Biomedical subjects

Peter Fitzgerald

Publications and source records attributed to Peter Fitzgerald.

18 recordsLinked to original sources

PubMed2007

Reciprocal modifications of CLIC4 in tumor epithelium and stroma mark malignant progression of multiple human cancers.

PURPOSE: CLIC4, a member of a family of intracellular chloride channels, is regulated by p53, c-Myc, and tumor necrosis factor-alpha. Regulation by factors involved in cancer pathogenesis, together with the previously shown proapoptotic activity of CLIC4, suggests that the protein may have a tumor suppressor function. To address this possibility, we characterized the expression profile, subcellular localization, and gene integrity of CLIC4 in human cancers and determined the functional consequences of CLIC4 expression in tumor epithelium and stromal cells. EXPERIMENTAL DESIGN: CLIC4 expression profiles were analyzed by genomics, proteomics, bioinformatics, and tissue microarrays. CLIC4 expression, as a consequence of crosstalk between stroma and epithelium, was tested in vitro by coculture of breast epithelial tumor cells and normal fibroblasts, and the functional consequences of CLIC4 expression was tested in vivo in xenografts of human breast tumor cell lines reconstituted with CLIC4 or mixed with fibroblasts that overexpress CLIC4 transgenically. RESULTS: In cDNA arrays of matched human normal and tumor tissues, CLIC4 expression was reduced in renal, ovarian, and breast cancers. However, CLIC4 protein levels were variable in tumor lysate arrays. Transcript sequences of CLIC4 from the human expressed sequence tag database and manual sequencing of cDNA from 60 human cancer cell lines (NCI60) failed to reveal deletion or mutations in the CLIC4 gene. On matched tissue arrays, CLIC4 was predominantly nuclear in normal human epithelial tissues but not cancers. With advancing malignant progression, CLIC4 staining became undetectable in tumor cells, but expression increased in stromal cells coincident with up-regulation of alpha-smooth muscle actin, suggesting that CLIC4 is up-regulated in myofibroblasts. Coculture of cancer cells and fibroblasts induced the expression of both CLIC4 and alpha-smooth muscle actin in fibroblasts adjacent to tumor nests. Introduction of CLIC4 or nuclear targeted CLIC4 via adenovirus into human breast cancer xenografts inhibited tumor growth, whereas overexpression of CLIC4 in stromal cells of xenografts enhanced tumor growth. CONCLUSION: Loss of CLIC4 in tumor cells and gain in tumor stroma is common to many human cancers and marks malignant progression. Up-regulation of CLIC4 in tumor stroma is coincident with myofibroblast conversion, generally a poor prognostic indicator. Reactivation and restoration of CLIC4 in tumor cells or the converse in tumor stromal cells could provide a novel approach to inhibit tumor growth.

Actins↗

PubMed2006

Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy.

OBJECTIVE: Approximately 30% of patients with depression fail to respond to a selective serotonin reuptake inhibitor (SSRI). Few studies have attempted to define these patients from a biological perspective. Studies suggest that overall patients with depression show increased production of proinflammatory cytokines. We examined pro- and anti-inflammatory cytokine levels in patients who were SSRI resistant. METHODS: Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in DSM-1V major depressives who were SSRI resistant, in formerly SSRI resistant patients currently euthymic and in healthy controls. RESULTS: Patients with SSRI-resistant depression had significantly higher production of the pro-inflammatory cytokines IL-6 (p=0.01) and TNF-alpha (p=0.004) compared to normal controls. Euthymic patients who were formerly SSRI resistant had proinflammatory cytokine levels which were similar to the healthy subject group. Anti-inflammatory cytokine levels did not differ across the 3 groups. CONCLUSION: Suppression of proinflammatory cytokines does not occur in depressed patients who fail to respond to SSRIs and is necessary for clinical recovery.

Adult↗

PubMed2006

Axial plaque redistribution after coronary stent deployment.

We report a case of axial plaque redistribution after coronary stent deployment assessed by intravascular ultrasound (IVUS) as well as coronary angiography. A 72-year-old male with a history of hypertension, hyperlipidemia and a nuclear stress test demonstrating anterior and lateral ischemia was admitted for cardiac catheterization. Coronary angiography and IVUS examination revealed eccentric stenoses in the left anterior descending artery (LAD) and the left circumflex artery (LCx), just before the bifurcation of the first obtuse marginal branch. After successful LAD stent placement, the LCx was also stented, jailing the obtuse marginal branch. Immediately after dilatation, however, the coronary angiogram showed a new significant stenosis at the distal adjacent segment. IVUS examination after administration of nitroglycerin revealed a secondary critical lesion that was not observed before the interventional procedure. A significant plaque increase at the new lesion site presumably resulted from axial plaque redistribution (extrusion from the stented segment, otherwise known as plaque shift). After additional stenting, the patient had an uneventful course.

Aged↗

PubMed2005

Humanitarian Use Devices/Humanitarian Device Exemptions in cardiovascular medicine.

The Second Dartmouth Device Development Symposium held in October 2004 brought together leaders from the medical device community, including clinical investigators, senior representatives from the US Food and Drug Administration, large and small device manufacturers, and representatives from the financial community to examine difficult issues confronting device development. The role of the Humanitarian Use Device/Humanitarian Device Exemption (HUD/HDE) pathway in the development of new cardiovascular devices was discussed in this forum. The HUD/HDE pathway was created by Congress to facilitate the availability of medical devices for "orphan" indications, ie, those affecting <4000 individuals within the United States each year. The HUD/HDE pathway streamlines the approval process and permits less well-characterized devices to enter the market. HDE approval focuses primarily on issues of safety and scientific soundness and does not require demonstration of efficacy. In the 7 years since the first device was approved in 1997, a total of 35 HDEs have been granted (23 devices, 6 diagnostic tests). As the costs to gain regulatory approval for commonly used devices increase, companies often seek alternative ways to gain market access, including the HUD/HDE pathway. For a given device, there may be multiple legitimate and distinct indications, including indications that meet the HUD criteria. Companies must choose how and when to pursue each of these indications. The consensus of symposium participants was for the HUD/HDE pathway to be reserved for true orphan indications and not be viewed strategically as part of the clinical development plan to access a large market.

Altruism↗

PubMed2005

Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression.

BACKGROUND: There is evidence to indicate that peripheral glucocorticoid receptor (GR) function is reduced in major depression, and a possible molecular explanation for this is the impact of raised pro-inflammatory cytokines. The topical steroid vasoconstriction assay provides a convenient probe of peripheral GR function. The present study sought to assess the sensitivity of peripheral GRs in antidepressant-resistant major depressives and investigate the association between GR sensitivity and circulating plasma cytokines. METHOD: Nineteen antidepressant-resistant depressives together with age- and sex-matched healthy controls underwent the steroid vasoconstriction assay using three commercial preparations of corticosteroids containing clobetasol propionate 0.05%, betamethasone valerate 0.1%, and clobetasone butyrate 0.05%, corresponding to very potent, potent, and moderately potent steroid creams respectively. The pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured using enzyme-linked immunosorbent assays. The severity of the depressive episode was assessed using the Hamilton Depression Scale (HAMD). RESULTS: Depressed subjects had a significantly reduced vasoconstriction response across all three strengths of steroid. They also had significantly higher concentrations of TNF-alpha and IL-6. There was a significant inverse correlation between TNF-alpha concentration and vasoconstriction response and also between the HAMD score and vasoconstriction response. CONCLUSIONS: These findings suggest that cutaneous GR function is abnormal in antidepressant-resistant depression, that circulating TNF-alpha may play a significant role in this abnormality and that the efficacy of topical steroids in antidepressant-resistant depressives is reduced.

Adult↗

PubMed2005

IMPACT Trial: angiographic and intravascular ultrasound observations of the first human experience with mycophenolic acid-eluting polymer stent system.

The purpose of the study was to examine the safety and efficacy of two different formulations of mycophenolic acid (MPA)-eluting Duraflex stents on coronary de novo lesions. Recent data indicate that local delivery of MPA in the porcine overstretch coronary model significantly reduces neointimal hyperplasia (NIH). Patients were divided into three consecutive groups. The first (n=50) and second (n=55) groups received moderate- and slow-release MPA-eluting Duraflex stent, respectively. The last group (n=50) received the bare metal Duraflex stent. Clinical, angiographic, and intravascular ultrasound analysis were performed at 6-month follow-up. All stents were successfully deployed and patients were discharged home without clinical events. Compared to controls, 6-month in-lesion and in-stent minimum luminal diameter as well as late lumen loss were not significantly different in the moderate- and slow-release treatment groups. At follow-up, percentage obstruction and NIH volume were also similar between the three groups. At 30 days and 6 and 12 months, there were no differences noted between the three groups with respect to major adverse cardiac events as well as the individual rates of mortality, myocardial infarction, or repeat revascularization. There were no cases of subacute or late thrombosis. In this feasibility trial, the MPA-eluting Duraflex stents in either slow- or moderate-release formulations were well tolerated, but showed no benefit for treatment of coronary lesions when compared to controls. Further testing with different drug dosing or delivery rate might improve these results.

Antibiotics, Antineoplastic↗

PubMed2005

Ten-year experience with pediatric laparoscopic appendectomy--are we getting better?

BACKGROUND/PURPOSE: The purpose of this study was to compare our initial (1994-1997) and recent (2001-2003) experiences in laparoscopic appendectomy (LA). METHODS: A 2-year (2001-2003) retrospective chart review of cases of appendicitis was performed and compared with data obtained from 1994 to 1997 cases. Operating and anesthetic times as well as postoperative outcomes were analyzed. Cases of conversion to open appendectomy were included in the analysis. RESULTS: Two hundred and thirty-three LA cases from 2001 to 2003 were compared with 119 cases from 1994 to 1997. Operating time decreased significantly from 58 to 47 minutes in acute appendicitis (AA) and from 80 to 58 minutes in perforated appendicitis (PA). Anesthetic time decreased significantly in both AA (82 to 71 minutes) and PA (106 to 84 minutes). There were significant decreases in the conversion rate in PA (23.4% to 3.5%), although no change was seen in AA. In PA, the incidence of postoperative abscess decreased from 36.2% to 16.5%. There was no significant decrease in length of stay, amount of analgesia used, time to resume regular diet, or incidence of wound infections and bowel obstructions. CONCLUSIONS: Ten years of experience in LA has resulted in decreases in anesthetic and operating times for AA and PA as well as decreases in the incidence of abscesses and conversion rates.

Abscess↗

PubMed2005

Inter-individual variation of inflammatory markers of cardiovascular risks and diseases.

Cardiovascular diseases are a real public health problem and have multifactorial origin. Full comprehension of these diseases is very difficult because of their clinical and biological heterogeneity. The best way to understand the development of these diseases is to first investigate each biological system involved in the diseases and secondly, interactions between them. Studying intermediate phenotype variation for these biological systems is a new and promising approach for their elucidation. Among these metabolic systems, inflammation is known to be implicated in the occurrence and worsening of cardiovascular diseases. For this review, we chose to report the most important results concerning environmental, genetic and epigenetic determinants that influence intermediate phenotypes (protein and RNA levels) of inflammation. Indeed, numerous studies have investigated these determinants in healthy populations, in other words, without the influence of either disease or medication. This new approach will help to better understand the regulation of these intermediate phenotypes and to identify a panel of risk markers, which may be useful in predicting and warning those at risk and in giving adequate treatment to each patient.

Adult↗

PubMed2005

Breast imaging in general practice.

This is the fourth article in a series of breast disorders with an emphasis on diagnosis and management in the general practice setting. This article provides guidance for general practitioners on the role of breast imaging in screening and the investigation of breast symptoms, with an emphasis on indications for imaging and common abnormal findings. It is presented as a summary of key facts supplemented by a mini-atlas of breast imaging to facilitate use of imaging in routine general practice.

Breast Neoplasms↗

PubMed2004

Acute and long-term clinical and angiographic outcome after S-Stent implantation: S-Stent multicenter safety and efficacy trial.

The purpose of this study is to demonstrate safety and effectiveness of the S-Stent in de novo coronary lesions treated with conventional percutaneous coronary balloon angioplasty. Between January 2000 and June 2001, 120 patients were prospectively enrolled at four study centers. Patients were treated with coronary stenting in a total of 137 lesions. Procedural success was achieved in 100% of 137 attempted lesions. Clinical success was 99.8%. In-hospital mortality was 0.8%; myocardial infarction occurred in 0.8% and stent thrombosis in 0.8%. After stent implantation, the minimal lumen diameter increased from 0.92 +/- 0.43 to 2.74 +/- 0.36 mm (P < 0.0001) and the percent diameter stenosis decreased from 68.0 +/- 16.2 to 4.5 +/- 12.0 (P < 0.0001). At 6-month follow-up, the percent diameter stenosis was 33.5 +/- 21.3 and the angiographic restenosis rate was 16.5%. Target lesion revascularization was required in 12 patients (10.1%). We conclude that the use of S-Stent for coronary intervention resulted in a high procedural success rate and low angiographic restenosis at 6 months after implantation.

Aged↗

PubMed2004

Effect of rosiglitazone on restenosis after coronary stenting in patients with type 2 diabetes.

BACKGROUND: Thiazolidinediones have been shown to have an antiproliferative vascular effect in experimental models. We sought to study the effect of rosiglitazone on in-stent restenosis in patients with established type 2 diabetes. METHODS: Patients with treated type 2 diabetes (mean duration 5.5 +/- 7.5 years) referred for coronary stenting were randomized in a double-blind fashion to receive oral rosiglitazone or placebo for 6 months. Quantitative coronary angiography and intravascular ultrasound data were obtained at baseline and follow-up. Plasma plasminogen activator inhibitor-1 levels were prospectively measured. RESULTS: Sixteen patients were enrolled. There were no significant differences in follow-up in-stent luminal diameter stenosis measured by quantitative coronary angiography or in-stent luminal area stenosis and neointimal volume index obtained by intravascular ultrasound, nor were there any differences in plasma plasminogen activator inhibitor-1 levels after long-term use despite improvement in diabetes control and insulin sensitivity. CONCLUSIONS: Rosiglitazone, given at the time of stent implantation in treated diabetics, did not reduce in-stent restenosis in this small series. The vascular biological effects of this agent await further clarification in humans and evaluation in larger clinical trials.

Administration, Oral↗

PubMed2004

Rural policy development: an NRHA and PACE association collaborative model.

The Program of All-Inclusive Care for the Elderly (PACE) offers a unique model of comprehensive care for frail, elderly people. To date, all of the PACE programs have been located in urban areas. Rural advocates and policymakers, however, believe the program may hold great promise for use in rural areas, which have higher percentages of elderly residents than urban areas. In 2002, the National Rural Health Association and the National PACE Association convened a meeting that brought together PACE experts, policymakers, and rural health care providers to examine PACE and its applicability for rural communities. The meeting participants concluded that there were many rural communities where the PACE model might not only be appropriate but also highly successful in caring for rural, frail, elderly people. This article examines the notion of expanding the PACE model to rural communities, including some of the barriers and some of the possible solutions that might make PACE a viable part of the rural health care delivery system.

Aged↗

PubMed2003

Phase I drug and light dose-escalation trial of motexafin lutetium and far red light activation (phototherapy) in subjects with coronary artery disease undergoing percutaneous coronary intervention and stent deployment: procedural and long-term results.

BACKGROUND: Motexafin lutetium (MLu; Antrin) is a photosensitizer that is taken up by atherosclerotic plaque and concentrated within macrophages and vascular smooth muscle cells. After photoactivation with far red light, MLu facilitates production of cytotoxic oxygen radicals that mediate apoptosis. We assessed the safety and tolerability of phototherapy (PT) with MLu in patients undergoing percutaneous coronary intervention with stent deployment. METHODS AND RESULTS: An open-label, phase I, drug and light dose-escalation clinical trial of MLu PT enrolled 80 patients undergoing de novo coronary stent deployment. MLu was administered to 79 patients by intravenous infusion 18 to 24 hours before procedure, and photoactivation was performed after balloon predilatation and before stent deployment. Clinical evaluation, serial quantitative angiography, and intravascular ultrasound were performed periprocedurally and at 6 months follow-up. MLu PT was well tolerated without serious dose-limiting toxicities, and side effects (paresthesia and rash) were minor. No adverse angiographic outcomes were attributed to phototherapy. CONCLUSIONS: This study demonstrates that coronary MLu PT seems safe, and the maximum well-tolerated MLu dose and range of tolerated light doses were identified. These data can be used in phase II efficacy trials of MLu PT for the treatment of coronary atherosclerosis or vulnerable plaque.

Adult↗

PubMed2003

Sirolimus (rapamycin) monotherapy prevents graft vascular disease in nonhuman primate recipients of orthotopic aortic allografts.

BACKGROUND: Delayed treatment with sirolimus (SRL) halts progression of graft vascular disease (GVD) in nonhuman primate (NHP) aortic allograft recipients. In this study, we investigated whether SRL monotherapy prevents the development of GVD. METHODS AND RESULTS: Pairs of 3-cm infrarenal aortic segments were exchanged between mixed lymphocyte reaction-mismatched, blood group-compatible NHPs (n=12). Six NHPs were untreated controls, and 6 were treated orally with SRL starting on the day of transplantation. Follow-up was 105 days. SRL doses were adjusted individually by assessing SRL blood concentrations, immune function, and clinical status. The severity of GVD was determined every 3 weeks by intravascular ultrasound, which quantified intimal area (IA) and intimal volume (IV) for the middle 1-cm graft segments. The mean+/-SEM SRL plasma levels were 14.5+/-9 ng/mL. In grafts from treated NHPs, IA and IV values on days 63, 84, and 105 were significantly lower than for controls (P<0.05 to P<0.001). On day 105, in the grafts from SRL-treated NHPs compared with grafts from controls, values (mean+/-SEM) were IA, 2.9+/-0.9 versus 5.5+/-0.7 mm2, P<0.001 and IV, 29.6+/-4.6 versus 55.2+/-2.8 mm3, P<0.001; IA and IV values for grafts from SRL-treated NHPs did not increase significantly between days 21 and 105. CONCLUSIONS: We show that SRL monotherapy prevented GVD in NHP aortic allograft recipients, suggesting the value of SRL for controlling GVD in clinical transplantation.

Animals↗

PubMed2003

Is adjunctive balloon postdilatation necessary after coronary stent deployment? Final results from the POSTIT trial.

Early-generation balloon-expandable stents required postdilatation with noncompliant balloons at high pressure to optimize stent deployment. The need for adjunctive balloon postdilatation with modern stent delivery systems is unknown. Patients undergoing elective stenting were randomized to Boston Scientific NIR, Guidant Tri-Star/Tetra, and Medtronic AVE S670 stents. The primary endpoint was optimum stent deployment defined as a minimal stent diameter (MSD) >/= 90% of the average reference lumen diameter assessed by intravascular ultrasound (IVUS) performed immediately following stent deployment. If, by operator assessment, the primary endpoint was not achieved with the stent delivery system, adjunctive postdilatation with noncompliant balloons was performed. Of 256 patients with IVUS studies adequate for core laboratory analysis, only 29% achieved optimum stent deployment with the stent delivery system. None of the baseline clinical or angiographic variables predicted optimum stent deployment. Of the procedural variables, the type of stent and nominal stent size were not predictors, but higher deployment pressures were associated with a higher frequency of optimum stent deployment (< 12 atm 14% vs. >/= 12 atm 36%; P = 0.007). The inability to achieve optimum stent deployment was not due to undersizing the stent delivery balloon, but rather to an inability of the stent delivery balloon to expand fully the stent to nominal size. In patients who underwent postdilatation, the frequency of achieving optimum stent deployment increased from 21% to 42%, minimal stent area increased from 6.6 +/- 2.2 to 7.8 +/- 2.3 mm(2), and MSD increased from 2.6 +/- 0.5 to 2.8 +/- 0.4 mm. These data stress the continued need for adjunctive balloon postdilatation with modern stent delivery systems. Cathet Cardiovasc Intervent 2003;59:184-192.

Aged↗

PubMed2003

Immediate versus delayed access of implantable venous access devices: does the timing of access make a difference to the frequency of complications?

PURPOSE: In many institutions protocols have not been developed as to when implantable venous access devices are accessed in children with cancer. The differences in complication rates (infection, hematoma, mechanical failure, and extravasation) between immediate versus delayed access remain unknown. PATIENTS AND METHODS: This retrospective study looks at the incidence of complications in two groups of pediatric patients who had an implantable venous access device inserted between 1998 and 2001 at McMaster Children's Hospital. Group 1 (immediate access group) had 23 patients and group 2 (delayed access) had 74 patients. RESULTS: The incidence of infection was 22% in group 1 and 14% in group 2. The difference between these infection rates was not statistically significant. All infections occurred in patients with a diagnosis of acute lymphoblastic leukemia. Of the patients in this study with acute lymphoblastic leukemia, 33% in group 1 and 36% in group 2 developed infections. CONCLUSIONS: These results suggest that implantable venous access devices can be accessed at the time of device insertion to decrease painful needle punctures in children with cancer and to provide secure immediate central venous access.

Adolescent↗

PubMed2002

Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial.

BACKGROUND: Restenosis after percutaneous coronary intervention (PCI) is a major problem affecting 15% to 30% of patients after stent placement. No oral agent has shown a beneficial effect on restenosis or on associated major adverse cardiovascular events. In limited trials, the oral agent tranilast has been shown to decrease the frequency of angiographic restenosis after PCI. METHODS AND RESULTS: In this double-blind, randomized, placebo-controlled trial of tranilast (300 and 450 mg BID for 1 or 3 months), 11 484 patients were enrolled. Enrollment and drug were initiated within 4 hours after successful PCI of at least 1 vessel. The primary end point was the first occurrence of death, myocardial infarction, or ischemia-driven target vessel revascularization within 9 months and was 15.8% in the placebo group and 15.5% to 16.1% in the tranilast groups (P=0.77 to 0.81). Myocardial infarction was the only component of major adverse cardiovascular events to show some evidence of a reduction with tranilast (450 mg BID for 3 months): 1.1% versus 1.8% with placebo (P=0.061 for intent-to-treat population). The primary reason for not completing treatment was > or =1 hepatic laboratory test abnormality (11.4% versus 0.2% with placebo, P<0.01). In the angiographic substudy composed of 2018 patients, minimal lumen diameter (MLD) was measured by quantitative coronary angiography. At follow-up, MLD was 1.76+/-0.77 mm in the placebo group, which was not different from MLD in the tranilast groups (1.72 to 1.78+/-0.76 to 80 mm, P=0.49 to 0.89). In a subset of these patients (n=1107), intravascular ultrasound was performed at follow-up. Plaque volume was not different between the placebo and tranilast groups (39.3 versus 37.5 to 46.1 mm(3), respectively; P=0.16 to 0.72). CONCLUSIONS: Tranilast does not improve the quantitative measures of restenosis (angiographic and intravascular ultrasound) or its clinical sequelae.

Administration, Oral↗

PubMed1996

Parents' management of children's pain following 'minor' surgery.

The aim of the investigation was to evaluate the prevalence, severity, and parents' management of children's pain following short-stay and day surgery. The subjects were 189 parents of children (2-12 years of age) who had undergone short-stay or day surgery. Parents completed a 3-day diary of their child's pain and the methods used to alleviate it. There were clear differences in pain reported according to type of surgery. Some surgery, such as insertion of myringotomy tubes, appeared to cause little pain. Other procedures, including tonsillectomy, circumcision, and strabismus repair, resulted in about one-half the children experiencing clinically significant pain (> or = 30 mm on a 100 mm VAS). Sixty-eight percent of the parents reported they had been instructed to use acetaminophen for pain 'if necessary', 13% had been told to use acetaminophen regularly, and 8% recalled no instructions. Of the parents who rated their child's pain as significant, 13% administered no pain medication and 47% gave 1-3 doses on day 2. On day 3, 17% gave no medication and 45% gave 1-3 doses. Some types of 'minor' surgery result in significant pain postoperatively. Even when parents recognise that their children are in pain, most give inadequate doses of medication to control the pain.

Acetaminophen↗