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Biomedical subjects

J Nixon

Publications and source records attributed to J Nixon.

At least 19 recordsLinked to original sources
PubMed2002

(E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide (Ro 32-7315), a selective and orally active inhibitor of tumor necrosis factor-alpha convertase.

Tumor necrosis factor-alpha (TNF-alpha), a cytokine secreted by inflammatory cells, has been implicated in several inflammatory disease states. (E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide (Ro 32-7315), is a potent, orally active inhibitor of the TNF-alpha convertase (TACE), an enzyme responsible for proteolytic cleavage of the membrane bound precursor, pro-TNF-alpha. Ro 32-7315 inhibited a recombinant form of TACE (IC(50) = 5.2 nM) with selectivity over related matrix metalloproteinases. In a cellular assay system, THP-1 cell line, and in human and rat whole blood, Ro 32-7315 significantly reduced lipopolysaccharide (LPS)-induced TNF-alpha release with IC(50) values of 350 +/- 14 nM (n = 5), 2.4 +/- 0.5 microM (n = 5), and 110 +/- 18 nM (n = 5), respectively. Oral administration of Ro 32-7315 to Wistar rats caused a dose-dependent inhibition of LPS-induced release of systemic TNF-alpha with an ED(50) of 25 mg/kg. Treatment (days 0-14) of Allen and Hamburys hooded rats with Ro 32-7315 (2.5, 5, 10, and 20 mg/kg, i.p., twice daily) significantly reduced adjuvant-induced secondary paw swelling (42, 71, 83, and 93%, respectively) as compared with the vehicle group. In the Ro 32-7315-treated group, the reduced paw swelling was associated with improved lesion score and joint mobility. Furthermore, in a placebo-controlled, single-dose study, Ro 32-7315 given orally (450 mg) significantly suppressed ex vivo, LPS-induced TNF-alpha release in the whole-blood samples taken from healthy male and female volunteers (mean inhibition of 42% over a 4-h duration, n = 6). These data collectively support the potential use of such a compound for the oral treatment of inflammatory disorders.

ADAM Proteins↗
PubMed2001

15-lipoxygenase-1 metabolites down-regulate peroxisome proliferator-activated receptor gamma via the MAPK signaling pathway.

Human colon tumors have elevated levels of 15-lipoxygenase-1 (15-LO-1), suggesting that 15-LO-1 may play a role in the development of colorectal cancer. Also, 15-LO-1 metabolites can up-regulate epidermal growth factor signaling pathways, which results in an increase in mitogenesis. However, metabolites of 15-LO-1 can serve as ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), and activation of this receptor causes most colon cancer cell lines to undergo a differentiative response and reverse their malignant phenotype. Hence, the role 15-LO-1 plays in colon cancer is not clear. To clarify the role of 15-LO-1 in carcinogenesis, the effect of 15-LO-1 and its metabolites on epidermal growth factor signaling and PPARgamma was investigated. In HCT-116 cells, exogenously added 15-LO-1 metabolites, 13-(S)-hydroxyoctadecadienoic acid, 13-(R)-hydroxyoctadecadienoic acid, and 13-(S)-hydroperoxyoctadecadienoic acid, up-regulated the MAPK signaling pathway, and an increase in PPARgamma phosphorylation was observed. Furthermore, in stable overexpressing 15-LO-1 HCT-116 cells, which produce endogenous 15-LO-1 metabolites, an up-regulation in mitogen-activated protein kinase and PPARgamma phosphorylation was observed. Incubation with a MAPK inhibitor ablated MAPK and PPARgamma phosphorylation. The 15-LO-1 up-regulates MAPK activity and increases PPARgamma phosphorylation, resulting in a down-regulation of PPARgamma activity. Thus, 15-LO-1 metabolites may not only serve as ligands for PPARgamma but can down-regulate PPARgamma activity via the MAPK signaling pathway.

Arachidonate 15-Lipoxygenase↗
PubMed2001

The effect of the interruption of agitation on platelet quality during storage for transfusion.

BACKGROUND: A considerable amount of data and the CFR suggest that platelet concentrates (PCs) should be stored with continuous, gentle agitation before transfusion. However, there are only limited data concerning the mechanisms of platelet damage that may occur when agitation is interrupted, and there are no CFR guidelines concerning shipment between periods of storage. STUDY DESIGN AND METHODS: PCs were prepared by the platelet-rich plasma method and stored for 5 days at 20 to 24 degrees C; agitation was interrupted for 1 to 3 days either by simply stopping the agitator or by placing the PCs in a stationary shipping container. Measurements of platelet metabolism and quality were made during storage and on Day 5. RESULTS: With interruption on the agitator, the production of lactic acid was increased during the interruption in proportion to the number of platelets in the PC and the duration of the interruption. The pO(2) was increased during agitation interruption, which suggested a decline in oxygen utilization. With the use of the hypotonic shock response and the extent of shape change as reflections of platelet quality, there was no evidence of platelet damage unless the pH fell to or below 6.5. No PC reached this level after an interruption of agitation for only 1 day, irrespective of which day was chosen for interruption. PCs whose agitation was interrupted for 2 and 3 days were at risk of having a pH less than 6.5 if their contents were greater than 1.25 x 10(11) and 0.75 x 10(11) platelets, respectively. Interruption of agitation for 1 day in the shipping container produced results essentially identical to those produced by interruption on the agitator. CONCLUSION: Interruption of agitation of PCs for 1 day, either on the agitator or in the shipping container, produces no platelet damage measurable by these in vitro techniques. However, an interruption of agitation for 2 days can result in significant damage in some components. Further studies will be required to learn more about the mechanisms that lead to the metabolic changes described and to determine if the same generalizations apply to apheresis PCs and PCs prepared from pooled buffy coats.

Blood Platelets↗
PubMed2001

An MRI and neuropathological study of a case of fatal status epilepticus.

We report a case of fatal status epilepticus of unknown origin resulting in acute neuropathological changes in the hippocampus and claustrum. The case history, brain magnetic resonance images, and results of neuropathological study of the whole brain were obtained. The subject was a 35 year old male with no significant previous medical history who presented with generalized epileptic seizures progressing to status epilepticus. He died 6 days after developing status epilepticus. Magnetic resonance imaging (MRI) brain scans were performed before and four days after developing status epilepticus. The first scan was normal and the second showed high signal lesions on T2 weighted images in the medial aspects of both temporal lobes and in the right claustrum. Neuropathological studies showed severe neuronal loss in the Sommer section of both hippocampi with early glial reactive changes. Similar changes were seen in the claustrum on both sides. There was no evidence of other causes of brain injury such as infectious encephalitis or global hypoxic-ischaemic change. The patient died of status epilepticus for which no underlying cause was found despite extensive investigation. In this case the radiological and pathological changes found bilaterally in the claustrum and hippocampus appear to be the direct result of the status epilepticus.

Adult↗
PubMed2001

Transmission of hepatitis C in a pharmacologic study.

OBJECTIVE: To describe an outbreak of hepatitis C in a clinical research study. DESIGN: Observational study. SETTING: Tertiary-care hospital. PATIENTS: Healthcare workers who volunteered to be subjects in a study of the metabolic effects of inhaled and oral corticosteroids who were unwittingly exposed to hepatitis C virus (HCV). METHODS: Epidemiological investigation and serological analyses. RESULTS: One chronic carrier of HCV was identified. Four fellow workers volunteering in the studies became infected with HCV, with 96% homology among strains. There was no evidence of spread from infected healthcare workers to patients on whom they had performed arterial punctures (2 of 214 positive, unrelated to each other and to the outbreak strain). CONCLUSION: Infection control standards in clinical research must be maintained vigorously to prevent transmission of blood-borne pathogens such as HCV.

Adrenal Cortex Hormones↗
PubMed2001

Does cytosine-thymine-guanine (CTG) expansion size predict cardiac events and electrocardiographic progression in myotonic dystrophy?

OBJECTIVE: To assess whether the size of the cytosine-thymine-guanine (CTG) expansion mutation in myotonic dystrophy predicts progression of conduction system disease and cardiac events. DESIGN: Longitudinal study involving ECG and clinical follow up over (mean (SD)) 4.8 (1.8) and 6.2 (1.9) years, respectively, of patients stratified by CTG expansion size (E0 to E4). PATIENTS: 73 adult patients under annual review in a regional myotonic dystrophy clinic. Patients were grouped into E0/E1 (n = 25), E2 (n = 34), and E3/E4 (n = 14). RESULTS: The proportion of patients with a QRS complex > 100 ms at baseline increased with the size of the CTG expansion (EO/E1, 4%; E2, 12%; E3/E4, 36%; p = 0.02). This trend was more pronounced at follow up (E0/E1, 4%; E2, 21%; E3/E4, 57%; p = 0.0004). The rate of widening of the QRS complex (ms/year) was similarly related to the size of the mutation (EO/E1, 0.4 (1.3); E2, 1.4 (2.5); E3/E4, 1.5 (1.6); p = 0.04). First degree atrioventricular block was present in 23% of patients at baseline and 34% at follow up, with no significant relation to expansion size. Seven patients suffered a cardiac event during follow up (sudden death in two, permanent pacemaker insertion in three, chronic atrial arrhythmia in two), of whom six were in CTG expansion group E2 or greater. Patients who experienced a cardiac event during follow up had more rapid rates of PR interval increase (9.9 (11.1) v 1.6 (2.9) ms/year; p = 0.008) and a trend to greater QRS complex widening (3.6 (4.5) v 0.9 (1.5) ms/year; p = 0.06) than those who did not. CONCLUSIONS: Larger CTG expansions are associated with a higher rate of conduction disease progression and a trend to increased risk of cardiac events in myotonic dystrophy.

Adult↗
PubMed2001

Patterns of wheel running are related to Fos expression in neuropeptide-Y-containing neurons in the intergeniculate leaflet of Arvicanthis niloticus.

A variety of nonphotic influences on circadian rhythms have been documented in mammals. In hamsters, one such influence, running in a novel wheel, is mediated in part by the pathway extending from neuropeptide-Y (NPY)-containing cells within the intergeniculate leaflet (IGL) of the thalamus to the hypothalamic suprachiasmatic nucleus (SCN). Arvicanthis niloticus is a species in which all individuals are diurnal with respect to general activity and body temperature when they are housed without a running wheel, but access to a running wheel induces a subset of individuals to become nocturnal. In the first study, the authors evaluated the possibility that nocturnal and diurnal patterns of wheel running in Arvicanthis are correlated with differences in IGL function. Adult male Arvicanthis housed in a 12:12 light-dark (LD) cycle were monitored in wheels, classified as nocturnal or diurnal, and then perfused either 4 h after lights-on or 4 h after lights-off. Sections through the intergeniculate leaflet were processed for immunohistochemical labeling of Fos and NPY. The percentage of NPY cells that expressed Fos was significantly influenced by an interaction between time of day and phenotype such that it rose from night to day in diurnal animals, and from day to night in nocturnal animals. In the second experiment, the authors established that running in a wheel actually induces Fos in the IGL of Arvicanthis. Specifically, the proportion of NPY cells expressing Fos was increased by access to wheels in nocturnal animals at night and in diurnal animals during the day. In the third experiment, the authors established that lesions of the IGL eliminate NPY fibers within the SCN, suggesting that these IGL cells project to the SCN in this species as has been established in other rodents. Together, these data demonstrate a clear difference in NPY cell function in nocturnal and diurnal Arvicanthis that appears to be caused, at least in part, by the differences in their wheel-running patterns, and that NPY cells within the IGL project to the SCN in Arvicanthis.

Animals↗
PubMed2000

Some practical issues in the design, monitoring and analysis of a sequential randomized trial in pressure sore prevention.

A sequential double blind (assessor and patient) triangular design was used to compare the incidence of pressure sores following elective major surgery among patients lying on a standard foam mattress with those on a dry visco-elastic polymer pad during their operation. A total of 446 patients were recruited into the trial between 1994 and 1996. Interim analyses were carried out after 181 patients were entered into the trial and then subsequently after approximately every 100 patients recruited. The trial unexpectedly reached a stopping boundary at the first interim analysis, however the Independent Data Monitoring Committee recommended continuation of the trial. They were concerned that there was a need for a larger definitive trial and about an apparent treatment by centre interaction. They required a substudy to be undertaken to further validate the subjective endpoint, and that further sensitivity analyses of the main trail endpoint should be carried out in the second interim analysis. The trial was stopped at the third interim analysis when again a stopping boundary was crossed indicating that the gel pad was associated with significantly fewer pressure sores than the standard mattress (log odds ratio -0.7, (95 per cent confidence interval (CI), -1.28, -0.11), p=0.02) (estimate CI, p-value adjusted for group sequential conduct). The design, monitoring and analysis of this trial will be presented as an example of the practical problems or non-problems encountered for the local hospitals, for the trials unit, for the data monitoring committee and for the funding committee.

Beds↗
PubMed2000

Prognostic factors associated with pressure sore development in the immediate post-operative period.

The purpose of this study was to identify variables associated with post-operative pressure sore incidence. The data were derived from a sequential, double triangular, randomised, blinded, controlled trial of the intra-operative use of a visco-elastic polymer pad conducted at two centres. Of 446 surgical patients recruited the main endpoint was assessed for 416 patients of whom 65 (15.6%) had a post-operative pressure sore. Analysis determined that the probability of a patient developing a pressure sore was associated with increased number of hypotensive episodes and mean core temperature during surgery, and reduced mobility Day 1 post-operatively. The development of a probability equation illustrates the future potential of prognostic factor research in the development of risk assessment tools and their application within clinical settings.

Aged↗
PubMed2000

The U.K. NHS economic evaluation database. Economic issues in evaluations of health technology.

OBJECTIVE: The U.K. NHS Economic Evaluation Database (EED) project is commissioned to identify papers on economic evaluations of health technologies and to disseminate their findings to NHS decision makers by means of structured abstracts that are available through a public database and the Cochrane Library. This paper discusses current issues relating to the economic aspects of producing NHS EED abstracts. METHODS: A review of NHS EED was undertaken between 1994 and 1999 to determine the methodologies adopted and issues that influence the usefulness of economic evaluations. Methods adopted to improve the quality of NHS EED abstracts are also reported. RESULTS: Eighty-five percent of NHS EED abstracts are cost-effectiveness analyses (CEAs), 9.3% are cost-utility analyses (CUAs), and only 1.4% are cost-benefit analyses (CBAs). Of the total abstracts, 65.9% are based on single studies, 19.5% on reviews, 3.9% on estimates of effectiveness, and 10.7% on combinations of these sources. Models are utilized in 16.7% of CEAs, 60.2% of CUAs, and 20% of CBAs. Analyses of CBA studies reveal a degree of misuse of well-established definitions. NHS EED internal control mechanisms are reported that provide a means of ensuring that abstracts are based on sound academic principles. CONCLUSIONS: Most economic evaluations are conducted by means of CEA, followed by CUA, while CBA accounts for an extreme minority of cases. Single studies form the principal source of effectiveness data, although models are widely used, principally in CUA. The structure of NHS EED abstracts provides decision makers with the principal results and an interpretation of the relative strengths and weaknesses of economic evaluations.

Abstracting and Indexing↗
PubMed1999

The diagnosis of early pressure sores: report of the pilot study.

Thirty-four vascular and general surgical patients were recruited to a pilot study exploring skin blood flow using laser Doppler imaging and clinical assessment of skin erythema in relation to pressure sore development. Brief details of the results, sample size calculations and main study methodology are described in this mid-term report of the Tissue Viability Society Research Fellowship (1998-2000).

Aged↗
PubMed1999

Facial burns in children: a series analysis with implications for resuscitation and forensic odontology.

This study comprises a continuous (1981-1995) unselected series of all children who died from thermal injuries in the State of Queensland, Australia. One hundred and six children, so identified, died from incineration (35 per cent), respiratory burns with smoke or carbon monoxide inhalation (33 per cent), body surface area burns comprising greater than 60 per cent (9 per cent) and electrocution (20 per cent). The burn fatality rate was 0.98 per hundred thousand children (0-14 years) per year, with no secular trend and, specifically, no reduction in the annual rate of such fatalities. Eighty-two children (49 males) had concomitant facial injuries, both thermal and nonthermal; of whom 55 per cent were under the age of five years. Sixty (73 per cent) child burn victims died in house fires. Forensic odontology is important in confirming the age of such victims in single incinerations but is of limited value when larger numbers of children are incinerated, because of the relative lack of dental restorations in the infant and pre-school age group. Of the 82 children with facial and airway injuries, 12 per cent had only mild or superficial facial damage and only seven (8 per cent) were alive or resuscitable at the time of rescue from the conflagration or burning injury. child deaths from burns contributed an annual loss rate of 506 years of potential life lost (YPLL) in a population of 3 million of whom 21.5 per cent were children under the age of 15 years. Airway management and resuscitation, in the context of managing surviving burn victims of any age with facial injuries, pose special difficulties. Inhalational burns (smoke and the gases of conflagration) result in a mortality greater than 60 per cent. Although 81 per cent of children showed evidence of airway obstruction, analysis of current data indicates that a maximum of 8 per cent could have survived with airway maintenance and protection. Inhalational burns (to both upper and lower airways) grossly reduce survivability. Primary prevention would seem vital and thus remains a major challenge to reduce the incidence of such deaths. Some strategies include advocacy to promote the compulsory installation of smoke alarms, family drills to practise escape and the teaching of 'first aid for all'

Adolescent↗
PubMed1998

A sequential randomised controlled trial comparing a dry visco-elastic polymer pad and standard operating table mattress in the prevention of post-operative pressure sores.

Four hundred and forty-six general, vascular and gynaecological surgical patients were recruited to a two centre, double triangular sequential randomised controlled trial to compare the post-operative pressure sore incidence in patients positioned on the standard operating table mattress with those positioned on the dry visco-elastic polymer pad (Action Products Inc.). Two hundred and twenty two patients were randomised to the experimental group and 224 to the standard mattress. The main endpoint failure rate (a pressure sore) was found to be 11% (22/205) for patients allocated to the dry visco-elastic polymer pad and 20% (43/211) for patients allocated to the standard operating table mattress. There was a significant reduction in the odds of developing a pressure sore on the dry visco-elastic polymer pad as compared to the standard, [symbol see text] = 0.46 with 95% confidence interval of (0.26, 0.82), P = 0.010. The adjusted point estimates of the probability of developing a pressure sore on the dry visco-elastic polymer pad and the standard operating table mattress were 0.11 and 0.21 respectively.

Aged↗
PubMed1998

"I want my mummy". Changes in the care of children in hospital.

The Welfare of Sick Children in Hospital' was the formal title of a report published in Britain in 1959 which came to be known as the Platt Report, after Sir Harry Platt, the chairman of the parliamentary committee which investigated the care of children in hospital. The committee found the hospitals were miserable places for children, where they were expected to conform to ward routines, not allowed to play; where to lie quietly was the accepted norm, and where, under no circumstances, were the parents allowed to visit outside the declared visiting hours. Subsequent to the publication of the Platt Report a revolution occurred in children's hospitals in Britain and other western countries, including Australia. This paper explores these changes, and discusses implications for paediatric care in hospitals and paediatric nursing education today.

Child↗
PubMed1998

Del(18p) shown to be a cryptic translocation using a multiprobe FISH assay for subtelomeric chromosome rearrangements.

We have previously described a fluorescence in situ hybridisation (FISH) assay for the simultaneous analysis of all human subtelomeric regions using a single microscope slide. Here we report the use of this multiprobe FISH assay in the study of a patient whose karyotype was reported by G banding analysis as 46,XX,del(18)(p11.2). Although the proband had some features suggestive of a chromosomal abnormality, relatively few of the specific features of del(18p) were present. She was a 37 year old female with mild distal spinal muscular atrophy (SMA), arthritis of the hands, an abnormal chest shape (pectus excavatum), and an unusual skin condition (keratosis pilaris). Reverse chromosome painting with degenerate oligonucleotide primer-polymerase chain reaction (DOP-PCR) amplified del(18p) chromosomes as a probe confirmed the abnormality as del(18p), with no evidence of any other chromosome involvement. Subsequently, the multiprobe FISH assay confirmed deletion of 18p subtelomeric sequence. However, the assay also showed that sequences corresponding to the 2p subtelomeric probe were present on the tip of the shortened 18p. The patient is therefore monosomic for 18p11.2-pter and trisomic for 2p25-pter, and the revised karyotype is 46,XX,der(18)t(2;18)(p25; p11.2). We believe that a proportion of all cases reported as telomeric deletions may be cryptic translocations involving other chromosome subtelomeric regions. Further studies such as this are necessary to define accurately the clinical characteristics associated with pure monosomy in chromosomal deletion syndromes.

Adult↗