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C Saunders

Publications and source records attributed to C Saunders.

At least 19 recordsLinked to original sources
PubMed2006

Dopamine transporter activity mediates amphetamine-induced inhibition of Akt through a Ca2+/calmodulin-dependent kinase II-dependent mechanism.

The primary mechanism for clearance of extracellular dopamine (DA) is uptake mediated by the dopamine transporter (DAT), which is governed, in part, by the number of functional DATs on the cell surface. Previous studies have shown that amphetamine (AMPH) decreases DAT cell surface expression, whereas insulin reverses this effect through the action of phosphatidylinositol 3-kinase (PI3K). Therefore, it is possible that AMPH causes DAT cell surface redistribution by inhibiting basal insulin signaling. Here, we show in a heterologous expression system and in murine striatal synaptosomes that AMPH causes a time-dependent decrease in the activity of Akt, a protein kinase immediately downstream of PI3K. This effect was blocked by the DAT inhibitor cocaine, suggesting that AMPH must interact with DAT to inhibit Akt. We also showed that AMPH is able to stimulate Ca2+/calmodulin-dependent kinase II (CaMKII) activity, both in the heterologous expression system as well as in murine striatal synaptosomes. The ability of AMPH to decrease Akt activity was blocked by the CaMKII inhibitor 2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine (KN93), but not by its inactive analog 2-[N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine (KN92). Furthermore, preincubation with KN93 prevented the AMPH-induced decrease in DAT cell surface expression. Thus, AMPH, but not cocaine, decreases Akt activity through a CaMKII-dependent pathway, thereby providing a novel mechanism by which AMPH regulates insulin signaling and DAT trafficking.

Amphetamine↗
PubMed2006

Despite having a common P1 Leu, eglin C inhibits alpha-lytic proteinase a million-fold more strongly than does turkey ovomucoid third domain.

Results of the inhibition of alpha-lytic proteinase by two standard mechanism serine proteinase inhibitors, turkey ovomucoid third domain (OMTKY3) and eglin C, and many of their variants are presented. Despite similarities, including an identical P1 residue (Leu) in their primary contact regions, OMTKY3 and eglin C have vastly different association equilibrium constants toward alpha-lytic proteinase, with Ka values of 1.8 x 10(3) and 1.2 x 10(9) M(-1), respectively. Although 12 of the 13 serine proteinases tested in our laboratory for inhibition by OMTKY3 and eglin C are more strongly inhibited by the latter, the million-fold difference observed here with alpha-lytic proteinase is the largest we have seen. The million-fold stronger inhibition by eglin C is retained when the Ka values of the P1 Gly, Ala, Ser, and Ile variants of OMTKY3 and eglin C are compared. Despite the small size of the S1 pocket in alpha-lytic proteinase, interscaffolding additivity for OMTKY3 and eglin C holds well for the four P1 residues tested here. To better understand this difference, we measured Ka values for other OMTKY3 variants, including some that had residues elsewhere in their contact region that corresponded to those of eglin C. Assuming intrascaffolding additivity and using the Ka values obtained for OMTKY3 variants, we designed an OMTKY3-based inhibitor of alpha-lytic proteinase that was predicted to inhibit 10,000-fold more strongly than wild-type OMTKY3. This variant (K13A/P14E/L18A/R21T/N36D OMTKY3) was prepared, and its Ka value was measured against alpha-lytic proteinase. The measured Ka value was in excellent agreement with the predicted one (1.1 x 10(7) and 2.0 x 10(7) M(-1), respectively). Computational protein docking results are consistent with the view that the backbone conformation of eglin C is not significantly altered in the complex with alpha-lytic proteinase. They also show that the strong binding for eglin C correlates well with more favorable atomic contact energy and desolvation energy contributions as compared to OMTKY3.

Amino Acid Sequence↗
PubMed2005

Patients' preferences for adjuvant endocrine therapy in early breast cancer: what makes it worthwhile?

Adjuvant endocrine therapy improves recurrence and survival rates, but has side effects and is inconvenient. The aim of this study was to determine the preferences of premenopausal women who had adjuvant endocrine therapy in a randomised trial. In all, 85 (or eighty-five) women completed semistructured interviews 6-30 months after finishing adjuvant endocrine therapy. Hypothetical scenarios based on known potential survival times (5 or 15 years) and rates (60% or 80% at 5 years) without adjuvant endocrine therapy were used to determine the smallest gains women judged necessary to make their adjuvant endocrine therapy worthwhile. Although a third of the women considered gains of 1% in survival rates or 6 months in survival times sufficient to make their adjuvant endocrine therapy worthwhile, more than half the women required gains of at least 5% in survival rates or 3 years in survival time as necessary to make adjuvant endocrine therapy worthwhile. Larger benefits were required by women who had longer treatment, worse side effects, and by those who were treated with goserelin alone. The route of administration (tablet vs injection) did not affect preferences and some women judged small benefits sufficient to make their adjuvant endocrine therapy worthwhile, but many women required larger benefits than their counterparts in similar studies of preferences for adjuvant chemotherapy.

Adult↗
PubMed2005

In-vitro evaluation of the PALL Leukotrap Affinity Prion Reduction Filter as a secondary device following primary leucoreduction.

BACKGROUND AND OBJECTIVES: A filter (PRF1) designed to remove abnormal prion proteins from red-cell units has been developed. The purpose of this study was to evaluate the quality of red cells produced using this device. MATERIALS AND METHODS: Leucocyte-depleted red-cell units (CPD, CPD-A1 and CPD/SAGM) processed according to standard UK practices were filtered using PRF1. Filtered and control units were stored and sampled on day 1, day 7 and on the date of expiry and were tested using standard measures of red-cell quality. RESULTS: Filtered units were found to have significantly higher percentage haemolysis levels, lower haemoglobin levels and a smaller volume compared with controls. All results, however, were well within the permitted 0.8% haemolysis level at the end of storage and all units met the UK guidelines for haemoglobin and volume. The other test parameters measured showed no significant differences between the test and control units. CONCLUSIONS: The PRF1 filter was found to be easy to use and resulted in red-cell units that met all relevant UK and European Guidelines.

Erythrocyte Transfusion↗
PubMed2003

The utility of computerized neuropsychological assessment of cognitive dysfunction in patients with relapsing-remitting multiple sclerosis.

Traditional paper-and-pencil neuropsychological batteries used to document cognitive deficits in multiple sclerosis (MS) patients lack timing precision. This makes it difficult to accurately measure psychomotor slowing, a central cognitive symptom of MS. Additionally, traditional batteries lack multiple alternate forms necessary to control for practice effects when assessing cognition over time. Finally such batteries are lengthy and expensive. Computerized neuropsychological batteries address many of these shortcomings. They measure response time more precisely, require less administration time, include alternate forms, and are ideal for rapid screening/triage. Although there are normative data on the reliability and validity of computerized measures, there have been no controlled validation studies with MS patients. The current study was designed to validate a computerized neuropsychological battery (ANAM) for use with relapsing-remitting (RR) MS patients. Prior to initiation of interferon-beta-1a (Avonex) treatment, subjects participated in a neuropsychological evaluation consisting of traditional and computerized measures. Moderate-to-high correlations were found between computerized and traditional measures. Computerized tests accurately predicted performance on key traditional tests. The battery was also concordant with traditional measures in identifying RR MS patients with and without neurocognitive impairment. Findings are discussed with respect to increased accuracy and accessibility of neuropsychological evaluations for MS patients.

Adolescent↗
PubMed2002

Renal handling of salt and water in humans during exercise with or without hydration.

Plasma sodium (Na+) concentration, i.e. natraemia, results from body tonicity equilibrium. During exercise, a change in body tonicity can result from an imbalance between intake and loss of Na+, potassium (K+) and water (H2O) due to renal and/or extra-renal mechanisms. Whether exercise-induced changes in kidney function could be responsible for such an imbalance was studied by measuring glomerular filtration rate (creatinine clearance), proximal tubule activity (lithium clearance) and renal handling of Na+ and K+ at rest and during exercise. Since hyponatraemia during or after exercise has been reported, we also investigated whether a water load could be appropriately excreted during exercise. Ten young men pedalled on a cycle ergometer at 60% of maximal oxygen uptake for 45 min with (HE, hydrated exercise) or without (DHE, dehydrated exercise) a supply of water. In both conditions, creatinine, lithium, and electrolyte (Na+ + K+) clearances decreased and natraemia did not change. The DHE induced a loss of body mass (-1.29%), decreased diuresis and large extra-renal water loss [mean (SEM)] [880 (73) ml]. The HE led to no loss in body mass, increased diuresis and lower extrarenal water loss [680 (48) ml]. Electrolyte-free water excretion, negative for DHE, represented 60% of diuresis during HE. Thus the kidney, by increasing electrolyte reabsorption mainly in the proximal tubule, and appropriately excreting a water load, seems efficacious in regulating extracellular fluid volume and body tonicity and so not responsible for the imbalance between (Na+ + K+)/H2O intake and loss. Therefore, extra-renal changes could be the main causes of exercise-induced tonicity imbalances which could ultimately lead to dysnatraemia.

Adaptation, Physiological↗
PubMed2001

MR imaging of the skin and nipple of the breast: differentiation between tumour recurrence and post-treatment change.

Contrast-enhanced MR imaging of the breast has been found to be valuable in the assessment of local recurrence of previously treated breast cancer. We looked specifically at the appearances of the skin and nipple of the treated breast in order to describe the appearances of post-treatment change and recurrence in this region. Thirty-nine women treated for breast cancer had MR imaging of one or both breasts reviewed retrospectively with particular attention to the nipple and skin. The skin and chest wall were assessed for patients with mastectomies. All available histology of the skin and/or nipple, obtained following MR imaging, was reviewed. In patients who did not undergo surgery following MR imaging, clinical follow-up was obtained. Six of 39 cases had nodular enhancing areas seen on MR imaging, which correlated with histology demonstrating tumour recurrence within the skin and/or nipple. Of the remaining 33 patients, changes of linear or diffuse enhancement were seen in the skin and/or nipple of 15 patients. These changes were shown to be benign post-treatment changes at surgery/biopsy in 4 cases or by clinical follow-up in the remainder. In this article we demonstrate differing patterns of contrast enhancement within the skin and nipple in recurrent breast carcinoma vs. post-treatment changes. This suggests that contrast-enhanced MR imaging of the breast may be a useful tool in differentiating tumour recurrence from post-treatment changes within the skin and nipple.

Adenocarcinoma, Mucinous↗
PubMed2001

Aortic valve replacement in geriatric patients: determinants of in-hospital mortality.

BACKGROUND: Aortic valve replacement is a common procedure in elderly patients. There has been a great deal of controversy about the risks associated with early mortality. Uncertainty of the risk associated with a small valve continues to remain controversial. This study was designed to identify the risk factors influencing early mortality and establish an accurate model for the prediction of in-hospital mortality. METHODS: One hundred eighty septuagenarians and octogenarians (58% women; mean age, 76 +/- 4.7 years) underwent primary isolated aortic valve replacement between 1986 and 1997. There was an overall mortality of 16.7% (n = 180). Patients with a body surface area less than 1.8 m2 had an in-hospital mortality of 23.2% (n = 95) compared with 8.1% (n = 74; p = 0.009) for patients with a body surface area of 1.8 m2 or more. Patients with a cardiopulmonary bypass time of less than 100 minutes experienced an early mortality of 8.9% (n = 56) compared with a 10.2% (n = 59) early mortality for patients on bypass time between 100 and 124 minutes and a 29.6% (n = 64) early mortality in patients with a pump time longer than 124 minutes (p = 0.040). RESULTS: Multivariate logistic regression analysis identified small body surface area and long cardiopulmonary bypass time as independent risk factors. A higher mortality was seen in female patients and patients receiving smaller valves. However, there was a strong correlation between small body surface area, small valve size, and female gender. CONCLUSIONS: Small body surface area and long cardiopulmonary bypass time are two independent risk factors in early mortality for elderly patients undergoing primary isolated aortic valve replacement. The use of small valves does not influence early mortality.

Aged↗
PubMed2000

Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine-sensitive mechanism.

The dopamine transporter (DAT) is a target of amphetamine (AMPH) and cocaine. These psychostimulants attenuate DAT clearance efficiency, thereby increasing synaptic dopamine (DA) levels. Re-uptake rate is determined by the number of functional transporters at the cell surface as well as by their turnover rate. Here, we present evidence that DAT substrates, including AMPH and DA, cause internalization of human DAT, thereby reducing transport capacity. Acute treatment with AMPH reduced the maximal rate of [(3)H]DA uptake, decreased AMPH-induced currents, and significantly redistributed the immunofluorescence of an epitope-tagged DAT from the plasma membrane to the cytosol in human embryonic kidney 293 cells. Conversely, DAT inhibitors, such as cocaine, mazindol, and nomifensine, when administered with AMPH, blocked the reduction in [(3)H]DA uptake and the redistribution of DAT immunofluorescence to the cytosol. The reductions of [(3)H]DA uptake and AMPH-induced DAT internalization also were inhibited by coexpression of a dominant negative mutant of dynamin I (K44A), indicating that endocytosis modulates transport capacity, likely through a clathrin-mediated pathway. With this mechanism of regulation, acute application of AMPH would reduce DA uptake not only by direct competition for uptake, but also by reducing the available cell-surface DAT. Moreover, AMPH-induced internalization might diminish the amount of DAT available for DA efflux, thereby modulating the cytotoxic effects of elevated extracellular DA.

Amphetamine↗
PubMed2000

The evolution of palliative care.

An encounter with one patient in 1948 was the catalyst for the Hospice Movement. The challenge to undertake appropriate pain and symptom control together with experience in further listening to patients in the small number of homes especially planned for dying people, finally came together during the 1960s as the impetus for the first modern hospice which opened in 1967. Since then, palliative care has been developing worldwide and has shown that the basic principles demonstrated in those early years can be interpreted in various cultures and with different levels of resources. Symptom control by a multi-professional team backed by research and education of both professionals and public has spread both into home care and into general hospitals. The family is seen as the unit of care as it finds its own potential, searches for meaning and makes the achievements possible at the end of life.

Humans↗
PubMed2000

Diagnosis of breast cancer using elastic-scattering spectroscopy: preliminary clinical results.

We report on the first stages of a clinical study designed to test elastic-scattering spectroscopy, mediated by fiberoptic probes, for three specific clinical applications in breast-tissue diagnosis: (1) a transdermal-needle (interstitial) measurement for instant diagnosis with minimal invasiveness similar to fine-needle aspiration but with sensitivity to a larger tissue volume, (2) a hand-held diagnostic probe for use in assessing tumor/resection margins during open surgery, and (3) use of the same probe for real-time assessment of the "sentinel" node during surgery to determine the presence or absence of tumor (metastatic). Preliminary results from in vivo measurements on 31 women are encouraging. Optical spectra were measured on 72 histology sites in breast tissue, and 54 histology sites in sentinel nodes. Two different artificial intelligence methods of spectral classification were studied. Artificial neural networks yielded sensitivities of 69% and 58%, and specificities of 85% and 93%, for breast tissue and sentinel nodes, respectively. Hierarchical cluster analysis yielded sensitivities of 67% and 91%, and specificities of 79% and 77%, for breast tissue and sentinel nodes, respectively. These values are expected to improve as the data sets continue to grow and more sophisticated data preprocessing is employed. The study will enroll up to 400 patients over the next two years.

Adenocarcinoma↗
PubMed2000

Microtubule-dependent regulation of alpha(2B) adrenergic receptors in polarized MDCKII cells requires the third intracellular loop but not G protein coupling.

Previous studies in cultured, polarized Madin-Darby canine kidney II (MDCKII) renal epithelial cells have demonstrated that the apical steady-state localization and delivery of the A(1) adenosine receptor is modified by disruption of the microtubule network with colchicine, whereas the basolateral localization and trafficking of the alpha(2)-adrenergic receptors (alpha(2)AR) are not; instead, the binding capacity of the alpha(2B)AR, but not alpha(2A)AR or alpha(2C)AR subtypes, is increased in a time-dependent fashion. The present studies explore the molecular basis for this alpha(2B)AR subtype-selective phenomenon. Colchicine selectively increased alpha(2B)AR density at the cell surface, as determined by confocal microscopy, receptor binding, and surface biotinylation studies. The colchicine-induced increase in the functional density of the alpha(2B)AR requires the third intracellular loop because the alpha(2B)AR loop deletion (alpha(2B)ARtriangle upi3) mutant did not show an increased receptor density after colchicine treatment. Furthermore, the colchicine-mediated increase in alpha(2B)AR density is manifest only in polarized cells because colchicine treatment of nonpolarized MDCKII renal epithelial cells as well as simian kidney COSM6 and human embryonic kidney HEK293 cells did not effect an increase in alpha(2B)AR density. Colchicine-dependent increases in alpha(2B)AR density did not depend on functional coupling to G proteins, however, because pretreatment with pertussis toxin did not eliminate the effect of colchicine. These data indicate that microtubule-dependent regulation of alpha(2B)AR density at the basolateral surface of polarized MDCKII cells requires the third intracellular loop of alpha(2B)AR but not functional alpha(2B)AR-G protein coupling.

Animals↗