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Biomedical subjects

E O'Leary

Publications and source records attributed to E O'Leary.

At least 19 recordsLinked to original sources

Two-stage liver resection and chemotherapy for bilobar colorectal liver metastases.

BACKGROUND: A significant number of patients with colorectal metastatic disease confined to the liver are inoperable at assessment. For these patients, the outlook is poor. Chemotherapy can 'down-stage' some tumours and render them operable. The authors present a series of patients with inoperable disease despite down-staging with chemotherapy, who underwent a two-stage resection to clear their metastatic disease. METHODS: The case-notes of 11 patients who were found to have inoperable hepatic metastatic disease were identified using computerised medical records and mean hospital stay, survival and long-term follow-up data was noted. RESULTS: The mean follow-up from initial resection was 13.5 months (range of 5-20 months). Three deaths were recorded in the follow-up interval. Causes of death included recurrence of hepatic disease following completion of two-stage resection, progression of original hepatic disease leading to inoperability at second stage operation and recurrence of original primary colorectal tumour. The mean survival in the patients who died was 17 months (range of 15-19 months). The remaining patients are alive to date with six patients showing no evidence of hepatic recurrence, follow-up period of 13 months (range of 8-20 months). One patient developed de novo prostate cancer and is awaiting his second liver resection, and one patient has stable hepatic disease with no evidence of progression. CONCLUSION: Two-stage liver resection can prolong survival when compared to chemotherapy alone, with a recurrence rate equivalent to ablation techniques. Longer-term studies are needed for further evaluation.

Adult↗

Effects of SP500263, a novel selective estrogen receptor modulator, on bone, uterus, and serum cholesterol in the ovariectomized rat.

We describe here the activity of a novel selective estrogen receptor modulator, SP500263. When given to adult ovariectomized (OVX) rats for 28 days at doses of 0.3, 1, or 3 mg/kg/day, we found that SP500263 partially protected against OVX-induced loss of bone mineral content in the distal ends of femurs and in the whole bone. SP500263 also antagonized the OVX-induced increase in body weight. However, unlike 17beta-estradiol, SP500263 at efficacious doses did not prevent the OVX-induced loss in uterine wet weight. A small but significant effect on uterine wet weight was noted with raloxifene dosed at 1 mg/kg. As expected, SP500263 but not raloxifene acted as an estrogen antagonist on the uterus in adult rats when administered for 7 days at 30 mg/kg/day. Finally, SP500263 had no statistically significant effects on total serum cholesterol and serum triglycerides in OVX rats treated for 28 days. Raloxifene had no significant effects on body weight, bone mineral content, and serum cholesterol or triglycerides in the OVX-rat model. In summary, SP500263 is a new orally active SERM that acts in rats as an estrogen agonist on bone without causing uterine stimulatory effects.

Administration, Oral↗

Efficiency of Dispatch and Infiltrator cardiac infusion catheters in arterial localization of nanoparticles in a porcine coronary model of restenosis.

Localized intramural delivery of sustained release biodegradable nanoparticles containing an antiproliferative agent could provide prolonged drug effect at the site of vascular injury that could inhibit the proliferation of smooth muscle cells and hence restenosis. The efficiency of arterial localization of nanoparticles is crucial in maximizing the drug effect in the target tissue. Therefore, the objective of the present study was to determine the comparative efficiency of the Dispatch and the Infiltrator cardiac infusion catheters to localize nanoparticles in the arterial wall. Following a standard balloon angioplasty procedure on the left anterior descending artery (LAD) in a porcine coronary model of restenosis, a suspension of nanoparticles containing a fluorescent marker was infused at the site of injury using either the Dispatch or the Infiltrator catheter. One hour following the infusion, animals were sacrificed and the nanoparticle levels in the LAD and other tissue were analyzed. The Dispatch catheter resulted in 3.3 folds greater efficiency of nanoparticle localization in the LAD than the Infiltrator catheter (309 +/- 124 vs. 93 +/- 43 microg/g of tissue, n = 6 for Dispatch and n = 5 for Infiltrator, p = 0.082, t-test). It is estimated that about 2% of the arterial volume can be displaced with the nanoparticle infusion. Fluorescence microscopy of the cross-sections of the LAD revealed greater fluorescence activity in the intimal layer with both the catheters, however the arteries infused using the Dispatch catheter demonstrated relatively higher degree of fluorescence activity in the medial and adventitial layers. The transmission electron microscopy of the arterial sections demonstrated infiltration of nanoparticles in the arterial wall and the histological analysis of the sections demonstrated no apparent damage to the endothelium due to the infusion of nanoparticles.

Animals↗

TRIP-Br: a novel family of PHD zinc finger- and bromodomain-interacting proteins that regulate the transcriptional activity of E2F-1/DP-1.

We report the isolation of TRIP-Br1, a transcriptional regulator that interacts with the PHD-bromodomain of co-repressors of Krüppel-associated box (KRAB)-mediated repression, KRIP-1(TIF1beta) and TIF1alpha, as well as the co-activator/adaptor p300/CBP. TRIP-Br1 and the related protein TRIP-Br2 possess transactivation domains. Like MDM2, which has a homologous transactivation domain, TRIP-Br proteins functionally contact DP-1, stimulating E2F-1/DP-1 transcriptional activity. KRIP-1 potentiates TRIP-Br protein co-activation of E2F-1/DP-1. TRIP-Br1 is a component of a multiprotein complex containing E2F-1 and DP-1. Co-expression of the retinoblastoma gene product (RB) abolishes baseline E2F-1/DP-1 transcriptional activity as well as TRIP-Br/KRIP-1 co-activation, both of which are restored by the adenovirus E1A oncoprotein. These features suggest that TRIP-Br proteins function at E2F-responsive promoters to integrate signals provided by PHD- and/or bromodomain- containing transcription factors. TRIP-Br1 is identical to the cyclin-dependent kinase 4 (cdk4)-binding protein p34(SEI-1), which renders the activity of cyclin D/cdk4 resistant to the inhibitory effect of p16(INK4a) during late G(1). TRIP-Br1(p34(SEI-1)) is differentially overexpressed during the G(1) and S phases of the cell cycle, consistent with a dual role for TRIP-Br1(p34(SEI-1)) in the regulation of cell cycle progression through sequential effects on the transcriptional activity of E2F-responsive promoters during G(1) and S phases.

Animals↗

Deletion of cytosolic phospholipase A(2) suppresses Apc(Min)-induced tumorigenesis.

Although nonsteroidal antiinflammatory drugs (NSAIDs) show great promise as therapies for colon cancer, a dispute remains regarding their mechanism of action. NSAIDs are known to inhibit cyclooxygenase (COX) enzymes, which convert arachidonic acid (AA) to prostaglandins (PGs). Therefore, NSAIDs may suppress tumorigenesis by inhibiting PG synthesis. However, various experimental studies have suggested the possibility of PG-independent mechanisms. Notably, disruption of the mouse group IIA secretory phospholipase A(2) locus (Pla2g2a), a potential source of AA for COX-2, increases tumor number despite the fact that the mutation has been predicted to decrease PG production. Some authors have attempted to reconcile the results by suggesting that the level of the precursor (AA), not the products (PGs), is the critical factor. To clarify the role of AA in tumorigenesis, we have examined the effect of deleting the group IV cytosolic phospholipase A(2) (cPLA(2)) locus (Pla2g4). We report that Apc(Min/+), cPLA(2)(-/-) mice show an 83% reduction in tumor number in the small intestine compared with littermates with genotypes Apc(Min/+), cPLA(2)(+/-) and Apc(Min/+), cPLA(2)(+/+). This tumor phenotype parallels that of COX-2 knockout mice, suggesting that cPLA(2) is the predominant source of AA for COX-2 in the intestine. The protective effect of cPLA(2) deletion is thus most likely attributed to a decrease in the AA supply to COX-2 and a resultant decrease in PG synthesis. The tumorigenic effect of sPLA(2) mutations is likely to be through a completely different pathway.

Adenomatous Polyposis Coli Protein↗

PLIP, a novel splice variant of Tip60, interacts with group IV cytosolic phospholipase A(2), induces apoptosis, and potentiates prostaglandin production.

The group IV cytosolic phospholipase A(2) (cPLA(2)) has been localized to the nucleus (M. R. Sierra-Honigmann, J. R. Bradley, and J. S. Pober, Lab. Investig. 74:684-695, 1996) and is known to translocate from the cytosolic compartment to the nuclear membrane (S. Glover, M. S. de Carvalho, T. Bayburt, M. Jonas, E. Chi, C. C. Leslie, and M. H. Gelb, J. Biol. Chem. 270:15359-15367, 1995; A. R. Schievella, M. K. Regier, W. L. Smith, and L. L. Lin, J. Biol. Chem. 270:30749-30754, 1995). We hypothesized that nuclear proteins interact with cPLA(2) and participate in the functional effects of this translocation. We have identified a nuclear protein, cPLA(2)-interacting protein (PLIP), a splice variant of human Tip60, which interacts with the amino terminal region of cPLA(2). Like Tip60, PLIP cDNA includes the MYST domain containing a C2HC zinc finger and well-conserved similarities to acetyltransferases. Both PLIP and Tip60 coimmunoprecipitate and colocalize with cPLA(2) within the nuclei of transfected COS cells. A polyclonal antibody raised to PLIP recognizes both PLIP and Tip60. Endogenous Tip60 and/or PLIP in rat mesangial cells is localized to the nucleus in response to serum deprivation. Nuclear localization coincides temporally with apoptosis. PLIP expression, mediated by adenoviral gene transfer, potentiates serum deprivation-induced prostaglandin E(2) (PGE(2)) production and apoptosis in mouse mesangial cells from cPLA(2)(+/+) mice but not in mesangial cells derived from cPLA(2)(-/-) mice. Thus PLIP, a splice variant of Tip60, interacts with cPLA(2) and potentiates cPLA(2)-mediated PGE(2) production and apoptosis.

Acetyltransferases↗

Renal concentrating defect in mice lacking group IV cytosolic phospholipase A(2).

Eicosanoids regulate various cellular functions that are important in physiological and pathophysiological processes. Arachidonic acid is released from membranes by phospholipase A(2) (PLA(2)) activity. Activated macrophages derived from mice lacking the 85-kDa group IV cytosolic PLA(2) (cPLA(2)) have a markedly reduced release of prostaglandin E(2) and leukotrienes B(4) and C(4). Under basal conditions and after furosemide, urinary prostaglandin E(2) excretion is reduced in cPLA(2)-knockout (cPLA(2)(-/-)) mice. Serum creatinine, Na(+), K(+), and Ca(2+) concentrations, glomerular filtration rate, and fractional excretion of Na(+) and K(+) are not different in cPLA(2)(-/-) and cPLA(2)(+/+) mice. Maximal urinary concentration is lower in 48-h water-deprived cPLA(2)(-/-) mice compared with cPLA(2)(+/+) animals (1,934 +/- 324 vs. 3,541 +/- 251 mmol/kgH(2)O). Plasma osmolality is higher (337 +/- 5 vs. 319 +/- 3 mmol/kgH(2)O) in cPLA(2)(-/-) mice that lose a greater percentage of their body weight (20 +/- 2 vs. 13 +/- 1%) compared with cPLA(2)(+/+) mice after water deprivation. Vasopressin does not correct the concentrating defect. There is progressive reduction in urinary osmolality with age in cPLA(2)(-/-) mice. Membrane-associated aquaporin-1 (AQP1) expression, identified by immunocytochemical techniques, is reduced markedly in proximal tubules of older cPLA(2)(-/-) animals but is normal in thin descending limbs. However, Western blot analysis of kidney cortical samples revealed an equivalent AQP1 signal intensity in cPLA(2)(+/+) and cPLA(2)(-/-) animals. Young cPLA(2)(-/-) mice have normal proximal tubule AQP1 staining. Collecting duct AQP2, -3, and -4 were normally expressed in the cPLA(2)(-/-) mice. Thus mice lacking cPLA(2) develop an age-related defect in renal concentration that may be related to abnormal trafficking and/or folding of AQP1 in the proximal tubule, implicating cPLA(2) in these processes.

Animals↗

Detection of angiographically significant coronary artery disease with accelerated intermittent imaging after intravenous administration of ultrasound contrast material.

BACKGROUND: Accelerated intermittent harmonic imaging (AII) is used to detect myocardial perfusion abnormalities after intravenous injection of ultrasound contrast medium. A low mechanical index and frame rates of 10 to 20 Hz are used to allow simultaneous wall motion analysis. The purpose of this study was to determine whether the myocardial contrast enhancement achieved with AII can be used to detect angiographically significant coronary artery disease during stress echocardiography. METHODS: We gave intravenous perfluorocarbon containing microbubbles to 45 patients (total of 270 regions) during dobutamine (n = 27) or exercise (n = 18) stress testing with AII. Quantitative angiography was performed on all patients after the stress echocardiograms were interpreted. RESULTS: Quantitative angiography showed >50% diameter stenosis of at least 1 vessel in 32 patients (total of 118 regions). There were visually evident contrast defects in 100 (85%) of these regions, and wall motion was abnormal in 64 (54%). Overall, there was agreement between regional perfusion and quantitative angiographic findings in 217 of the 270 regions (kappa = 0.61; 80% agreement). Agreement with findings at quantitative angiography was good for both dobutamine stress (kappa = 0.66; 83% agreement) and exercise (kappa = 0.53; 77% agreement). The greatest incremental benefit of AII versus wall motion was gained during dobutamine stress. The contrast studies depicted 90% of the regions supplied by a vessel with >50% stenosis, whereas wall motion depicted only 32% (P =.001). CONCLUSIONS: The results of this study indicated that accelerated intermittent perfusion imaging during stress echocardiography can improve the sensitivity of the study in detecting angiographically significant coronary artery disease, especially during dobutamine stress.

Adult↗

Recruiting participants for community-based research: the Diabetic Retinopathy Awareness Program.

PURPOSE: Recruiting participants is a major challenge for population studies. We present the recruitment methods followed by the Diabetic Retinopathy Awareness Program (DRAP), a community-based, randomized, masked, controlled trial to meet and exceed its sample size goals. METHODS: A county-wide multi-media promotional campaign to recruit and enroll participants in the trial was planned and executed from October 1993 through April 1994, with the assistance of the local news media and community and professional groups. A toll-free 800 number recruitment line was established, and postage-paid recruitment postcards distributed. The trial was designed to examine whether a mailed educational intervention could increase compliance with vision care guidelines among persons with diabetes in the community. RESULTS: A total of 2308 persons with diabetes were interviewed for eligibility and 813 enrolled in the intervention trial, exceeding the original recruitment goals of 1800 and 600, respectively. Those who completed the enrollment interview reflected county demographics. During recruitment, newspaper, television and radio stories featured the study; pharmacies and physician offices displayed study materials; public service announcements appeared in local print and broadcast media. The largest single recruitment response was a local television news report, followed by a newspaper story. CONCLUSIONS: These experiences substantiate the need for a comprehensive coordinated approach, using planned multiple sources, to achieve recruitment success. By engaging the lay and professional communities along with the media, recruitment costs can be kept to a minimum. Participant costs can be minimized by employing a toll-free number and eliminating study participant travel, thus allowing for inclusion of traditionally underserved populations. This approach is applicable to other studies, where community-based participation is desired.

Adolescent↗

Expression of the transcriptional repressor protein Kid-1 leads to the disintegration of the nucleolus.

The rat Kid-1 gene codes for a 66-kDa protein with KRAB domains at the NH2 terminus and two Cys2His2-zinc finger clusters of four and nine zinc fingers at the COOH terminus. It was the first KRAB-zinc finger protein for which a transcriptional repressor activity was demonstrated. Subsequently, the KRAB-A domain was identified as a widespread transcriptional repressor motif. We now present a biochemical and functional analysis of the Kid-1 protein in transfected cells. The full-length Kid-1 protein is targeted to the nucleolus and adheres tightly to as yet undefined nucleolar structures, leading eventually to the disintegration of the nucleolus. The tight adherence and nucleolar distribution can be attributed to the larger zinc finger cluster, whereas the KRAB-A domain is responsible for the nucleolar fragmentation. Upon disintegration of the nucleolus, the nucleolar transcription factor upstream binding factor disappears from the nucleolar fragments. In the absence of Kid-1, the KRIP-1 protein, which represents the natural interacting partner of zinc finger proteins with a KRAB-A domain, is homogeneously distributed in the nucleus, whereas coexpression of Kid-1 leads to a shift of KRIP-1 into the nucleolus. Nucleolar run-ons demonstrate that rDNA transcription is shut off in the nucleolar fragments. Our data demonstrate the functional diversity of the KRAB and zinc finger domains of Kid-1 and provide new functional insights into the regulation of the nucleolar structure.

Animals↗

Etomidate and the osteocalcin response to gynaecological surgery.

Circulating osteocalcin is a good marker of osteoblastic activity and decreases significantly after stressful physiological states such as major surgery. Glucocorticoids are known to inhibit osteoblastic activity and result in a decline in circulating osteocalcin. We used etomidate to inhibit the cortisol response to routine gynaecological surgery to determine if this would prevent the postoperative decline in osteocalcin. Twenty-four patients were allocated randomly to receive either thiopental or etomidate for induction of anaesthesia; all other aspects of anaesthesia and perioperative management were standardized. In the thiopental group, circulating cortisol increased significantly at 2 and 6 h after the start of surgery and plasma osteocalcin concentrations decreased significantly to almost 50% of baseline values at 48 h. Etomidate abolished the cortisol response to surgery, and circulating osteocalcin concentrations did not change after operation. There was a significant difference in osteocalcin concentration between the groups at 48 h. We conclude that the cortisol response to surgery is associated with a postoperative decrease in circulating osteocalcin.

Adult↗

Magnetic field exposure assessment: a comparison of various methods.

The accurate and valid measurement of personal exposure to magnetic fields poses a major challenge for epidemiologic studies. When considering the various methods to assess exposure, it is unclear which measures are most relevant for studies of human disease, if any. Given these uncertainties, the Electromagnetic Fields and Breast Cancer on Long Island Study (EBCLIS) undertook a pilot study to develop the data collection protocol for a case-control study of breast cancer and magnetic fields. The pilot study used and compared various methods to assess residential exposures to magnetic fields, and related these measures to personal exposures. It included 31 women without breast cancer (mean age, 63+/-7 yr) who lived in their present homes for at least 15 yr. The pilot study consisted of an in-home interview, spot and 24-h magnetic field waveforms and broadband recordings, ground currents, wire coding, and personal 24-h broadband measurements. From the regression analyses, the model that best predicted personal magnetic field exposures included 24-h measurements in the bedroom and in the most lived-in room; as well as ground current test loads taken at the center of this most lived in room (r(2)=86%). The addition of other variables in this regression model yielded only small and nonsignificant increases in r(2). As a direct result of this pilot, EBCLIS will include ground current measurements in its protocol, which have not previously been collected as part of an epidemiologic study. Ground currents may be important because they may be richer in 180 Hz components than are the other currents in a power system. EBCLIS will have the opportunity to examine the ground-current hypothesis in the context of female breast cancer.

Air Pollution, Indoor↗

Canadian Bardet-Biedl syndrome family reduces the critical region of BBS3 (3p) and presents with a variable phenotype.

There are at least five distinct Bardet-Biedl syndrome (BBS) loci, four of which have been mapped: 11q (BBS1), 16q (BBS2), 3p (BBS3), and 15q (BBS4). A comparative study of the three Arab-Bedouin kindreds used to map the BBS2, BBS3, and BBS4 loci suggests that the variability in the number and severity of clinical manifestations, particularly the pattern of polydactyly, reflects chromosome-specific subtypes of BBS [Carmi et al., 1995a; Am J Med Genet 59:199-203]. We describe a Newfoundland kindred of northern European descent and confirm the initial finding of a BBS locus on chromosome 3. However, the "BBS3 phenotype," which includes polydactyly of all four limbs and a progression to morbid obesity, was not observed. Rather, four of the five BBS patients in this family had polydactyly restricted to their feet. The obesity in these patients was reversible with caloric restriction and/or exercise. Mental retardation has been considered a major symptom of BBS. However, formal IQ testing shows that these patients are of average intelligence. Haplotype analysis reduces the BBS3 critical region to a 6-cM interval between D3S1595-D3S1753.

Adult↗

Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2.

Phospholipase A2 (PLA2) enzymes are critical regulators of prostaglandin and leukotriene synthesis and can directly modify the composition of cellular membranes. PLA2 enzymes release fatty acids and lysophospholipids, including the precursor of platelet-activating factor, PAF, from phospholipids. Free fatty acids, eicosanoids, lysophospholipids and PAF are potent regulators of inflammation, reproduction and neurotoxicity. The physiological roles of the various forms of PLA2 are not well defined. The cytosolic form, cPLA2, preferentially releases arachidonic acid from phospholipids and is regulated by changes in intracellular calcium concentration. We have now created 'knockout' (cPLA2-/-) mice that lack this enzyme, in order to evaluate its physiological importance. We find that cPLA2-/- mice develop normally, but that the females produce only small litters in which the pups are usually dead. Stimulated peritoneal macrophages from cPLA2-/- animals did not produce prostaglandin E2 or leukotriene B4 or C4. After transient middle cerebral artery occlusion, cPLA2-/- mice had smaller infarcts and developed less brain oedema and fewer neurological deficits. Thus cPLA2 is important for macrophage production of inflammatory mediators, fertility, and in the pathophysiology of neuronal death after transient focal cerebral ischaemia.

Animals↗

Angioscopic evaluation of site-specific administration of ReoPro.

Systemic administration of newer antiplatelet agents such as the GP IIb/IIIa agent ReoPro (Centocor BV Leiden, The Netherlands) has been shown to decrease the early incidence of recurrent ischemia and recurrent myocardial infarction. The currently approved protocol for administration of ReoPro involves an initial weight adjusted bolus followed by a systemic infusion over the next 12 hr. The systemic administration is proposed as the only route of administration because it is stated that the drug must be exposed to circulating platelets. An alternative approach would be to deliver ReoPro locally and allow the platelets to disaggregate only when in contact with the local arterial wall. The optimal method of monitoring the efficacy of such a strategy is to visually assess the presence of platelet rich or red blood cell rich thrombus using angioscopy. We report our initial experience in 12 patients who received local administration of ReoPro using currently approved catheters for local administration of agents into coronary arteries who were evaluated before and after intervention using intracoronary angioscopy. None of the patients received a subsequent 12-hr infusion. There was successful resolution of thrombus in 11 of 12 patients. Recurrent ischemia occurred in one patient without myocardial infarction.

Abciximab↗

Novel technique for coil embolization of intercostal branch of internal mammary artery graft.

Coronary artery steal resulting from a large unligated intercostal or pericardial side branch of the internal mammary artery graft causing postoperative angina has been previously described. Transcatheter coil occlusion of internal mammary artery side branch has successfully been performed to treat coronary steal syndrome. Unsuccessful deployment of the microcoils can be due to inadequate guiding support in the LIMA or prolapse of the delivery catheter in the side branch. We report a new approach for the precise deployment of coils in the side branch of a LIMA graft, when inadequate guiding support is present.

Angina Pectoris↗