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Biomedical subjects

P J Young

Publications and source records attributed to P J Young.

At least 19 recordsLinked to original sources
PubMed2006

Relapses and subsequent worsening of disability in relapsing-remitting multiple sclerosis.

OBJECTIVE: To investigate whether relapses contribute to the development of subsequent sustained increase of impairment and disability in patients with multiple sclerosis (MS). METHODS: In a random sampled subset of 256 relapsing-remitting MS (RRMS) patients from the placebo arms of 20 randomized, controlled clinical trials contained in the Sylvia Lawry Centre for MS Research (SLCMSR) open database (mean follow-up time 2.66 years), the authors tested whether time to an increase of the Expanded Disability Status Scale (EDSS) score (confirmed after 6 months) was related to the occurrence of prior relapses. In the primary analysis, EDSS progressions starting within the period used to calculate the on-study relapse rate (sacrifice period) were not counted. The result obtained was then validated in an independent validation part of the SLCMSR database (n = 320). RESULTS: Although in the first subset of 256 RRMS patients, occurrence of relapses in the first 4 months on study appeared to be the best predictor for a shorter time to subsequent sustained increase in the EDSS score (hazard ratio [HR] 2.26 [95% CI: 1.36 to 3.75]), this finding was not confirmed in the validation dataset (HR 1.35, one-sided Wald test, lower limit of the 95% CI: 0.90). CONCLUSION: Although relapses may result into permanent damage and Expanded Disability Status Scale (EDSS) progression, there is no consistent effect of on-study relapses on the subsequent development of sustained EDSS score increase during a typical clinical study observation period.

Adult↗
PubMed2003

Inflation of a pressure-limited cuff inside a model trachea.

A theory of the elastic behaviour of thin rubber films is developed to describe inflation of pressure-limited tracheal tube cuffs (a) outside and (b) inside rigid cylindrical model tracheas. At each stage, assumptions and results were successfully checked against experiment. The theory predicts cylinder wall versus intracuff pressure. This allows, for any suitable cuff (of which there are many), the determination of a single intracuff pressure that ensures a satisfactory seal, for any diameter within the human adult range, the wall pressure staying below some chosen safety limit.

Computer Simulation↗
PubMed2003

The incidence and immediate respiratory consequences of pulmonary aspiration of enteral feed as detected using a modified glucose oxidase test.

Pulmonary micro-aspiration of enteral feed in intubated critically ill patients has been reported to occur commonly. In this prospective observational study the incidence of micro-aspiration, diagnosed by a modified glucose oxidase test, is reported in 25 enterally fed critically ill and tracheally intubated patients on a general intensive care unit. Episodes of microaspiration were correlated with changes in PaO2/FiO2 ratio as an index of changes in degree of lung injury. The modified glucose oxidase test differs from the traditional glucose oxidase test because of the enrichment of the feed with glucose (10 g glucose added to 500 ml enteral feed resulting in a tenfold increase in glucose concentration). Pulmonary aspiration of feed was detected by exposing a glucose oxidase strip to tracheal secretions. The feed was enriched with glucose to improve the ability of the reagent strip to detect the feed. The incidence of aspiration of feed was 44% with a prevalence of 6.9% per day of intubation. Only 43% of these episodes of aspiration were detected by the feed being seen in the tracheal secretions. Aspiration was associated with a mean fall in the PaO2/FiO2 ratio of 5.6 kPa from 27.1 kPa to 21.5 kPa (P = 0.002). Aspiration of enteral feed is common and causes a demonstrable morbidity. Detection using this simple bedside test may alert the clinician to institute measures to minimize further aspiration.

Enteral Nutrition↗
PubMed2002

Matrix effects in applying mono- and polyclonal ELISA systems to the analysis of weathered oils in contaminated soil.

Commercial mono- and polyclonal enzyme-linked immunosorbent assay (ELISA) systems were applied to the on-site analysis of weathered hydrocarbon-contaminated soils at a former integrated steelworks. Comparisons were made between concentrations of solvent extractable matter (SEM) determined gravimetrically by Soxhlet (dichloromethane) extraction and those estimated immunologically by ELISA determination over a concentration range of 2000-330,000 mg SEM/kg soil dry weight. Both ELISA systems tinder-reported for the more weathered soil samples. Results suggest this is due to matrix effects in the sample rather than any inherent bias in the ELISA systems and it is concluded that, for weathered hydrocarbons typical of steelworks and coke production sites, the use of ELISA requires careful consideration as a field technique. Consideration of the target analyte relative to the composition of the hydrocarbon waste encountered appears critical.

Enzyme-Linked Immunosorbent Assay↗
PubMed2001

Nuclear gems and Cajal (coiled) bodies in fetal tissues: nucleolar distribution of the spinal muscular atrophy protein, SMN.

SMN, the affected protein in spinal muscular atrophy (SMA), is a cytoplasmic protein that also occurs in nuclear structures called "gems" and is involved in snRNP maturation. Coilin-p80 is a marker protein for nuclear Cajal bodies (coiled bodies; CBs) which are also involved in snRNP maturation, storage or transport. We now show that gems and CBs are present in all fetal tissues, even those that lack gems/CBs in the adult. Most gems and CBs occur as separate nuclear structures in fetal tissues, but their colocalization increases with fetal age and is almost complete in the adult. In adult tissues, up to half of all gems/CBs are inside the nucleolus, whereas in cultured cells they are almost exclusively nucleoplasmic. The nucleolar SMN is often more diffusely distributed, compared with nucleoplasmic gems. Up to 30% of cells in fetal tissues have SMN distributed throughout the nucleolus, instead of forming gems in the nucleoplasm. The results suggest a function for gems distinct from Cajal bodies in fetal nuclei and a nucleolar function for SMN. Spinal cord, the affected tissue in SMA, behaves differently in several respects. In both fetal and adult motor neurons, many gems/CBs occur as larger bodies closely associated with the nucleolar perimeter. Uniquely in motor neurons, gems/CBs are more numerous in adult than in fetal stages and colocalization of gems and CBs occurs earlier in development. These unusual features of motor neurons may relate to their special sensitivity to reduced SMN levels in SMA patients.

Adult↗
PubMed2001

The natural history of diabetic peripheral neuropathy determined by a 12 year prospective study using vibration perception thresholds.

The development and long term progression of diabetic peripheral neuropathy was studied using vibration perception threshold (VPT) as a validated measure. Three hundred and ninety-two patients had a normal age corrected VPT (12.1 +/- 3.7 volts) at baseline, with an age corrected logarithmic VPTscore < 12. 19.9% developed an abnormal VPT over a 12 year period, increasing from 14.2 +/- 3.7 volts (VPTscore 10.4 +/- 0.6) at baseline to 35.9 +/- 9.5 volts (VPTscore 12.6 +/- 0.45) at follow up (P = 0.0001), and from 10.1 +/- 3.7volts (VPTscore 9.4 +/- 0.8) to 14.2 +/- 4.7 (VPTscore 9.8 +/- 0.8) in the rest. Over 80% thus retained a "normal" VPT after a mean diabetes duration of 16 years despite only average glycaemic control, suggesting that non-ideal long term glycaemic control leads to neuropathy in a subset of predisposed patients. VPT was correlated in 123 diabetic patients with definitive criteria for neuropathy and a range of quantitative sensory and autonomic tests. 62/63 patients with abnormal VPT fulfilled neuropathy criteria; of patients with normal VPT who fulfilled neuropathy criteria, all had at least one abnormal thermal threshold test result. We conclude that a combination of log-transformed VPT values (VPTscore > 10.1) and thermal thresholds can identify diabetic patients at risk of developing peripheral neuropathy and select patients likely to benefit from prophylaxis in clinical trials.

Adult↗
PubMed2001

Gel lubrication of the tracheal tube cuff reduces pulmonary aspiration.

BACKGROUND: Leakage of fluid occurs along the longitudinal folds within the wall of an inflated high-volume, low-pressure cuff. Theoretically, lubrication of the cuff with a water-soluble gel might prevent aspiration by plugging the channels in the cuff wall. Pulmonary aspiration during anesthesia has been linked with postoperative pneumonia and during critical illness causes ventilator-associated pneumonia. METHODS: Lubricated cuffs were compared with nonlubricated cuffs for leakage of dye placed in the subglottic space to the tracheobronchial tree in a benchtop model (n = 5) and in a prospective double-blinded randomized controlled trial of anesthetized patients (n = 36). The duration of the efficacy of the lubricant was determined in a prospective open observational study of critically ill patients with tracheostomies (n = 9). Dye was detected clinically by dye coloration of secretions during tracheal suctioning. RESULTS: In the benchtop model the incidence of leakage was 0% in the lubrication group and 100% in the nonlubrication group (P < 0.01). Dye leakage in anesthetized patients was 11% in the lubrication group and 83% in the nonlubrication group (P < 0.0001). In the critically ill patients with lubricated cuffed tracheostomy tubes, leakage first occurred after a median period of 48 h (range, 24-120 h). CONCLUSIONS: Cuff lubrication with a water-soluble gel reduces pulmonary aspiration in anesthetized patients. In the critically ill patient with a tracheostomy the protective effect is lost after 24-120 h.

Adult↗
PubMed2001

A spoonful of sugar--improving the sensitivity of the glucose oxidase test strip method for detecting subclinical pulmonary aspiration of enteral feed.

A 74-year-old woman was admitted to the intensive care unit (ICU) with respiratory failure. Following intubation and mechanical ventilation, nasogastric enteral feeding was begun. The sensitivity of the glucose oxidase strip method for detecting aspiration of enteral feed has been questioned because the glucose levels in commonly used feeds are similar to those of normal tracheal aspirates. In order to increase the glucose concentration of the feed, 10 g of glucose was added to each 500 ml feed carton. Testing oral and tracheal secretions with standard glucose oxidase strips allowed the accurate detection of both pharyngeal regurgitation and tracheal aspiration. An episode of subclinical aspiration was detected and this was associated with a fall in the PaO2/FiO2 ratio. There were no further episodes of aspiration following the introduction of a gastric motility agent, maintaining the patient in the semi-recumbent position and an increase in the positive end expiratory pressure (PEEP).

Aged↗
PubMed2001

Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes.

The metabolism of cis-tramadol has been studied in human liver microsomes and in cDNA-expressed human cytochrome P-450 (CYP) isoforms. Human liver microsomes catalyzed the NADPH-dependent metabolism of tramadol to the two primary tramadol metabolites, namely, O-desmethyl-tramadol (metabolite M1) and N-desmethyl-tramadol (metabolite M2). In addition, tramadol was also metabolized to two minor secondary metabolites (each comprising < or =3.0% of total tramadol metabolism), namely, N,N-didesmethyl-tramadol (metabolite M3) and N,O-didesmethyl-tramadol (metabolite M5). Kinetic analysis revealed that multiple CYP enzymes were involved in the metabolism of tramadol to both M1 and M2. For the high-affinity enzymes involved in M1 and M2 formation, K(m) values were 116 and 1021 microM, respectively. Subsequent reaction phenotyping studies were performed with a tramadol substrate concentration of 250 microM. In studies with characterized human liver microsomal preparations, good correlations were observed between tramadol metabolism to M1 and M2 and enzymatic markers of CYP2D6 and CYP2B6, respectively. Tramadol was metabolized to M1 by cDNA-expressed CYP2D6 and to M2 by CYP2B6 and CYP3A4. Tramadol metabolism in human liver microsomes to M1 and M2 was markedly inhibited by the CYP2D6 inhibitor quinidine and the CYP3A4 inhibitor troleandomycin, respectively. In summary, this study demonstrates that cis-tramadol can be metabolized to tramadol metabolites M1, M2, M3, and M5 in human liver microsomal preparations. By kinetic analysis and the results of the reaction phenotyping studies, tramadol metabolism in human liver is catalyzed by multiple CYP isoforms. Hepatic CYP2D6 appears to be primarily responsible for M1 formation, whereas M2 formation is catalyzed by CYP2B6 and CYP3A4.

Analgesics, Opioid↗
PubMed2000

The exon 2b region of the spinal muscular atrophy protein, SMN, is involved in self-association and SIP1 binding.

Spinal muscular atrophy (SMA) is caused by mutations in the SMN (survival of motor neurons) gene and there is a correlation between disease severity and levels of functional SMN protein. Studies of structure-function relationships in SMN protein may lead to a better understanding of SMA pathogenesis. Self-association of the spinal muscular atrophy protein, SMN, is important for its function in RNA splicing. Biomolecular interaction analysis core analysis now shows that SMN self-association occurs via SMN regions encoded by exons 2b and 6, that exon 2b encodes a binding site for SMN-interacting protein-1 and that interaction occurs between exon 2- and 4-encoded regions within the SMN monomer. The presence of two separate self-association sites suggests a novel mechanism by which linear oligomers or closed rings might be formed from SMN monomers.

Antibodies, Monoclonal↗
PubMed2000

The relationship between SMN, the spinal muscular atrophy protein, and nuclear coiled bodies in differentiated tissues and cultured cells.

The spinal muscular atrophy protein, SMN, is a cytoplasmic protein that is also found in distinct nuclear structures called "gems." Gems are closely associated with nuclear coiled bodies and both may have a direct role in snRNP maturation and pre-RNA splicing. There has been some controversy over whether gems and coiled bodies colocalize or form adjacent/independent structures in HeLa and other cultured cells. Using a new panel of antibodies against SMN and antibodies against coilin-p80, a systematic and quantitative study of adult differentiated tissues has shown that gems always colocalize with coiled bodies. In some tissues, a small proportion of coiled bodies (<10%) had no SMN, but independent or adjacent gems were not found. The most striking observation, however, was that many cell types appear to have neither gems nor coiled bodies (e.g., cardiac and smooth muscle, blood vessels, stomach, and spleen) and this expression pattern is conserved across human, rabbit, and pig species. This shows that assembly of distinct nuclear bodies is not essential for RNA splicing and supports the view that they may be storage sites for reserves of essential proteins and snRNPs. Overexpression of SMN in COS-7 cells produced supernumerary nuclear bodies, most of which also contained coilin-p80, confirming the close relationship between gems and coiled bodies. However, when SMN is reduced to very low levels in type I SMA fibroblasts, coiled bodies are still formed. Overall, the data suggest that gem/coiled body formation is not determined by high cytoplasmic SMN concentrations or high metabolic activity alone and that a differentiation-specific factor may control their formation.

Animals↗
PubMed2000

Showing neuropathy is related to increased mortality in diabetic patients - a survival analysis using an accelerated failure time model.

Diabetic subjects still have a reduced life expectancy despite many potential advances in patient care. Furthermore, population-based studies in well-defined cohorts of patients, to investigate the reduced life expectancies, are generally lacking. Computerized baseline data on a cohort of diabetic patients first attending our clinic during 1982-1985 were used to identify risk factors for increased mortality. This was carried out using an accelerated failure time (ACF) model. Out of 794 patients entered into the model, 201 (25.3%) patients died between 1982 and 1995. Baseline microvascular diabetic complications (peripheral sensory neuropathy and nephropathy) were found to be associated with increased mortality in patients, indicating that these are important, often overlooked, markers for those at greatest risk. Patients with type I (insulin dependent) diabetes mellitus were also identified as being at greater risk.

Diabetes Mellitus↗
PubMed2000

The prevention of pulmonary aspiration with control of tracheal wall pressure using a silicone cuff.

A prospective open randomized controlled study was performed to assess the ability of Euromedical ILM endotracheal tube cuff (silicone cuff) to prevent pulmonary aspiration. The inflation characteristics of this silicone cuff enables the control of tracheal wall pressure. The silicone cuffed tube was shortened and an adjustable flange was used to convert it to a cuffed tracheostomy tube. Twelve patients requiring a tracheostomy on a four-bed intensive care unit (ICU) in a district general hospital received either a silicone or a Shiley cuffed tracheostomy tube. Tracheal wall pressures of both cuffs were maintained at 30 cm H2O with a constant pressure inflation device. Blue food dye was instilled once daily into the subglottic space through a fine catheter above the cuff. There were six patients in the Shiley group and six patients in the silicone cuff group. Dye leaked to the trachea in six (100%) of the Shiley group compared with none (0%) of the silicone cuff group (P = 0.001). This study confirms the effectiveness of this silicone cuff at preventing aspiration and the high incidence of leakage with the conventional high-volume low-pressure tracheostomy tube cuff.

Aged↗
PubMed1999

Compliance characteristics of the Portex Soft Seal Cuff improves seal against leakage of fluid in a pig trachea model.

BACKGROUND: The Portex Soft Seal high-volume, low-pressure cuffed tracheal tube was compared with the Mallinckrodt HiLo, Sheridan Preformed and Portex Profile tracheal tubes for leakage of dye placed in the subglottic space of a pig's trachea which was used in a benchtop mechanical ventilation model and in six isolated pig tracheas. RESULTS: There was no leakage, either in the ventilation model or in the isolated tracheas in the Portex Soft Seal group. There was rapid leakage in the ventilation model and in all the isolated tracheas for the Mallinckrodt HiLo, and five out of six isolated tracheas for the Sheridan Preformed and the Portex Profile group. CONCLUSIONS: This benchtop study suggests that the improved compliance characteristics of the Portex Soft Seal cuff are beneficial in preventing leakage of fluid in these models.

Animals↗
PubMed1999

The analysis of a bivariate multi-state Markov transition model for rheumatoid arthritis with an incomplete disease history.

In many long-term chronic diseases, patients pass through an observable sequence of ordered clinical states as their condition progressively worsens. Often the information on which disease state the patient is in is incompletely recorded, usually with information only available on the occasion of a clinic visit. This article describes a novel analysis of data from a clinical trial, in which several such outcome measures of disease state have been recorded simultaneously. The article is motivated by the analysis of a multi-centre double-blind placebo-controlled clinical study into the effect of continual low dose corticosteroid treatment on the progression of X-ray scores for patients with rheumatoid arthritis. Previous methods of analysis of such data have been based on an independence analysis, thus ignoring any correlation that may exist between the outcomes. This article shows that such an approach can lead to biased underestimates of the covariate effects if an independence model is used. Biased estimates of the covariate effects were found when the model was fitted to the trial data. The bivariate model was also shown to provide a significantly better fit to the data. However, the bivariate model did prove more difficult to fit, and both models demonstrated a highly significant treatment effect with comparable clinical effect.

Adolescent↗
PubMed1999

Prevention of tracheal aspiration using the pressure-limited tracheal tube cuff.

A new design of tracheal tube cuff, the pressure-limited cuff, used with a constant-pressure inflation system, was compared with a high-volume low-pressure cuffed tracheal tube for leakage of dye placed in the subglottic space into the trachea. Patients requiring ventilation on the intensive care unit were randomly allocated into two groups, one for each type of cuff, and blue food dye was instilled daily via a fine catheter above the cuff into the subglottic space. There were eight patients in the high-volume low-pressure group and seven in the pressure-limited cuff group. Dye leaked into the trachea in seven (87%) of the high-volume low-pressure group compared with none (0%) of the pressure-limited cuff group (p < 0.01). This study demonstrates that the pressure-limited cuffed tracheal tube, in combination with a constant-pressure inflation device, prevents leakage of fluid into the lungs that occurs with high-volume low-pressure cuffs in the critically ill, intubated patient.

Air Pressure↗