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Biomedical subjects

S Henderson

Publications and source records attributed to S Henderson.

At least 19 recordsLinked to original sources
PubMed2006

N-sulfonato-N,O-carboxymethylchitosan: a novel polymeric absorption enhancer for the oral delivery of macromolecules.

Chitosan has been shown to act on the mucosal epithelial barriers mainly when protonated at acidic pH values in which it is soluble. Soluble chitosan is able to improve the permeation and absorption of neutral to cationic macromolecules only, as it forms polyelectrolyte complexes with anionic macromolecules. LMWH (Low Molecular Weight Heparin) is an anionic polysaccharide finding clinical application as an improved antithrombotic agent compared to Unfractionated Heparin (UFH). In this study we have employed N-sulfonato-N,O-carboxymethylchitosan (SNOCC) as a potential intestinal absorption enhancer of LMWH, Reviparin. SNOCC was prepared at 3 different viscosity grades 20, 40 and 60 cps and identified as SNOCC-20, SNOCC-40 and SNOCC-60, respectively. SNOCC materials were tested in vitro for their ability to decrease the Trans Epithelial Electrical Resistance (TEER) of Caco-2 cell monolayers. They were further tested as transport enhancers of hydrophilic compounds such as (14)C-mannitol, FITC-Dextran (MW 4400 Da) and Reviparin (LMWH). Solutions of Reviparin, with or without SNOCC, were administered intraduodenally in vivo in rats and the absorption of the drug was assessed by measuring the Anti-Xa levels in rat plasma. In vitro studies showed that SNOCC materials were able to induce a concentration dependent decrease in the TEER of the Caco-2 monolayers. SNOCC-40 and -60 were shown to decrease resistance more readily compared to the low viscosity SNOCC-20. (14)C-mannitol permeation data across intestinal epithelia were in agreement with the observed decrease in TEER; the higher viscosity SNOCC-60 was the most effective demonstrating a 51-fold enhancement of the permeation of the radiolabeled marker. Studies with both FITC-Dextran and Reviparin demonstrated significantly increased permeation across Caco-2 cell monolayers when they were co-incubated at the apical side of the monolayer. Intestinal absorption of Reviparin in rats was increased when it was co-administered with SNOCC-40 and -60, in agreement with in vitro data. Anti-Xa levels were elevated to and above the antithrombotic levels and were sustained for at least 6 h, giving an 18.5-fold increase in the AUC of LMWH in rats. In conclusion, SNOCC-40 and -60 have been shown to enhance both permeation and absorption of Reviparin across intestinal epithelia proving their potential as polymeric absorption enhancers.

Adjuvants, Pharmaceutic↗
PubMed2006

Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas.

Chordomas are malignant tumours that occur along the spine and are thought to derive from notochordal remnants. There is significant morphological variability between and within chordomas, with some showing prominent areas of chondroid differentiation. Our microarray data from a broad range of connective tissue neoplasms indicate that, at the transcriptional level, chordomas resemble cartilaginous neoplasms. Here we show that chordomas express many genes known to be involved in cartilage development, but they also uniquely express genes distinguishing them from chondroid neoplasms. The brachyury transcription factor, known to be involved in notochordal development, is only expressed by chordomas. Using a polyclonal antibody, we show that brachyury is expressed in the embryonic notochord and in all 53 chordomas analysed, labelling both chondroid and chordoid areas of these tumours. In contrast, the protein was not detected in over 300 neoplasms, including 163 chondroid tumours. Brachyury was not detected in the nucleus pulposus, arguing against the hypothesis that this tissue derives directly from the notochord. These data provide compelling evidence that chordomas derive from notochord and demonstrate that brachyury is a specific marker for the notochord and notochord-derived tumours.

Biomarkers, Tumor↗
PubMed2004

Predicting biomarkers for ovarian cancer using gene-expression microarrays.

Ovarian cancer has the highest mortality rate of gynaecological cancers. This is partly due to the lack of effective screening markers. Here, we used oligonucleotide microarrays complementary to approximately 12 000 genes to establish a gene-expression microarray (GEM) profile for normal ovarian tissue, as compared to stage III ovarian serous adenocarcinoma and omental metastases from the same individuals. We found that the GEM profiles of the primary and secondary tumours from the same individuals were essentially alike, reflecting the fact that these tumours had already metastasised and acquired the metastatic phenotype. We have identified a novel biomarker, mammaglobin-2 (MGB2), which is highly expressed specific to ovarian cancer. MGB2, in combination with other putative markers identified here, could have the potential for screening.

Biomarkers, Tumor↗
PubMed2004

Proposal for molecular mechanism of thionins deduced from physico-chemical studies of plant toxins.

We propose a molecular model for phospholipid membrane lysis by the ubiquitous plant toxins called thionins. Membrane lysis constitutes the first major effect exerted by these toxins that initiates a cascade of cytoplasmic events leading to cell death. X-ray crystallography, solution nuclear magnetic resonance (NMR) studies, small angle X-ray scattering and fluorescence spectroscopy provide evidence for the mechanism of membrane lysis. In the crystal structures of two thionins in the family, alpha(1)- and beta-purothionins (MW: approximately 4.8 kDa), a phosphate ion and a glycerol molecule are modeled bound to the protein. (31)P NMR experiments on the desalted toxins confirm phosphate-ion binding in solution. Evidence also comes from phospholipid partition experiments with radiolabeled toxins and with fluorescent phospholipids. This data permit a model of the phospholipid-protein complex to be built. Further, NMR experiments, one-dimensional (1D)- and two-dimensional (2D)-total correlation spectroscopy (TOCSY), carried out on the model compounds glycerol-3-phosphate (G3P) and short chain phospholipids, supported the predicted mode of phospholipid binding. The toxins' high positive charge, which renders them extremely soluble (>300 mg/mL), and the phospholipid-binding specificity suggest the toxin-membrane interaction is mediated by binding to patches of negatively charged phospholipids [phosphatidic acid (PA) or phosphatidyl serine (PS)] and their subsequent withdrawal. The formation of proteolipid complexes causes solubilization of the membrane and its lysis. The model suggests that the oligomerization may play a role in toxin's activation process and provides insight into the structural principles of protein-membrane interactions.

Antimicrobial Cationic Peptides↗
PubMed2003

Gene expression array profile of human osteosarcoma.

The aims of this pilot study were to determine whether needle and open biopsies from osteosarcoma (OS) provide sufficient quality of mRNA for cDNA array analyses to gain insights into the expression profile of OS. A total of 22 samples collected from OS were used for array analyses. A primary cell culture was also established from one of the OS biopsies. Total RNA was extracted and probes were generated for cDNA arrays. cDNA probes were made for all the 22 samples. Two of these samples were needle core bone biopsies. Statistical analysis confirmed the reliability of array data obtained in 16 of the 22 samples. Known genes involved in bone metabolism and osteosarcoma were identified as highly expressed, and the putative new marker Ezrin was also identified. Confirmatory immunohistochemical staining using the Ezrin antibody was performed in a selection of samples.

Adolescent↗
PubMed2002

Longevity genes in the nematode Caenorhabditis elegans also mediate increased resistance to stress and prevent disease.

More than 40 single-gene mutants in Caenorhabditis elegans have been demonstrated to lead to increased lifespan (a rigorous, operational test for being a gerontogene) of 20% or more; these are referred to collectively as 'Age' mutants. Age mutants must change key functions that are rate-limiting determinants of longevity; moreover, important genes can be identified independently of prior hypotheses as to actual mode of gene action in extending longevity and/or 'slowing' of ageing. These Age mutants define as many as nine (possibly) distinct pathways and/or modes of action, as defined by primary phenotype. Each of three well-studied mutants (age-1, clk-1, and spe-26) alters age-specific mortality rates in a fashion unique to itself. In age-1 mutants, the decreases in mortality rates are quite dramatic, with an almost tenfold drop in mortality throughout most of life. All Age mutants (so far without exception) increase the ability of the worm to respond to several (but not all) stresses, including heat, UV, and reactive oxidants. We have used directed strategies as well as random mutagenesis to identify novel genes that increase the worm's ability to resist stress. Two genes (daf-16 and old-1) are epistatic to the long-life phenotype of most mutants and also yield over-expression strains that are stress-resistant and long-lived. We have also used a variety of approaches to determine what transcriptional alterations are associated with increased longevity (and with ageing itself), including whole-genome expression studies using microarrays and GFP reporter constructs. We suggest that the role of the Age genes in both longevity and stress resistance indicates that a major evolutionary determinant of longevity is the ability to respond to stress. In mammals, both dietary restriction and hormesis are phenomena in which the endogenous level of resistance to stress has been upregulated; both of these interventions extend longevity, suggesting possible evolutionary conservation.

Animals↗
PubMed2002

Evaluation in an anaesthetic simulator of a prototype of a new drug administration system designed to reduce error.

Ten anaesthetists were observed while providing anaesthesia for two simulated surgical procedures, twice using conventional methods and twice using a prototype of a new drug administration system designed to reduce error. Aspects of each method were rated by users on 10-cm visual analogue scales (10 being best) and comments were invited. Median safety scores were 7.7 cm (range 4.3-8.9) for the new system and 4.6 cm (1.3-8.2) for conventional methods (p = 0.009). The new system was compared favourably with conventional methods in respect of safety (p = 0.005), clinical acceptability (p = 0.008), organisation and layout (p = 0.047), and acceptability for use on patients (p = 0.005). The new system saved time in the preparation of drugs both before anaesthesia (105 vs. 346 s; p < 0.001) and during anaesthesia (20 vs. 104 s; p < 0.001). Comments facilitated development of the system and the evaluation endorsed proceeding to a clinical trial.

Anesthesiology↗
PubMed2002

Polyploidy, phylogeography and Pleistocene refugia of the rockfern Asplenium ceterach: evidence from chloroplast DNA.

Chloroplast DNA sequences were obtained from 331 Asplenium ceterach plants representing 143 populations from throughout the range of the complex in Europe, plus outlying sites in North Africa and the near East. We identified nine distinct haplotypes from a 900 bp fragment of trnL-trnF gene. Tetraploid populations were encountered throughout Europe and further afield, whereas diploid populations were scarcer and predominated in the Pannonian-Balkan region. Hexaploids were encountered only in southern Mediterranean populations. Four haplotypes were found among diploid populations of the Pannonian-Balkans indicating that this region formed a northern Pleistocene refugium. A separate polyploid complex centred on Greece, comprises diploid, tetraploid and hexaploid populations with two endemic haplotypes and suggests long-term persistence of populations in the southern Mediterranean. Three chloroplast DNA (cpDNA) haplotypes were common among tetraploids in Spain and Italy, with diversity reducing northwards suggesting expansion from the south after the Pleistocene. Our cpDNA and ploidy data indicate at least six independent origins of polyploids.

Base Sequence↗
PubMed2002

Neurological and perceptual-motor outcome at 5 - 6 years of age in children with neonatal encephalopathy: relationship with neonatal brain MRI.

OBJECTIVE: The aims of this study were 1) to determine the incidence of minor neurological dysfunction and perceptual-motor difficulties in children aged 5-1/2 -- 6-1/2, who had been born full-term but presented with neonatal encephalopathy (NE) and low Apgar scores and 2) to examine the relationships between the presence/absence of these difficulties with neonatal brain MRI. PARTICIPANTS AND METHODS: Sixty-eight full-term infants with one minute Apgar scores less than or equal to 5 and neurological abnormalities during the first 48 hours after birth were included in the study. All children had a neonatal MRI brain scan. Surviving infants were assessed between the age of 5 and 6 years using the Touwen Examination, the Movement ABC and the WPPSI-R. RESULTS: Fifteen of the 68 infants (22 %) died in the neonatal period. Of the 53 surviving infants, 19 (36 %) had cerebral palsy. The remaining 34 were considered normal at 2 years of age but, when assessed at school age, 8 (15 %) had minor neurological dysfunction and/or perceptual-motor difficulties, 1 (2 %) had only cognitive impairment and 25 (47 %) were normal. The outcome largely reflected the pattern of lesions on brain imaging. While 83 % of those with a normal outcome had normal scans or minimal white matter lesions, 80 % of those with minor neurological dysfunction and/or perceptual-motor difficulties had mild or moderate basal ganglia or more marked white matter lesions. CONCLUSION: Continued surveillance is recommended for children with apparently normal outcome at two years of age after NE, particularly when abnormalities are detected on brain MRI.

Age Factors↗
PubMed2001

Direct measurements of colloidal friction coefficients.

The time-independent hydrodynamic forces operating between two hard spheres were studied as a function of the interparticle separation r. Two colloids were positioned a distance r apart using a dual-beam optical tweezer similar to that described by Meiners and Quake [Phys. Rev. Lett. 82, 2211 (1999)]. Brownian fluctuations in the positions of the two spheres were followed by recording the intensity of forward scattered laser light. The two particles move cooperatively as a result of hydrodynamic forces. The strength of the correlation increased strongly with decreasing separation r. We show that the temporal and spatial correlations in the particle displacements are determined by the distance dependence of the pair friction tensor xi. The distance and geometry dependence of the measured friction tensor is found to be in excellent agreement with the predictions of low-Reynolds number calculations.

Journal Article↗
PubMed2001

PDSA review.

Explore the source record for details and available documents.

Animals↗
PubMed2001

Relationship between increased longevity and stress resistance as assessed through gerontogene mutations in Caenorhabditis elegans.

We review the status of the hypothesis that interventions that increase the resistance to stress offer the potential for effective life prolongation and increased health. The work focuses on research in the nematode worm Caenorhabditis elegans and describes both published and unpublished results consistent with this hypothesis. Correlation between stress resistance and longevity among many gerontogene mutants is provided.

Aging↗
PubMed2001

The effects of endurance training and exhaustive exercise on mitochondrial enzymes in tissues of the rat (Rattus norvegicus).

The aim of the present study was to ascertain the effects of training and exhaustive exercise on mitochondrial capacities to oxidize pyruvate, 2-oxoglutarate, palmitoylcarnitine, succinate and ferrocytochrome c in various tissues of the rat. Endurance capacity was significantly increased (P<0.01) by an endurance training program over a period of 5-6 weeks. The average run time to exhaustion was 214.2+/-23.8 min for trained rats in comparison with 54.5+/-11.7 min for their untrained counterparts. Oxidative capacities were reduced in liver (P<0.05) and brown adipose tissue (P<0.05) as a result of endurance training. On the contrary, the oxidative capacity of skeletal muscle was slightly increased and that of heart almost unaffected except for the oxidation of palmitoylcarnitine, which was significantly reduced (P<0.05) as a result of training.

Adipose Tissue, Brown↗
PubMed2001

Non-disabled cases in a national survey.

BACKGROUND: Lifetime and 12-month prevalence estimates of mental disorders consistently reported in large-scale community surveys have met with deserved scepticism. A crucial variable is the extent to which people who are considered cases are also disabled by their symptoms. In a national population survey, we hypothesized that an administratively significant proportion of persons with anxiety or depressive disorders according to ICD-10 and DSM-IV would report no disability. METHODS: Interviews were sought on a nationally representative sample of people aged 18 and over across Australia. The Composite International Diagnostic Interview on laptop (CIDI-A) was used by professional survey interviewers to identify persons meeting ICD-10 or DSM-IV criteria for anxiety or depressive disorders in the previous 4 weeks, together with self-reported data on associated disability and medical consultations for the same period. RESULTS: In an achieved sample of 10,641 persons (response rate = 78%), no disability in daily life was reported by 28% of persons with an anxiety disorder and 15% with a depressive disorder by ICD-10 criteria; and by 20.4% and 13.9% respectively by DSM-IV. Non-disabled respondents had lower scores on two measures of psychological distress and markedly lower rates for having consulted a doctor for their symptoms. CONCLUSION: The ICD-10 and DSM-IV criteria for anxiety and depressive disorders, when applied to the information on symptoms elicited by the CIDI-A, inadequately discriminate between people who are and are not disabled by their symptoms. There may be a group of highly symptomatic people in the general population who tolerate their symptoms and are not disabled by them.

Adult↗
PubMed2001

The use of permanent pacemakers in the detection of cardiac arrhythmias.

AIMS: To compare pacemaker telemetry with simultaneous Holter recordings in the diagnosis of atrial fibrillation and to evaluate the STOP-AF study telemetry criteria for the presence of atrial fibrillation. METHODS AND RESULTS: 18 consecutive patients enrolled in the STOP-AF study had simultaneous 24 h Holter recordings and down-loaded pacemaker telemetry. There was good agreement on heart rate, but the STOP-AF pacemaker criteria achieved only 57% sensitivity with 64% specificity for the presence of atrial fibrillation on Holter recording over 24 h. False-positives appeared to result from far-field sensing while false-negatives occurred with very short episodes of atrial fibrillation. The pacemaker's antitachycardia responses were not specific for the presence of atrial fibrillation. CONCLUSION: Pacemaker telemetry is a potentially important source of data on cardiac arrhythmias. Further studies are required to define the limitations of these data in specific devices before they can be interpreted with confidence.

Arrhythmias, Cardiac↗
PubMed2001

Enhancing wire-composite bond strength of bonded retainers with wire surface treatment.

Bonded orthodontic retainers with wires embedded in composite resin are commonly used for orthodontic retention. The purpose of this study was to test, in vitro, various wire surface treatments to determine the optimal method of enhancing the wire-composite bond strength. Coaxial wires and stainless steel wires with different surface treatments were bonded to bovine enamel and then pulled along their long axes with an Instron universal testing machine. Wire surface treatments included placing a right-angle bend in the wire, microetching the wire, and treating the wire with adhesion promoters; combinations of treatments were also examined. The results demonstrated a 24-fold increase in the wire-composite bond strength of wire that was microetched (sandblasted), compared with that of untreated straight wire. The difference between the amount of force required to break the bond produced by microetching alone (246.1 +/- 46.0 MPa) and that required for the bonds produced by the retentive bend (87.8 +/- 16.3 MPa), the adhesion promoters (silane, 11.0 +/- 3.1 MPa; Metal Primer, 28.5 +/- 15.8 MPa), or for any combination of surface treatments, was statistically significant. Microetching a stainless steel wire produced a higher wire-composite bond strength than that obtained from a coaxial wire (113.5 +/- 27.5 MPa). The results of this study indicate that microetching or sandblasting a stainless steel wire significantly increases the strength of the wire-composite bond.

Animals↗