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Biomedical subjects

P Sharp

Publications and source records attributed to P Sharp.

At least 19 recordsLinked to original sources
PubMed2003

Investing in new technology: the PET experience.

As funding available to health services is limited, demonstrating the cost effectiveness of new technologies is an important step in their introduction. This is especially challenging for diagnostic technologies, for which the usual paradigm of reliance on well-designed, randomised controlled trials may not be appropriate. A recently completed Health Technology Assessment of fluorine-18 deoxyglucose (FDG)-positron emission tomography (PET) imaging in cancer management, focused on addressing whether the introduction of PET imaging would be beneficial to patients in the NHS in Scotland, exemplifies some of the challenges. Although a substantial body of published literature exists for this technology, most of the studies report diagnostic accuracy rather than improved patient outcomes. Direct evidence that such improvement occurs, and is sufficient to meet the NHS' criteria for cost effectiveness, from well-designed trials would constitute the most immediately persuasive case for the introduction of PET imaging. In the absence of such evidence, collaboration is required between a variety of disciplines to synthesise evidence from a variety of sources to create informative decision models that estimate long-term patient outcomes. The use of such decision models enabled the Health Technology Board for Scotland (now a part of NHS Quality Improvement Scotland) to determine that FDG-PET imaging is likely to be cost effective in selected applications and identified long-term patient benefits that it would not be possible to study in a randomised controlled trial.

Cost-Benefit Analysis↗
PubMed2002

Reduced oviposition of Boophilus microplus feeding on sheep vaccinated with vitellin.

The most abundant protein present in Boophilus microplus eggs, vitellin, was isolated and purified as a non-covalent complex of six glyco-polypeptides of Mr 44-107kDa. The protein complex bound haem. Immuno-blots demonstrated that antibodies raised to vitellin recognised a 200kDa polypeptide in the haemolymph of adult female ticks. This is consistent with the general proposal that in arthropods vitellin is derived by proteolytic processing from a large precursor protein, vitellogenin. In parallel with this study, an 80kDa glycoprotein (GP80) was independently purified from larvae of B. microplus using efficacy in vaccination trials as an assay. Antibodies to GP80 also recognised a 200kDa protein in the haemolymph of ticks and a major 87kDa polypeptide present in the vitellin complex. Conversely, antibodies to purified vitellin recognised GP80. The amino-terminal amino acid sequences of the 87kDa vitellin polypeptide and GP80 were identical for at least the first 11 residues and internal peptide sequences from both polypeptides were co-located in a single but incomplete deduced amino sequence of B. microplus vitellogenin. Thus, GP80 is a processed product from vitellogenin and highly related to but not completely identical with the 87kDa vitellin polypeptide. Vaccination trials in the model host sheep were performed with purified vitellin and GP80. Sheep vaccinated with either purified vitellin or GP80 returned significantly reduced numbers of engorged female ticks with decreased weights and reduced oviposition. In contrast, sheep vaccinated with recombinant hexahis-GP80, which was incorrectly folded and not glycosylated showed no significant effects on ticks. It was concluded that vitellin and GP80 could induce immune responses that partially protect sheep from the tick, B. microplus. However, critical protective epitopes are associated with the folding of the protein and/or the oligosaccharides attached to it.

Animals↗
PubMed2001

Zinc regulates the function and expression of the iron transporters DMT1 and IREG1 in human intestinal Caco-2 cells.

Trace metals influence the absorption of each other from the diet and it has been suggested that the divalent metal transporter (DMT1) represents a common uptake pathway for these important micronutrients. However, compelling evidence from our laboratory suggests that DMT1 is predominantly an iron transporter, with lower affinity for other metals. Several studies have shown that increasing dietary iron downregulates DMT1. Interestingly, our current data indicate that zinc upregulates DMT1 protein and mRNA expression and also pH-dependent iron uptake. Transepithelial flux of iron was also increased and was associated with a rise in IREG1 mRNA expression.

Caco-2 Cells↗
PubMed2001

Recruitment of participants for the Estrogen Replacement and Atherosclerosis (ERA) trial. a comparison of costs, yields, and participant characteristics from community- and hospital-based recruitment strategies.

This paper documents recruitment for the Estrogen Replacement and Atherosclerosis trial, a multicenter, placebo-controlled, double-blind angiographic trial of the effects of opposed and unopposed estrogen on coronary atherosclerosis in postmenopausal women (average scheduled duration of follow-up 3.2 years). We compare costs, yields, and participant characteristics between community-based and hospital-based recruitment strategies. We further compare community-based enriched sources (i.e., those that allowed self-selection or targeted women with known health characteristics) and nonenriched sources. Data gathered on potential participants include method of contact, clinical site, eligibility, completion of screening visits, and randomization rates. Demographic data on participants include age, race, education, marital status, and income. Self-reported health status, smoking status, lipid level, ejection fraction as well as history of chest pain, hypertension, and diabetes were recorded at baseline. Recruitment costs were estimated from employee salaries and costs of screening tests and procedures. Yields were compared by clinical site and by method of contact. Enriched sources of recruitment yielded higher percentages of enrolled participants than nonenriched sources. Both types of source resulted in demographically similar participants. Costs of community-based recruitment were less than hospital-based recruitment; however, screening costs were higher. Overall, screening and recruitment averaged $2508 per randomized participant. Control Clin Trials 2001;22:13-25

Aged↗
PubMed2001

Correlation between carotid artery distensibility and serum vascular endothelial growth factor concentrations in type 1 diabetic subjects and nondiabetic subjects.

The relationships between serum vascular endothelial growth factor (VEGF) concentrations and vessel wall ultrasonic characteristics in type 1 diabetic and nondiabetic subjects were assessed. Serum VEGF concentration was measured, and ultrasound imaging and blood pressure recordings were performed in 41 type 1 diabetic subjects (hemoglobin A(1c) [HbA(1c)], 7.63 [1.17%]; duration of diabetes, 12 (0 to 23) years), and 50 nondiabetic subjects. Change in carotid artery luminal diameter during the cardiac cycle was measured using M-mode ultrasound, from which percentage increase in carotid artery luminal diameter was calculated; the carotid artery distensibility index was calculated as the ratio of percentage increase in carotid artery luminal diameter and pulse pressure. Serum VEGF concentration was higher in the diabetic subjects (217 [135 to 336] v 137 [80 to 237] pg/mL; P =.009). The percentage increase in carotid luminal diameter during the cardiac cycle was not significantly different between the 2 groups (12.9 [10.2 to 15.7] v 13.0 [10.6 to 15.0%]; P =.270) despite significantly greater pulse pressure in the type 1 diabetic group (55 [45 to 71] v 46 [41 to 51] mm Hg; P =.0003). The distensibility index was therefore lower in the diabetic subjects (0.24 [0.10] v 0.28 [0.08%]/mm Hg; P =.031). There was a significant negative correlation between serum VEGF concentrations and mean percentage increase in carotid luminal diameter during the cardiac cycle in the diabetic group (r = -.36, P =.021) and in the nondiabetic group (r = -.28, P =.047). This negative correlation could be strengthened by relating mean percentage increase in luminal diameter to pulse pressure to give the distensibility index. Therefore, serum VEGF concentrations correlated strongly and inversely with the distensibility index in the diabetic group (r = -.49, P =.001), in the nondiabetic group (r = -.29, P =.041), and in both groups analyzed together (r = -.42, P <.0001). Vessel wall distensibility may be an important determinant of serum VEGF concentrations in both diabetic and nondiabetic populations and may underlie the previously observed association between blood pressure and serum VEGF concentrations. The pathophysiologic relevance of these findings remains to be elucidated.

Adult↗
PubMed2001

Distribution analysis of the two chicken estrogen receptor-alpha isoforms and their transcripts in the hypothalamus and anterior pituitary gland.

Estrogen plays a key role in the control of reproductive behavior and in the regulation of the neuroendocrine system. To elucidate the mechanisms by which it controls these functions it is important to understand how estrogenic effects are mediated. We have investigated the distribution of the two isoforms of the chicken estrogen receptor alpha (cER-alpha) protein; the previously characterized cER-alpha 66 and a new N-terminal truncated isoform, cER-alpha 61. Immunolocalization demonstrated the presence of cER-alpha 66 protein in hypothalamic areas, principally the nucleus septalis lateralis, bed nucleus striae terminalis medialis, nucleus preopticus medialis, and nucleus infundibuli hypothalami, and in the anterior pituitary gland. When the distribution of ER-alpha immunoreactive cells was compared using the antibodies H 222 (directed against the hormone-binding domain) and ER 221 (directed against the 21-amino acid N-terminus), no apparent differences could be detected. Because this immunocytochemical approach was not able to distinguish whether full-length cER-alpha 66 is the only isoform observed in the ER-positive regions or whether both cER-alpha receptor isoforms are present, SI nuclease assays were performed to compare the relative abundance in these regions of the two distinct classes of cER-alpha mRNA variants (A1-D and A2), which encode the cER-alpha 66 and cER-alpha 61 protein isoforms, respectively. In cockerels and hens, both variants of cER-alpha mRNA are expressed in the anterior pituitary gland and basal hypothalamus with a dominance of the mRNA that encodes cER-alpha 66, whereas the mRNA that encodes cER-alpha 61 was not detectable in the anterior hypothalamus. Therefore, because both receptor isoforms differ in their ability to modulate estrogen target gene expression in a promoter and cell type-specific manner, these differences may mediate the pleiotropic actions of estrogen in reproductive behavior and neuroendocrine functions.

Animals↗
PubMed2000

A chicken gonadotropin-releasing hormone receptor that confers agonist activity to mammalian antagonists. Identification of D-Lys(6) in the ligand and extracellular loop two of the receptor as determinants.

Mammalian receptors for gonadotropin-releasing hormone (GnRH) have over 85% sequence homology and similar ligand selectivity. Biological studies indicated that the chicken GnRH receptor has a distinct pharmacology, and certain antagonists of mammalian GnRH receptors function as agonists. To explore the structural determinants of this, we have cloned a chicken pituitary GnRH receptor and demonstrated that it has marked differences in primary amino acid sequence (59% homology) and in its interactions with GnRH analogs. The chicken GnRH receptor had high affinity for mammalian GnRH (K(i) 4.1 +/- 1.2 nM), similar to the human receptor (K(i) 4.8 +/- 1.2 nM). But, in contrast to the human receptor, it also had high affinity for chicken GnRH ([Gln(8)]GnRH) and GnRH II ([His(5),Trp(7),Tyr(8)]GnRH) (K(i) 5.3 +/- 0.5 and 0.6 +/- 0.01 nM). Three mammalian receptor antagonists were also pure antagonists in the chicken GnRH receptor. Another three, characterized by D-Lys(6) or D-isopropyl-Lys(6) moieties, functioned as pure antagonists in the human receptor but were full or partial agonists in the chicken receptor. This suggests that the Lys side chain interacts with functional groups of the chicken GnRH receptor to stabilize it in the active conformation and that these groups are not available in the activated human GnRH receptor. Substitution of the human receptor extracellular loop two with the chicken extracellular loop two identified this domain as capable of conferring agonist activity to mammalian antagonists. Although functioning of antagonists as agonists has been shown to be species-dependent for several GPCRs, the dependence of this on an extracellular domain has not been described.

Amino Acid Sequence↗
PubMed2000

Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco-2 cells.

The absorption of dietary non-heme iron by intestinal enterocytes is crucial to the maintenance of body iron homeostasis. This process must be tightly regulated since there are no distinct mechanisms for the excretion of excess iron from the body. An insight into the cellular mechanisms has recently been provided by expression cloning of a divalent cation transporter (DCT1) from rat duodenum and positional cloning of its human homologue, Nramp2. Here we demonstrate that Nramp2 is expressed in the apical membrane of the human intestinal epithelial cell line, Caco 2 TC7, and is associated with functional iron transport in these cells with a substrate preference for iron over other divalent cations. Iron transport occurs by a proton-dependent mechanism, exhibiting a concurrent intracellular acidification. Taken together, these data suggest that the expression of the Nramp2 transporter in human enterocytes may play an important role in intestinal iron absorption.

Animals↗
PubMed1999

An instrument for the multiparameter assessment of speech.

This paper describes the development of SNORS+, a clinical, user-friendly instrument for measurement of the articulators during speech. The design criteria for the instrument were based upon a wide-ranging review of current practice and available techniques. SNORS+ allows objective assessment of the function and co-ordination of key articulators. Appropriate targeting of therapy is therefore possible. Visual feedback is provided, for therapy, and an objective measurement of outcome is easily obtained. Preliminary results are presented. These suggest that the instrument will prove extremely useful in the assessment and management of many speech disorders.

Adult↗
PubMed1999

Tomographic reconstruction of the retina using a confocal scanning laser ophthalmoscope.

Retinal imaging with a confocal scanning laser ophthalmoscope (cSLO) involves scanning a small laser beam over the retina and constructing an image from the reflected light. By applying the confocal principle, tomographic images can be produced. However, the thickness of such slices, when compared with the retinal thickness, is too large to give useful 3D retinal images. In this study an algorithm has been developed which fits a double Gaussian curve to the axial intensity profiles generated from a stack of image slices. The underlying assumption is that the laser light has mainly been reflected by two structures in the retina, the internal limiting membrane and the retinal pigment epithelium. From the fitted curve, topographic images and novel thickness images of the retina can be generated. The technique has been applied to three normal volunteers and seven patients with macular pathology (cystoid macular oedema and macular hole) demonstrating the clinical value of the technique. The improvement in accuracy achieved by using a double rather than a single Gaussian is also demonstrated.

Humans↗
PubMed1999

Evaluation of 18F-FDG positron emission tomography in gastric and oesophageal carcinoma.

The aim of this study was to evaluate 18F-fluoro-deoxyglucose (FDG) positron emission tomography (PET) in gastric and oesophageal carcinoma. 16 patients with biopsy proven oesophageal or gastric carcinoma had PET scans. Four patients had advanced disease and received palliative treatment. The remaining 12 patients were randomized to immediate surgery or neoadjuvant chemotherapy. Three patients had repeat PET scans following chemotherapy. PET detected the primary tumour in all cases including stage T1 lesions. Involved locoregional nodes (N1, N2) were not identified separately from the primary tumour. Semiquantitative analysis was performed in the form of tumour to liver activity ratios (TLR). In general, the TLR values were higher in the higher T stages, although there was only one case each of T1 and T2 lesions. PET scanning using 18F-FDG is a sensitive method for detecting primary oesophageal and gastric cancers but is limited in locoregional staging.

Adult↗
PubMed1998

X-linked adrenoleukodystrophy: the Australasian experience.

Our objective was to review the Australasian experience of X-linked adrenoleukodystrophy (ALD), to compare the spectrum of disease seen in Australasia with previously published data from elsewhere, and to assess the reliability of carrier testing. Study design was a retrospective review of records collected over a 15-year period, the setting was an international referral laboratory for the study of metabolic disease, and the subjects were all known cases of ALD diagnosed in Australia and New Zealand between 1981 and 1996 and their families. We estimate that the combined incidence of ALD and its variants in Australasia is at least 1.6 per 100,000. Of 95 affected males, 51 had cerebral adrenoleukodystrophy, 24 had adrenomyeloneuropathy, 15 had Addison's disease only, and 5 remained asymptomatic when last examined. However, the distribution of phenotypes among newly diagnosed patients has changed substantially over the last 15 years, with cerebral forms of the disease forming a decreasing proportion of new diagnoses. The measurement of plasma very long chain fatty acids (VLCFAs) alone detects 93% of women who can be proven to be carriers. The addition of genetic linkage studies or assay of VLCFAs in cultured fibroblasts improved this detection rate to the point that there were no obligate carriers who could not be detected using a combination of two or more techniques.

Adrenoleukodystrophy↗
PubMed1998

99mTc-nanocolloid scintigraphy for assessing osteomyelitis in diabetic neuropathic feet.

Distinguishing osteomyelitis from neuropathic osteoarthropathy in diabetic feet is a common and difficult clinical problem with no highly accurate discriminatory investigation. This study assesses the novel use of marrow scintigraphy and compares it with magnetic resonance imaging (MRI) for the diagnosis of osteomyelitis in neuropathic osteoarthropathic diabetic feet. Nine diabetic patients with chronic foot ulcers were prospectively assessed independently using 99mTc-nanocolloid scintigraphy and MRI. Those patients showing features of osteomyelitis underwent percutaneous bone biopsy or surgical ray excision for histological confirmation. Other patients were followed up clinically for a minimum of 6 months to exclude osteomyelitis. Marrow scintigraphy, in agreement with MRI, demonstrated all four cases of biopsy proven osteomyelitis and excluded three cases with neuropathic osteoarthropathy alone. One case of suspected osteomyelitis of the ankle on marrow scintigraphy, but not MRI, was not confirmed clinically. One case of suspected osteomyelitis on both imaging modalities was shown on biopsy to demonstrate changes of avascular necrosis but not osteomyelitis. In this study 99mTc-nanocolloid scintigraphy shows a sensitivity of 100% and specificity of 60%. An important false positive result is seen with avascular necrosis, both on marrow scintigraphy and on MRI. Although larger studies are needed to evaluate this technique, 99mTc-nanocolloid marrow scintigraphy may be an alternative to MRI for assessing diabetic feet for osteomyelitis.

Adult↗
PubMed1998

Acetylcholine-induced calcium signaling along the rat colonic crypt axis.

BACKGROUND & AIMS: Acetylcholine-induced calcium signaling dynamics have been described in cell monolayers derived from colonic mucosa, but not in intact colonic crypts. The aim of this study was to characterize the spatiotemporal characteristics of calcium signaling induced by acetylcholine in isolated intact rat colonic crypts and to identify the muscarinic receptor subtype coupled to this signaling pathway. METHODS: Isolated crypts from the distal colon of male Wistar rats were loaded with the calcium-sensitive dye Fura-2 and imaged with a charge-coupled device video camera. RESULTS: Acetylcholine mobilized intracellular calcium with an EC50 of 3.9 micromol/L. The response was initiated at the base of the crypt and progressed toward the surface. The velocity of propagation was dose dependent. Addition of muscarinic antagonists inhibited the response (pKb values calculated for pirenzepine and 4-DAMP, 6.08 and 8.65, respectively). Microperfusion of acetylcholine initiated a calcium signal throughout the lower half of the crypt. Microinjection of inositol 1,4,5-triphosphate induced a propagation of a calcium signal along the crypt axis. Heptanol inhibited the velocity of acetylcholine-induced wave propagation by 33%. CONCLUSIONS: M3 muscarinic receptors are coupled to the mobilization of calcium from intracellular stores of intact, isolated rat colonic crypts. Intercellular communication potentiates the propagation of the acetylcholine-induced calcium signal along the crypt axis.

Acetylcholine↗
PubMed1998

Gamma emission imaging in the management of breast disorders.

Breast cancer is the commonest malignancy to affect women. The malignant process may present clinicians with problems in establishing the diagnosis expeditiously, accurately staging the disease and assessing tumour response to primary systemic chemotherapy. Considerable recent interest has focused on the application of imaging techniques that utilize tumour-specific gamma-ray-emitting radiopharmaceuticals to resolve these problems. The wide availability of gamma camera systems makes single photon-imaging techniques, using radiopharmaceuticals incorporating conventional isotopes, attractive options. However, results concerning the detection of the primary breast cancer and the staging of axillary lymph nodes suggest that these techniques would appear to offer no significant advantages, when compared with those obtained using standard diagnostic methods. Dual gamma-ray-emission imaging by positron emission tomography (PET) may offer an alternative solution. Studies performed show that PET can accurately detect primary breast cancers, stage locoregional lymph nodes and visualize distant tumour metastases. Furthermore, PET may be able to monitor early tumour response to chemotherapy agents. It would appear, therefore, that dual gamma emission might have an important role to play in the management of patients with breast cancer.

Bone Neoplasms↗
PubMed1998

Health education to increase screening for cervical cancer among Lumbee Indian women in North Carolina.

Although age-adjusted mortality rates from cancer among Native-Americans are generally lower than for the US population as a whole, cervical cancer mortality rates are higher. This report presents results from a National Cancer Institute-funded health education program conducted among the Lumbee tribe in North Carolina that was designed to increase the proportion of women, age 18 and older, who receive Pap smears to screen for cervical cancer. The Solomon Four Group research design was used for this project. Participants were selected at random from the enrollment records of the Lumbee tribe and data collection was carried out during face-to-face interviews. The health education program was provided one-on-one in women's homes by a trained lay health educator and included verbal, print and videotape information. A total of 979 women were enrolled in the study, and 125 were lost to follow-up between the pre-test and post-test. Women who received the education program were found to be more likely to have knowledge of the Pap smear and to report a Pap smear in the past year at the post-test than those in the control group, regardless of whether they received the pre-test interview, P < 0.05. Women most likely to respond to the education program were also likely to have reported that they receive an annual physical examination. Women with better knowledge of the Pap smear tended to have more education, higher income and greater identification with Native-American culture than those with less knowledge. We conclude that the health education program was associated with greater knowledge about cervical cancer prevention and higher proportions of Lumbee women obtaining Pap smears in the past year.

Adolescent↗
PubMed1998

Staging of the axilla in breast cancer: accurate in vivo assessment using positron emission tomography with 2-(fluorine-18)-fluoro-2-deoxy-D-glucose.

OBJECTIVE: To evaluate the ability of positron emission tomography (PET) with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) to determine noninvasively axillary lymph node status in patients with breast cancer. BACKGROUND: The presence of axillary lymph node metastasis is the most important prognostic factor in women with breast cancer. It signifies the presence of occult metastatic disease and indicates the need for adjuvant therapy. The only reliable way in which this important prognostic information may be obtained is by performing axillary dissection, which may be associated with significant complications and delay in discharge from the hospital. PET with 18F-FDG can visualize primary cancers in the breast and metastatic tumor deposits. METHODS: Fifty patients with untreated breast cancer had clinical examination of their axilla performed (graded as positive or negative), followed by PET of the axilla and midthorax. PET data were analyzed blindly and graded as positive or negative, depending on the presence or absence of axillary nodal metastases. Cytopathologic assessment of the axillary nodes was carried out within 1 week of PET, by fine-needle aspiration cytology in 5 patients and axillary dissection in 45; the excised specimens were examined by a single pathologist. RESULTS: The overall sensitivity of PET in 50 patients was 90% and the specificity was 97%. Clinical examination of the same patients had an overall sensitivity of 57% and a specificity of 90%. In the 24 patients with locally advanced breast cancer (T3, T4, TxN2), PET had a sensitivity of 93% and a specificity of 100%. In T1 tumors (seven patients), the sensitivity and specificity were 100%. PET had a high predictive value (>90%) and accuracy (94%) in staging the axilla. CONCLUSIONS: PET is a sensitive and specific method of staging the axilla in patients with breast cancer. It may obviate the need for axillary surgery in women with small primary tumors, define the women likely to benefit from axillary dissection, or allow radiotherapy to be substituted for surgery, particularly in post-menopausal women.

Adult↗