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Biomedical subjects

R Reilly

Publications and source records attributed to R Reilly.

At least 19 recordsLinked to original sources
PubMed2004

Pattern recognition approach to the detection of single-trial event-related functional magnetic resonance images.

Functional magnetic resonance imaging (FMRI) is an imaging technique for determining which regions of the brain are activated in response to a stimulus or event. Early FMRI experiment paradigms were based upon those used in positron emission tomography (PET), i.e. employing a block design consisting of extended periods of 'on' against 'off' activations. More recent experiments were based on event-related FMRI, harnessing the fact that very short stimuli trains or single events can generate robust responses. FMRI data suffer from low signal-to-noise ratios, and typical event-related experiment paradigms employ selective averaging over many trials before using statistical methods for determining active brain regions. The paper reports a pattern recognition approach to the detection of single-trial FMRI responses without recourse to averaging and at modest field strengths (1.5T). Linear discriminant analysis (LDA) was applied in conjunction with different feature extraction techniques. Use of the unprocessed data samples as features resulted in single-trial events being classified with an accuracy of 61.0 +/- 9.5% over five subjects. To improve classification accuracy, knowledge of the ideal template haemodynamic response was used in the feature extraction stage. A novel application of parametric modelling yielded an accuracy of 69.8 +/- 6.3%, and a matched filtering approach yielded an accuracy of 71.9 +/- 5.4%. Single-trial detection of event-related FMRI may yield new ways of examining the brain by facilitating new adaptive experiment designs and enabling tight integration with other single-trial electrophysiological methods.

Brain↗
PubMed1999

Human endothelin-1 clearance kinetics revealed by a radiotracer technique.

Levels of endothelin-1 (ET-1) are elevated in many disease states, although its total body kinetics of elimination are poorly understood. Therefore, it remains uncertain whether the presence of elevated levels of ET-1 in the setting of disease are secondary to changes in production or clearance or some combination thereof. Using a 125I-labeled ET-1 infusion technique, the volume of distribution and kinetics of clearance of endothelin were described in five normal volunteers. Heart rate, blood pressure, right atrial pressure, and arterial blood samples for the counting of 125I and the measurement of ET-1 were obtained at multiple time points before and up to 45 h after the start of the infusion. The radiotracer infusion had no effect on heart rate, blood pressure, right atrial pressure, or endogenous ET-1 levels. ET-1 clearance was best described by a three-compartment model, which revealed that ET-1 has a much longer terminal half-life and volume of distribution than was previously reported. This suggests extensive uptake of ET-1 in various organ systems and slow clearance. These new findings have important implications for the understanding of the pathophysiology of ET-1 in disease states as well as for the understanding and development of ET-1 receptor blockers and endothelin-converting enzyme inhibitors.

Adult↗
PubMed1998

Vasopressin-induced activation of protein kinase C in renal epithelial cells.

Recent studies indicate that the actions of arginine vasopressin (AVP) and other agonists that stimulate electrogenic sodium transport in renal epithelial A6 cells are linked to a Ca(2+)-mobilizing signal transduction mechanism that involves generation of inositol trisphosphate. Since diacylglycerol is the other product in this pathway, studies were performed to determine the possible role of PKC in the stimulation of sodium transport. AVP induced a biphasic increase in diacylglycerol generation, characterized by an initial rapid rise and then a sustained elevation, and PKC activation, reflected by phosphorylation of a specific 80 kDa myristoylated alanine-rich PKC substrate (MARCKS). To determine the PKC isoform(s) involved in this process, immunoblot analysis was performed using antisera that recognize both classical PKC isoforms, XPKC-I and XPCK-II, cloned from Xenopus oocytes. The transcripts of both isoforms were expressed in the A6 cell. Since protein recognized by antisera was translocated from cytosol to the particulate fraction after exposure to AVP, one or both isoforms were activated in the A6 cell. Further studies showed that cyclohexyladenosine and insulin, additional agonists of sodium transport in A6 cells, also stimulated phosphorylation of MARCKS. These results argue that Ca(2+)-dependent PKC is involved in the action of AVP, and that of other agonists, which stimulate sodium transport.

Adenosine↗
PubMed1998

The effect of glycemic control in the pre-conception period and early pregnancy on birth weight in women with IDDM.

OBJECTIVE: To examine data from pregnancies in women with IDDM to assess the relative effects of mean glycosylated hemoglobin levels before conception, at booking, and during the 3 trimesters of pregnancy on birth weight. Good glycemic control during pregnancy in women with IDDM is important to minimize the risk of fetal malformation and macrosomia. Recent studies have suggested that glycemic control in the 1st trimester is more important than glycemic control during the 2nd or 3rd trimesters. RESEARCH DESIGN AND METHODS: The case records of 65 deliveries to women with IDDM were reviewed. Fifty-seven deliveries were included in the present study. Of the deliveries reviewed, 32 women were in their first pregnancy and 25 women were multiparous. Only viable pregnancies were included because the major outcome variable of interest was birth weight. Glycosylated hemoglobin was recorded for each time period. RESULTS: The median standardized birth weight was 1.1 SD higher than the nondiabetic mean. When pregnancies, in which the birth weight was greater than 1 SD above the nondiabetic mean, were compared with pregnancies, in which birth weight was less than 1 SD above the mean, significant differences were observed between the groups in HbA1 at 6-12 months pre-conception (10.0 +/- 2.3 vs. 8.6 +/- 1.4%, P = 0.02), at 0-6 months pre-conception (10.2 +/- 2.4 vs. 8.7 +/- 2.0%, P = 0.03), at booking (9.5 +/- 2.2 vs. 8.4 +/- 1.6%, P = 0.04), and at 0-12 weeks' gestation (9.5 +/- 2.2 vs. 8.0 +/- 1.3%, P = 0.04), but HbA1 later in pregnancy did not differ significantly between the groups. Correlational analysis of all 57 pregnancies revealed significant correlations between birth weight and HbA1 at 0-6 months pre-conception (r = 0.44, P = 0.002), at booking (r = 0.43, P = 0.001), at 0-12 weeks' gestation (r = 0.48, P = 0.001), at 12-24 weeks' gestation (r = 0.45, P = 0.001), and at 24 weeks to term (r = 0.34, P = 0.009). However, with stepwise regression analysis, only HbA1 at 0-12 weeks' gestation entered into the equation with a multiple r value of 0.48. CONCLUSIONS: Glycemic control in the immediate pre-conception period and early 1st trimester appears to have a greater influence on birth weight than does glycemic control during the later weeks of pregnancy.

Adult↗
PubMed1997

Soluble human urokinase receptor is composed of two active units.

The mechanism by which single-chain urokinase (scuPA) binds to its receptor (uPAR) is incompletely understood. We report that a fragment comprising the first domain of recombinant soluble uPAR (sDI) as well as a fragment comprising the remaining domains (sDII-DIII) competes with the binding of recombinant full-length soluble uPAR (suPAR) to scuPA with an IC50 = 253 nM and an IC50 = 1569, respectively. sDII-III binds directly to scuPA with Kd = 238 nM. Binding of scuPA to each fragment also induces the expression of plasminogen activator activity. sDI and sDII-DIII (200 nM each) induced activity equal to 66 and 36% of the maximum activity induced by full-length suPAR (5 nM), respectively. Each fragment also stimulates the binding of scuPA to cells lacking endogenous uPAR. Although scuPA binds to sDI and to sDII-DIII through its amino-terminal fragment, the fragments act synergistically to inhibit the binding of suPAR and to stimulate plasminogen activator activity. Furthermore, sDII-DIII retards the velocity and alters the pattern of cleavage of sDI by chymotrypsin. These results suggest that binding of scuPA to more than one epitope in suPAR is required for its optimal activation and association with cell membranes.

Humans↗
PubMed1997

Sodium-hydrogen exchange isoform expression in blood cells: implications for studies in diabetes mellitus.

There have been many reports of increased Na-H exchange (NHE) activity in the peripheral blood cells (erythrocytes, lymphocytes and platelets) of patients with diabetes mellitus compared to nondiabetic controls. This raised NHE activity has been hypothesized to reflect increased NHE activity in kidney and vascular smooth muscle. Raised NHE activity in these tissues could play a pathophysiological role in mediating hypertension, vascular smooth muscle cell proliferation and progressive renal impairment. It is now known that there are at least five NHE isoforms, but a specific study examining expression of NHE isoforms in peripheral blood cells has not been reported. This study used specific antisera to NHE isoforms 1, 3 and 4 to examine NHE expression by immunoblot analysis. Erythrocyte, lymphocyte and platelet membranes from both rabbit and rat were separated by standard methods. A monoclonal antibody to NHE-1 reacted with a 100-110 kDa band in rabbit and rat platelets and lymphocytes (identical to that observed in basolateral-enriched renal cortical vesicles) and a 100 kDa band in rabbit and rat erythrocytes. In both species, the intensity of the staining was greatest in platelet membranes. A polyclonal antibody to NHE-3, the isoform present on the apical membranes of renal proximal tubule, showed no evidence of staining in any of the peripheral blood cell preparations. Similarly there was no evidence of expression of NHE-4 in the peripheral blood cell preparations. Peripheral blood cells express NHE-1, which likely accounts for amiloride-sensitive Na-H exchange in these cells, playing a role in cell volume and pH regulation. However, there is no evidence that there is expression of NHE-3 or NHE-4 in peripheral blood cells. These data have implications for studies in hypertension and diabetes mellitus which measure peripheral blood cell Na-H exchange and hypothesize regarding a direct pathophysiological role for this increased activity.

Animals↗
PubMed1996

Single-chain urokinase-type plasminogen activator bound to its receptor is relatively resistant to plasminogen activator inhibitor type 1.

Urokinase-type plasminogen activator (uPA) is synthesized as single-chain protein (scuPA) with little intrinsic activity. scuPA is activated when it is converted to two-chain urokinase (tcuPA) by plasmin or when it binds as a single-chain molecule to its cellular receptor (uPAR). Previous data indicate that complexes between scuPA and its receptor have somewhat higher affinity for plasminogen than does tcuPA. The current study indicates that plasminogen activator activity of scuPA bound to recombinant, soluble uPAR (suPAR) is also fivefold less sensitive to inhibition by plasminogen activator type 1 (PAI-1) than is soluble or receptor-bound tcuPA. Binding of PaI-1 to suPAR/scuPA complexes is totally reversible and can be overcome by increasing the concentration of plasminogen, suggesting a competitive mechanism of inhibition (Ki = 18 nmol/L). Binding of scuPA to suPAR also retards its cleavage by plasmin. These results indicates that binding of single-chain urokinase to its receptor promotes its activity, retards its inhibition, and protects it from conversion to a two-chain form of the enzyme, a step that may precede its inactivation and clearance from cell surfaces. These results are consistent with a physiologic role for receptor-bound single-chain urokinase as a cellular plasminogen activator.

Cell Line↗
PubMed1995

Expression of the thiazide-sensitive Na-Cl cotransporter in rat and human kidney.

An electroneutral thiazide-sensitive Na-Cl cotransport pathway (TSC) has been localized functionally to the distal convoluted tubule (DCT), although the TSC has also been detected in the connecting tubule (CNT), the cortical collecting duct, and the medullary collecting tubule as well. The present experiments were designed to localize expression of message for the TSC in rat and human kidney. A riboprobe, generated from the mouse TSC, was used for in situ hybridization. Simultaneous immunocytochemistry, using antibodies to Tamm-Horsfall protein, band 3, and the Na+/Ca2+ exchanger, permitted delineation of specific nephron segments. In rat, message for the TSC was highly expressed in DCT cells but not elsewhere. The transition from thick ascending limb to DCT was abrupt, whereas the transition to CNT was gradual. In the more distal region of rat DCT (DCT-2), which contained few intercalated cells, both TSC message and Na+/Ca2+ exchanger immunoreactivity were present. Treatment of rats with furosemide for 5 days increased expression of TSC message within the DCT but did not induce its expression elsewhere. In humans, expression of TSC message was also highest in cells of the DCT. In humans, however, expression extended well into the CNT. These experiments indicate that the TSC is expressed predominantly by DCT cells in both rat and humans, although expression extends into the CNT cells in humans. They also show that the TSC and Na+/Ca2+ exchanger are coexpressed by a subpopulation of DCT cells near the junction with the CNT.

Animals↗
PubMed1994

Discern--an integrated prospective decision support system.

We present a new integrated decision support tool, called Discern, for prospective case management within a comprehensive Healthcare Network Architecture (HNA). Discern is an event-driven, expert system tightly integrated into this architecture. It can perform a variety of actions including generating alerts, ordering tests, and entering results. Over 100 institutions use Discern to automate care processes. Discern was designed to meet the demanding requirements for effective decision support.

Decision Making, Computer-Assisted↗
PubMed1993

A randomized controlled trial of computerized pharmacokinetic theophylline dosing versus empiric physician dosing.

This study was undertaken to determine if a computerized pharmacokinetic program for adjusting theophylline infusion rates could attain a goal serum theophylline level more accurately than physician-derived adjustments and what clinical impact this would have. Thirty-five patients with diagnoses of asthma or chronic obstructive pulmonary disease were randomized to a control group (empiric) or experimental group (kinetic) after initial theophylline levels were drawn from each group. After second levels were drawn, patients in the kinetic group had their infusion rates adjusted by the computerized pharmacokinetic program to achieve a level of 15 mg/L, whereas patients in the empiric group had their infusions adjusted empirically by the primary care physicians to achieve a serum theophylline level of 15 mg/L. A final theophylline level was obtained just before the infusion was discontinued. The kinetic group was closer to the goal level of 15 mg/L than the empiric group, but this was not statistically significant (14.8 +/- 4.4 versus 12.6 +/- 4.1; p > 0.05). The total number of days that patients were receiving intravenous theophylline was slightly longer for the kinetic group (4.1 +/- 3.3 versus 3.2 +/- 1.5; p > 0.05) as was the total number of hospital days, but neither of these were statistically significant (11.4 +/- 21.6 versus 8.8 +/- 15.4 days; p > 0.05). There were no differences between the two groups in the number of subtherapeutic or toxic levels, and there were no significant differences in arterial blood gas measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

NHE3: a Na+/H+ exchanger isoform of renal brush border.

Na+/H+ exchangers in the brush-border (luminal, apical) membrane of renal proximal tubules are responsible for active, transcellular reabsorption of NaHCO3 and NaCl. Although well characterized kinetically, the protein that mediates Na+/H+ exchange in the renal brush border has not been identified. Several Na+/H+ exchanger genes, including NHE1, NHE2, NHE3, and NHE4, are expressed in the kidney. To identify the NHE3 gene product and to determine its cellular and subcellular localization in the rabbit kidney, an NHE3-isoform-specific antibody was prepared. Guinea pigs were immunized with purified fusion protein containing the carboxy-terminal 40 amino acids of NHE3 (fpNHE3-C40). After affinity purification, immune sera demonstrated specific reactivity to the NHE3 sequence within the fusion protein as well as to an 80-kDa polypeptide expressed in NHE3-transfected LAP1 cells. Western blot analysis showed that anti-fpNHE3-C40 specifically reacted with an 80-kDa protein that is relatively enriched in renal brush-border membrane compared with basolateral membrane. Immunocytochemical studies confirmed that the Na+/H+ exchanger isoform NHE3 is expressed along the microvillar membrane of the brush border of proximal tubule cells in the rabbit kidney.

Animals↗
PubMed1993

Radioimmunodetection of colorectal cancer metastases with 131I-labeled monoclonal antibody B72.3: a pilot study to determine efficacy of detection and pharmacokinetics.

We performed radioimmunoscintigraphy (RIS) and/or pharmacokinetic (PCK) studies in 12 patients with primary or metastatic colorectal carcinoma, utilizing an intravenous administration of 1-4 mCi (1 mg) of 131I-B72.3 monoclonal antibody. Metastatic lesions were correctly identified in 4/8 patients by RIS. Two patients with small lesions (> 2 cm diameter) had a false-negative RIS scan. Two patients had a true-negative RIS scan. Optimal images were obtained at 1 week postinjection. PCK studies showed that the plasma clearance of 131I-B72.3 was biexponential with an alpha-phase half-life ranging from 0.5 to 7.1 hr and a beta-phase half-life ranging from 47.5 to 85.3 hr. Systemic and renal clearance data indicated that 131I-B72.3 was cleared very slowly and almost entirely by deiodination. This pilot study was conducted to gain an understanding of the pharmacokinetics of this radiolabeled antibody. On the basis of these data, we are now studying second-generation antibodies as part of our long-range objectives to incorporate them in early detection and treatment protocols.

Adult↗
PubMed1992

Intraperitoneal therapy of malignant ascites associated with carcinoma of ovary and breast using radioiodinated monoclonal antibody 2G3.

A phase I/II study of intraperitoneal (ip) radioimmunotherapy was conducted in ovarian or breast cancer patients with symptomatic chemotherapy-resistant ascites using a novel anti-mucin monoclonal antibody (mAb) 2G3 labeled with 131I. Tracer doses of 2 mCi [131I]2G3 were given by ip injection to 11 patients, followed by increasing therapeutic doses up to 150 mCi (cumulative) in 9 patients. There was no serious toxicity. Temporary palliation of ascites was observed in 3 of 4 patients who received doses greater than 50 mCi. Total body elimination half-life of the radiolabeled antibody assessed by gamma scintigraphy ranged from 95 to 250 hr, longer than data previously reported in patients without ascites treated with ip administered radiolabeled antibodies. However, uptake of radiolabel by tumor nodules was small and variable (2 x 10(-4) - 2 x 10(-2) % ID/g), and preferential uptake by tumor compared to normal peritoneum was observed in only 2 of 5 patients in whom biopsies were obtained. These results suggest that the observed palliation of ascites is due to prolonged retention of radiolabeled antibody in the peritoneal cavity even in the absence of specific targeting.

Adult↗
PubMed1992

In vitro stability of EDTA and DTPA immunoconjugates of monoclonal antibody 2G3 labeled with indium-111.

Monoclonal antibody 2G3 directed against a high molecular weight glycoprotein on breast and ovarian cancer cells was conjugated with bicyclic DTPA (or EDTA) anhydride or benzyl isothiocyanate DTPA (benzyl DTPA) and labeled with 111In. DTPA anhydride was more reactive with the antibody than benzyl DTPA, and kinetics of labeling with 111In were more rapid for DTPA substituted 2G3 than for benzyl DTPA substituted 2G3. On the other hand, 111In-2G3 conjugates prepared using DTPA anhydride were subject to more extensive dimerization and higher losses in immunoreactivity than those prepared using benzyl DTPA. On the basis of measurement of transchelation to transferrin, the stability of 111In-2G3 prepared using DTPA anhydride or benzyl DTPA did not differ during incubation in human plasma for 6 days at 37 degrees C. These results suggest that an important advantage of benzyl DTPA over DTPA anhydride for preparing 111In-labeled antibodies is the prevention of intermolecular (and intramolecular) crosslinking during conjugation which ultimately leads to alterations in conformation and losses in immunoreactivity of the radioimmunoconjugate.

Antibodies, Monoclonal↗
PubMed1991

Imaging of human ovarian tumour xenografts in nude mice using a novel 111In-labelled monoclonal antibody (10B).

Monoclonal antibody (mAb) 10B, directed against the human ovarian adenocarcinoma cell line, HEY, was conjugated with cyclic DTPA anhydride and labelled with 111In. The biodistribution of 111In-DTPA-10B was determined in non-tumour bearing mice and mice bearing subcutaneous (s.c.) and intraperitoneal (i.p.) HEY tumours. The radiolabel was preferentially targeted to s.c. and i.p. tumours in comparison with a control mAb. 111In-DTPA-2G3, which does not bind to HEY cells. Among normal organs, the predominant uptake of radiolabel was into liver and kidney. Subcutaneous tumours were successfully imaged using external gamma scintigraphy following i.v. injection of 111-In-DTPA-10B. The results suggest that 111In-DTPA-10B may be a useful agent for the diagnostic imaging of tumour masses in patients with ovarian cancer.

Animals↗
PubMed1991

Transabdominal esophagomyotomy and partial fundoplication for treatment of achalasia.

The most common surgical treatment for achalasia is a modified anterior extramucosal esophagomyotomy. Unfortunately, a poor outcome may result secondary to recurrent dysphagia or gastroesophageal reflux. The reported incidence of reflux is 4 to 50 per cent. Our treatment for achalasia is an esophagomyotomy carried onto the cardia combined with a partial gastric fundoplication. Of 22 patients who presented with achalasia and moderate to severe symptoms of dysphagia and odynophagia, 19 had this procedure performed. Of these 19 patients, only two required a second procedure (postoperative dilatation) for recurrent symptoms. All three patients who had a full fundoplication required further surgical correction. Although fundoplication has been condemned in the past as treatment of achalasia to avoid the postoperative outcome of reflux, we have been successful with a partial fundoplication added to the standard esophagomyotomy. Given the fine line that needs to be tread to prevent recurrent signs and symptoms of achalasia or reflux when performing esophagomyotomy, our procedure offers a viable alternative to transthoracic esophagomyotomy alone.

Adult↗
PubMed1989

Labelling of monoclonal antibodies 10B, 8C, and M2A with indium-111.

Monoclonal antibodies 10B, 8C and M2A were conjugated with cyclic DTPA anhydride to a substitution level of 1-2 mol DTPA/mol antibody. The DTPA-conjugated antibodies were purified by size-exclusion mini-column chromatography and labelled with [111In]In acetate to a specific activity of 37-74 kBq/micrograms (1-2 microCi/micrograms). The radiochemical purity of the antibody preparation was 76-81%. The immunoreactive fraction of the radiolabelled antibodies ranged from 0.17 to 0.31, significantly lower than that of their radioiodinated analogs.

Antibodies, Monoclonal↗