest is one possible means to glean subtle clues as to the functions of these proteins. There are limitations to this approach to gene identification and a survey of the expected reliability of different protein structure prediction techniques has been undertaken.

Animals↗
PubMed2000

The PSIPRED protein structure prediction server.

SUMMARY: The PSIPRED protein structure prediction server allows users to submit a protein sequence, perform a prediction of their choice and receive the results of the prediction both textually via e-mail and graphically via the web. The user may select one of three prediction methods to apply to their sequence: PSIPRED, a highly accurate secondary structure prediction method; MEMSAT 2, a new version of a widely used transmembrane topology prediction method; or GenTHREADER, a sequence profile based fold recognition method. AVAILABILITY: Freely available to non-commercial users at http://globin.bio.warwick.ac.uk/psipred/

Protein Folding↗