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Biomedical subjects

Michael Scott

Publications and source records attributed to Michael Scott.

15 recordsLinked to original sources
PubMed2007

Effects of collagen fiber orientation on the response of biologically derived soft tissue biomaterials to cyclic loading.

In the present study, the effects of initial collagen fiber orientation on the medium-term (up to 50 x 10(6) cycles) fatigue response of heart valve soft tissue biomaterials was investigated. Glutaraldehyde treated bovine pericardium (GLBP), preselected for uniform structure and collagen fiber orientation, was used as the representative heart valve biomaterial. Using specialized instrumentation, GLBP specimens were subjected to cyclic tensile loading to maximum stress levels of 500 +/- 50 kPa at a frequency of 22 Hz. Two sample groups were examined, one with the preferred collagen fiber direction parallel (PD) and perpendicular (XD) to the direction of applied strain. The primary findings indicated that GLBP fatigue response was highly sensitive to the direction of loading with respect to fiber orientation. Specifically, when loading perpendicular to the preferred collagen fiber orientation, fiber reorientation is the dominant mechanism. In contrast, when loaded parallel to the preferred fiber direction a reduction in both collagen fiber crimp and fiber reorientation occurred. Moreover, alterations in the degree and direction of mechanical anisotropy can be inducted by cyclic loading when specimens are loaded perpendicular to the preferred fiber direction. Fourier Transform Infrared Spectroscopy (FT-IR) results indicate that molecular-level damage to collagen occurs in both groups after only 20 x 10(6) cycles. Taken as a whole, the results of this study suggest that initial collagen orientation plays a critical role in bioprosthetic heart valve biomaterial fatigue response.

Animals↗
PubMed2006

Lmx1b is required for maintenance of central serotonergic neurons and mice lacking central serotonergic system exhibit normal locomotor activity.

Central serotonergic neurons have been implicated in numerous animal behaviors and psychiatric disorders, but the molecular mechanisms underlying their development are not well understood. Here we generated Lmx1b (LIM homeobox transcription factor 1 beta) conditional knock-out mice (Lmx1b(f/f/p)) in which Lmx1b was only deleted in Pet1 (pheochromocytoma 12 ETS factor-1)-expressing 5-HT neurons. In Lmx1b(f/f/p) mice, the initial generation of central 5-HT neurons appeared normal. However, the expression of both 5-HT-specific and non-5-HT-specific markers was lost in these neurons at later stages of development. The loss of gene expression is concomitant with downregulation of Lmx1b expression, with the exception of serotonin transporter Sert and tryptophan hydroxylase TPH2, whose expression appears to be most sensitive to Lmx1b. Interestingly, the expression of Pet1 is tightly coupled with expression of Lmx1b during later stages of embryonic development, indicating that Lmx1b maintains Pet1 expression. In Lmx1b(f/f/p) mice, almost all central 5-HT neurons failed to survive. Surprisingly, Lmx1b(f/f/p) mice survived to adulthood and exhibited normal locomotor activity. These data reveal a critical role of Lmx1b in maintaining the differentiated status of 5-HT neurons. Lmx1b(f/f/p) mice with normal locomotor function should provide a unique animal model for examining the roles of central 5-HT in a variety of animal behaviors.

Animals↗
PubMed2006

Altered patterns of transcription of the septin gene, SEPT9, in ovarian tumorigenesis.

Ovarian carcinoma represents the most lethal gynaecological malignancy. A variety of morphological subtypes are recognised (e.g. serous, mucinous, endometrioid), which may be benign, borderline or malignant. While their relationship is controversial, knowledge of the molecular mechanisms of ovarian tumorigenesis may help resolve this issue and perhaps identify early markers of disease. Perturbed patterns of expression of the SEPT9 gene on chromosome 17q25.3 have been implicated in a variety of tumour types including both breast and ovarian neoplasia. In preliminary studies, we showed that SEPT9 mRNA was upregulated in a bank of ovarian tumours, which included benign, borderline and malignant tumours, and reported increased levels of one splice variant, SEPT9_v4*. We now describe a comprehensive analysis of SEPT9 expression specifically in serous and mucinous ovarian tumours (benign, borderline and malignant), using cDNA microarray, semi- and quantitative RTPCR of microdissected archival tumour material. Our data show consistent and specific overexpression of both SEPT9_v1 and SEPT9_v4* transcripts in the epithelial component of ovarian tumours. These transcripts show highest levels of expression in serous and mucinous borderline tumours. SEPT9_v1 is also upregulated in both serous and mucinous carcinomas. Interestingly, highest levels of expression are observed in serous borderline and low-grade tumours rather than high-grade in keeping with a model of progression of benign, borderline and low-grade serous tumours.

Cell Transformation, Neoplastic↗
PubMed2006

Atypical reactive proliferation of endocervix: a common lesion associated with endometrial carcinoma and likely related to prior endometrial sampling.

We describe a common, but hitherto not well described, reactive change of the endocervical surface epithelium, commonly seen in association with endometrial carcinoma, and which we term 'atypical reactive proliferation'. This lesion, especially when florid, has the potential to be misinterpreted as a manifestation of a stage 2A endometrial cancer (endocervical glandular involvement). We examined the cervical sections in 80 consecutive hysterectomy specimens of endometrial cancer. In 22 cases (27.5%), there was cervical involvement by tumour and these cases were excluded from further analysis. Of the remaining cases, atypical reactive proliferation involved the endocervical surface in 40 of 58 (69%) cases, although the degree of abnormality varied widely between individual cases. Histological features characteristic of atypical reactive proliferation (not all features were present in each case) included nuclear stratification and multilayering with short micropapillary processes, squamoid change, hobnail cells and mild cytological atypia. Other features present in some cases were surface erosion, clearing of the cytoplasm, fibrin deposition, an inflammatory cell infiltrate and fibrosis of the subepithelial tissue. In 20 control cases, comprising hysterectomy specimens for benign conditions, similar changes were not seen. Vimentin immunohistochemistry was undertaken in eight cases in which atypical reactive proliferation was particularly florid. Five cases were completely negative and three exhibited very focal positivity. Atypical reactive proliferation involving the endocervical surface is commonly seen in association with endometrial cancer and has the potential to be misinterpreted as endocervical involvement by tumour. Although this could represent a reactive change associated with the presence of an endometrial cancer, we feel atypical reactive proliferation is most likely a reactive/reparative response to recent endometrial biopsy or curettage. The vimentin-negative immunophenotype may be of value in cases where the uterine carcinoma is endometrioid in type as these neoplasms are generally vimentin positive.

Adult↗
PubMed2006

Inactivation of prions by acidic sodium dodecyl sulfate.

Prompted by the discovery that prions become protease-sensitive after exposure to branched polyamine dendrimers in acetic acid (AcOH) (S. Supattapone, H. Wille, L. Uyechi, J. Safar, P. Tremblay, F. C. Szoka, F. E. Cohen, S. B. Prusiner, and M. R. Scott, J. Virol. 75:3453-3461, 2001), we investigated the inactivation of prions by sodium dodecyl sulfate (SDS) in weak acid. As judged by sensitivity to proteolytic digestion, the disease-causing prion protein (PrPSc) was denatured at room temperature by SDS at pH values of < or =4.5 or > or =10. Exposure of Sc237 prions in Syrian hamster brain homogenates to 1% SDS and 0.5% AcOH at room temperature resulted in a reduction of prion titer by a factor of ca. 10(7); however, all of the bioassay hamsters eventually developed prion disease. When various concentrations of SDS and AcOH were tested, the duration and temperature of exposure acted synergistically to inactivate both hamster Sc237 prions and human sporadic Creutzfeldt-Jakob disease (sCJD) prions. The inactivation of prions in brain homogenates and those bound to stainless steel wires was evaluated by using bioassays in transgenic mice. sCJD prions were more than 100,000 times more resistant to inactivation than Sc237 prions, demonstrating that inactivation procedures validated on rodent prions cannot be extrapolated to inactivation of human prions. Some procedures that significantly reduced prion titers in brain homogenates had a limited effect on prions bound to the surface of stainless steel wires. Using acidic SDS combined with autoclaving for 15 min, human sCJD prions bound to stainless steel wires were eliminated. Our findings form the basis for a noncorrosive system that is suitable for inactivating prions on surgical instruments, as well as on other medical and dental equipment.

Animals↗
PubMed2006

Impact of Modified System of Objectified Judgement Analysis (SOJA) methodology on prescribing costs of ACE inhibitors.

BACKGROUND AND OBJECTIVES: System of Objectified Judgement Analysis (SOJA) is a structured approach to the selection of drugs for formulary inclusion. How- ever, while SOJA is a very important advance in drug selection for formulary purposes, it is hospital based and can only be applied to one indication at a time. In SOJA, cost has been given a primary role in the selection process as it has been included as a selection criterion from the start. Cost may therefore drive the selection of a particular drug product at the expense of other basic criteria such as safety or efficacy. The aims of this study were to use a modified SOJA approach in the selection of ACE inhibitors (ACEIs) for use in a joint formulary that bridges primary and secondary care within a health board in Northern Ireland, and to investigate the potential impact of the joint formulary on prescribing costs of ACEIs in that health board. METHODS: The modified SOJA approach involved four phases in sequence: an evidence-based pharmacotherapeutic evaluation of all available ACEI drug entities, a separate safety/risk assessment analysis of products containing agents that exceeded the pharmacotherapeutic threshold, a budget-impact analysis and, finally, the selection of product lines. A comprehensive literature review and expert panel judgement informed the selection of criteria (and their relative weighting) for the pharmacotherapeutic evaluation. The resultant criteria/scoring system was circulated (in questionnaire format) to prescribers and stakeholders for comment. Based on statistical analysis of the latter survey results, the final scoring system was developed. Drug entities that exceeded the evidence threshold were sequentially entered into the second and third phases of the process. RESULTS: Five drug entities (11 currently available in the UK) exceeded the evidence threshold and 22 of 26 submitted product lines containing these drug entities satisfied the safety/risk assessment criteria. Three product lines, each containing a different drug entity, were selected for formulary inclusion after budget impact analysis was performed. The estimated potential annual cost savings for ACEIs (based on estimated annual usage in defined daily doses) for this particular health board was 42%. CONCLUSION: The modified SOJA approach has a significant contribution to make in containing the costs of ACEIs. Applying modified SOJA as a practical method for all indications will allow the development of a unified formulary that bridges secondary and primary care.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Multimodality expression profiling shows SEPT9 to be overexpressed in a wide range of human tumours.

Septins are an evolutionarily conserved family of GTPases with diverse functions including roles in cytokinesis that have been implicated in neoplasia. To address the potential role of SEPT9 in tumorigenesis, we assessed the expression of SEPT9 in 7287 fresh frozen human tissue samples and 292 human cell lines by microarray analysis. In addition, we used a sensitive RT-PCR strategy to define the expression of SEPT9 isoforms in archival formalin-fixed and paraffin-embedded normal human tissues. The mRNA data were further confirmed by immunohistological analyses of SEPT9 protein expression in normal human tissues using antisera that detect SEPT9 isoforms. Using these complementary approaches, we demonstrate that SEPT9 mRNA and protein are expressed ubiquitously, with the isoforms showing tissue-specific expression. The microarray analysis indicates that there is consistent overexpression of SEPT9 in diverse human tumours including breast, CNS, endometrium, kidney, liver, lung, lymphoid, oesophagus, ovary, pancreas, skin, soft tissue and thyroid. Since tumours are commonly associated with enhanced cell proliferation, we examined the possible correlation of Ki67 and SEPT9 expression in normal tissues and tumours. Our data indicate that the overexpression of SEPT9 in neoplasia is not simply a proliferation-associated phenomenon, despite its role in cytokinesis.

Cell Movement↗
PubMed2004

Response of heterograft heart valve biomaterials to moderate cyclic loading.

We have recently demonstrated that noncalcific tissue damage can lead to significant collagen degradation in clinically explanted bioprosthetic heart valves (BHVs). In the present study we quantified the early response of glutaraldehyde treated bovine pericardium (GLBP) to cyclic tensile loading to begin to elucidate the mechanisms of noncalcific tissue degeneration in BHV biomaterials. GLBP specimens were cycled at 30 Hz to a maximum uniaxial strain of 16% (corresponding to approximately 1-MPa peak stress), with the loading direction parallel to the preferred collagen fiber (PD) direction. After 30 x 10(6) cycles, specimens were subjected to biaxial mechanical testing, then cycled until 65 x 10(6) cycles. The results indicated a permanent change in the unloaded tissue dimensions of +7.1% strain in the PD direction and -7.7% strain in the cross fiber direction (XD) after 65 x 10(6) cycles and an increase of the collagen crimp period from 40.6 to 45.2 microm by 65 x 10(6) cycles (p = 0.05). Fourier transform IR spectroscopy analysis indicated that cyclic fatigue of GLBP leads to both collagen conformational changes and early denaturation. Furthermore, no significant changes in areal strain were found under 1-MPa equibiaxial stress, indicating that cyclic loading changed the collagen fiber orientation but not the overall tissue compliance. These observations suggest that while deterioration of collagen begins immediately, fiber straightening and reorientation dominates the changes in the mechanical behavior up to 65 x 10(6) cycles. The present study underscores the complexity of the response of biologically derived biomaterials to cyclic mechanical loading. Improved understanding of these phenomena can potentially guide the development of novel chemical treatment methods that seek to improve BHV durability by minimizing these degenerative processes.

Animals↗
PubMed2004

Evaluation of a hospital-based community liaison pharmacy service in Northern Ireland.

OBJECTIVE: To evaluate the impact of a hospital based community liaison pharmacy service on a range of outcomes in patients aged more than 55 years and taking more than 3 prescribed drugs, who had been admitted to the medical unit of a district general hospital in Northern Ireland. METHODS: Having recruited 243 patients, a total of 162 patients completed the full protocol (81 randomly assigned to intervention and 81 to control; mean age of control patients 75 years; mean age of intervention patients 73 years). The interventions by the community liaison pharmacist included: preparation of an accurate medication record following a full review of current medication use; medication counselling; provision of a medicines record sheet informing the patient how to take their drugs; provision of a pharmaceutical discharge letter detailing changes made to drug therapy (this was faxed to the patient's GP and community pharmacist on the day of discharge); provision of a Medicines Helpline. RESULTS: The key findings were as follows: problems were identified in 80% of the intervention patients' prescription charts, 49% of which related to drug omissions from the patients' domiciliary prescriptions. The GP practice record was the most accurate (mean error rate 12.6%) while the GP referral letter was the least accurate (mean error rate 47.3%) source of medication information. Drugs patients brought to hospital were also an inaccurate source (mean error rate 44.0%). The intervention group patients, when compared with control patients, had a significant reduction (P = 0.005) in drug mismatch between drugs prescribed at discharge and taken at home, and had a greater knowledge of their drug regimen 10-14 days after discharge (P < 0.001). The vast majority of patients (96%) felt that the provision of a medicine helpline was a useful service. CONCLUSIONS: The study indicated clear benefits from the involvement of a hospital based community liaison pharmacist in achieving seamless pharmaceutical care between the primary and secondary healthcare settings.

Aged↗
PubMed2004

Bone loss at the os calcis compared with bone loss at the knee in individuals with spinal cord injury.

BACKGROUND/OBJECTIVE: The objective of this study was to document acute bone loss at the os calcis and compare it with bone loss at the knee following spinal cord injury (SCI) as a potential proxy for bone loss in individuals with SCI. METHODS: Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DEXA) at the knee and os calcis, which also was assessed by ultrasound in 6 individuals--5 with complete SCI and 1 with incomplete SCI--at means of 33.5 and 523 days following injury. RESULTS: Bone mineral was progressively greater as measured from proximal to distal sites. The net average BMD of the knee declined 24% (P = 0.017). The distal femur lost 27% (P = 0.038) and the proximal tibia lost 32% (P = 0.015), whereas the os calcis lost 38% (P = 0.001) as measured by DEXA and 49% (P < 0.001) as estimated from ultrasound. The mean loss of 24% at the knee was significantly different from the loss percentages at the os calcis as measured by both techniques: DEXA (P = 0.036) and ultrasound (P = 0.043). Differences between annualized loss rates at the knee and the os calcis measured by both techniques also were significant: DEXA (P = 0.032) vs ultrasound (P = 0.038). However, annualized loss rates demonstrated the same trend for differential loss at the sites examined in the 5 individuals with complete injuries but not for the 1 participant with an incomplete injury. The loss rates were similar for the complete and incomplete participants at the os calcis, but not at the knee. CONCLUSION: The BMD of the os calcis declined 38% by DEXA and 49% by ultrasound compared with 24% at the knee when measured 1 to 1.5 years after injury. BMD of the os calcis and distal femur measured by DEXA in persons with complete SCI were highly correlated (r = 0.84, P < 0.0001).

Absorptiometry, Photon↗
PubMed2003

Methods for a randomized trial of weight-supported treadmill training versus conventional training for walking during inpatient rehabilitation after incomplete traumatic spinal cord injury.

The authors describe the rationale and methodology for the first prospective, multicenter, randomized clinical trial (RCT) of a task-oriented walking intervention for subjects during early rehabilitation for an acute traumatic spinal cord injury (SCI). The experimental strategy, body weight-supported treadmill training (BWSTT), allows physical therapists to systematically train patients to walk on a treadmill at increasing speeds typical of community ambulation with increasing weight hearing. The therapists provide verbal and tactile cues to facilitate the kinematic, kinetic, and temporal features of walking. Subjects were randomly assigned to a conventional therapy program for mobility versus the same intensity and duration of a combination of BWSTT and over-ground locomotor retraining. Subjects had an incomplete SCI (American Spinal Injury Association grades B, C, and D) from C-4 to T-10 (upper motoneuron group) or from T-11 to L-3 (lower motoneuron group). Within 8 weeks of a SCI, 146 subjects were entered for 12 weeks of intervention. The 2 single-blinded primary outcome measures are the level of independence for ambulation and, for those who are able to walk, the maximal speed for walking 50 feet, tested 6 and 12 months after randomization. The trial's methodology offers a model for the feasibility of translating neuroscientific experiments into a RCT to develop evidence-based rehabilitation practices.

Exercise Test↗
PubMed2002

Measuring prions causing bovine spongiform encephalopathy or chronic wasting disease by immunoassays and transgenic mice.

There is increasing concern over the extent to which bovine spongiform encephalopathy (BSE) prions have been transmitted to humans, as a result of the rising number of variant Creutzfeldt-Jakob disease (vCJD) cases. Toward preventing new transmissions, diagnostic tests for prions in livestock have been developed using the conformation-dependent immunoassay (CDI), which simultaneously measures specific antibody binding to denatured and native forms of the prion protein (PrP). We employed high-affinity recombinant antibody fragments (recFab) reacting with residues 95-105 of bovine (Bo) PrP for detection and another recFab that recognizes residues 132-156 for capture in the CDI. We report that the CDI is capable of measuring the disease-causing PrP isoform (PrP(Sc)) in bovine brainstems with a sensitivity similar to that of end-point titrations in transgenic (Tg) mice expressing BoPrP. Prion titers were approximately 10(7) ID(50) units per gram of bovine brainstem when measured in Tg(BoPrP) mice, a figure approximately 10 times greater than that determined by bioassay in cattle and approximately 10,000x greater than in wild-type mice. We also report substantial differences in BoPrP(Sc) levels in different areas of the obex region, where neuropathology has been consistently observed in cattle with BSE. The CDI was able to discriminate between PrP(Sc) from BSE-infected cattle and Tg(BoPrP) mice as well as from chronic wasting disease (CWD)-infected deer and elk. Our findings argue that applying the CDI to livestock should considerably reduce human exposure to animal prions.

Animals↗
PubMed2002

Influence of a nurse practitioner on non-attendance rate for barium enema.

Non-attendance for barium enema investigation wastes resources, prolongs waiting times and delays diagnosis of colorectal carcinoma. In an inner-city hospital with a previous non-attendance rate of over 20% for barium enema we investigated the value of systematic personal contact with a nurse practitioner at the time of booking. We compared two groups of patients, all of whom received an explanation of the procedure from the referring clinician. Patients referred from the colorectal clinic were accompanied by the colorectal nurse practitioner to the radiology department for booking, an appointment being sent later by mail. The nurse practitioner reiterated the details of the procedure, provided supplementary information, confirmed the patient's contact details and provided a telephone number in case further information or assistance was needed. Patients referred from the gastroenterology clinic were managed as previously, making their own way to the radiology department and receiving supplementary information only on request. The patients referred from the two clinics were closely similar; however, the non-attendance rate for the intervention (colorectal) clinic was 4/157 (2.5%) compared with 17/110 (15.5%) for the comparison clinic (P<0.001). A year previously the non-attendance rates in these clinics had been 23% and 20%, respectively. These results indicate that personal contact, with supplementary information, can substantially reduce the non-attendance rate for barium enema.

Appointments and Schedules↗