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P J Sheridan

Publications and source records attributed to P J Sheridan.

At least 19 recordsLinked to original sources
PubMed2006

Observations of mercury-containing aerosols.

In situ analyses with a laser ionization mass spectrometer have shown that a large fraction of aerosols in the bottom few kilometers of the stratosphere contain small amounts of mercury (1). Electron microscopy of particles collected near the tropopause has also detected mercury. The distribution of mercury onto many particles, including those less than 20 nm in diameter, indicates that the mercury is from local condensation of mercury compounds onto particles rather than transport of mercury-rich aerosols from surface sources. Although the results are only semiquantitative, they suggest that most of the mercury in the lower stratosphere is converted into the particulate phase. Mercury-containing particles were present at both middle latitudes and the tropics in two seasons. There is therefore good reason to believe that particulate mercury above the tropopause is global and could affect the atmospheric lifetime of mercury. There are indications that bromine and/ or iodine may be involved in the conversion of mercury from the gas to particle phase. Measurements at altitudes below 5 km did not find mercury in any particles despite sampling some particles that clearly originated in the stratosphere. This indicates that the particulate mercury from the lower stratosphere may be volatile enough to evaporate or decompose once particles reach warmer temperatures.

Aerosols↗
PubMed2006

Management and outcomes of acute coronary syndrome with minimal myocardial necrosis: analysis of a large prospective registry from a non-interventional centre.

The aim of this study was to assess the clinical risk of minimal myonecrosis below the cut-off for acute myocardial infarction (MI) in comparison with other grades of acute coronary syndrome (ACS). One-thousand four hundred and sixty seven consecutive patients with ACS admitted between May 2001 and April 2002 were studied in a non-interventional centre. Patients were divided into unstable angina (UA) (cTnT < 0.01 microg/l), non-ST elevation ACS with minimal myonecrosis (0.01 or= 0.1 microg/L) and ST elevation myocardial infarction (STEMI). UA (n = 638) was associated with the fewest events at 6 months (2% cardiac death or MI). Patients with any myonecrosis (n = 829) had worse outcomes (6-month cardiac death or MI 18.3-23.3%). Compared with ACS patients with minimal myonecrosis, UA patients were at significantly lower risk (OR 0.21, 95% CI 0.12-0.45, p < 0.001), NSTEMI patients were at similar risk (OR 1.45, 95% CI 0.89-2.35, p = 0.13), and STEMI patients were at higher risk (OR 2.12 95% CI 1.26-3.85, p = 0.008) in adjusted analyses. Nearly 85% of cardiac deaths occurred within 6 months. The risk of adverse events was higher among patients managed by non-cardiologists (OR 1.66, 95% CI 1-2.75, p = 0.049). Patients with non-ST elevation ACS and minimal myonecrosis are a high-risk group more comparable with NSTEMI and clearly distinguishable from patients with UA.

Aged↗
PubMed2005

Ultrasound-mediated delivery of TIMP-3 plasmid DNA into saphenous vein leads to increased lumen size in a porcine interposition graft model.

Progressive saphenous vein graft (SVG) narrowing and occlusion remains a major limitation of coronary artery bypass grafting and is an important target for gene therapy. Ex vivo adenoviral gene transfer of tissue inhibitor of metalloproteinase 3 (TIMP-3) reduces adverse SVG remodelling postarterialization, but concerns remain over the use of viral vectors in patients. Ultrasound exposure (USE) in the presence of echocontrast microbubbles (ECM) substantially enhances nonviral gene delivery. We investigated the effects of ultrasound-enhanced gene delivery (UEGD) of TIMP-3 plasmid on vascular remodelling in porcine SVG. Maximal luciferase activity (3000-fold versus naked plasmid alone) and TIMP-3 transgene expression in porcine vascular smooth muscle cells in vitro was achieved using USE at 1 MHz, 1.8 mechanical index (MI), 6% duty cycle (DC) in the presence of 50% (v/v) BR14 ECM (Bracco). These conditions were therefore utilized for subsequent studies in vivo. Yorkshire White pigs received carotid interposition SVG that were untransfected or had undergone ex vivo UEGD of lacZ (control) or TIMP-3 plasmids. At 28 d postgrafting, lumen and total vessel area were significantly greater in the TIMP-3 group (10.1+/-1.2 and 25.5+/-2.2 mm2, respectively) compared to untransfected (6.34+/-0.5 and 20.8+/-1.9 mm2) or lacZ-transfected (6.1+/-0.7 and 19.7+/-1.2 mm2) controls (P<0.01). These data indicate that nonviral TIMP-3 plasmid delivery by USE achieves significant biological effects in a clinically relevant model of SV grafting, and is the first study to demonstrate the potential for therapeutic UEGD to prevent SVG failure.

Animals↗
PubMed2005

Oral ulcerations are associated with the loss of response to infliximab in Crohn's disease.

We describe a 25-year-old Caucasian man with a 13-year history of inflammatory Crohn's disease (CD) who was suffering recurrent severe oral and esophageal ulcerations for the past 3 years. His CD had been treated with infliximab infusions among other medications. The loss of efficacy was confirmed by antibodies to infliximab (ATI) and serum infliximab tests that showed high levels of ATIs and undetectable levels of infliximab respectively. These findings were consistent with significant immunogenic response to infliximab leading to loss of effect. Infliximab infusions and prednisone were discontinued and treatment of the CD was instituted with adalimumab, a human anti-tumor necrosis factor (TNF)-alpha biologic agent, to control the inflammatory small intestinal disease and dapsone for the oral and esophageal CD ulcerations. The patient's oral and esophageal lesions as well as the enteric CD are under control after 5 months of therapy.

Adalimumab↗
PubMed2002

Critical review of unstable angina and non-ST elevation myocardial infarction.

Within the coronary vasculature the progression of a stable atherosclerotic plaque into a vulnerable and ultimately unstable lesion leads to a cascade of events culminating in the clinical presentation of unstable angina or acute myocardial infarction. In recent years studies have provided new insights in to the pathology and natural history, stimulating advances in diagnosis, treatment, and management. The review discusses the progress made including the role of inflammation, cardiac biomarkers, antiplatelet therapy, and percutaneous intervention. Current issues of debate and future directions are also addressed.

Angina, Unstable↗
PubMed2001

Erythema multiforme secondary to herpes simplex infection: a case report.

BACKGROUND: Erythema multiforme (EM) is a complex disease that may have cutaneous and/or mucosal involvement. The severity may range from mild to severe and potentially life threatening. The literature cites many factors including viruses, infections, and medications as causes. This report documents a patient who developed EM secondary to a herpes simplex viral (HSV) infection. METHODS: Two weeks following an eruption of herpes labialis, a 20-year-old white female patient developed acutely painful oral and labial ulcers accompanied by target skin lesions. A diagnosis of erythema multiforme (EM) was made. The patient was treated with antivirals, analgesics, and symptomatic therapy. RESULTS: Nine days after the onset of symptoms, the oral and cutaneous lesions had started to heal and the patient no longer required pain medication. CONCLUSIONS: Although the etiology of EM is still often unknown, infections with herpes simplex virus have been implicated as a possible precipitating factor. This case illustrates the association of the occurrence of EM with an HSV infection.

Acyclovir↗
PubMed2000

Substrate-assisted catalysis of the PAR1 thrombin receptor. Enhancement of macromolecular association and cleavage.

Platelet activation and aggregation are mediated by thrombin cleavage of the exodomain of the PAR1 receptor. The specificity of thrombin for PAR1 is enhanced by binding to a hirudin-like region (Hir) located in the receptor exodomain. Here, we examine the mechanism of thrombin-PAR1 recognition and cleavage by steady-state kinetic measurements using soluble PAR1 N-terminal exodomains. We determined that the primary role of the PAR1 Hir sequence is to reduce the kinetic barriers to formation of the docked thrombin-PAR1 complex rather than to form high affinity ground-state interactions. In addition, the exosite I-bound Hir motif facilitates the productive interaction of the PAR1 (38)LDPR/SFL(44) sequence with the active site of thrombin. This locking process is the most energetically unfavorable step of the overall reaction. The subsequent irreversible steps of peptide bond cleavage are rapid and allosterically enhanced by the presence of the docked Hir sequence. Furthermore, the C-terminal exodomain product of thrombin cleavage, corresponding to the activated receptor, binds tightly to thrombin. This would suggest that an additional role of the Hir sequence in the thrombin-activated receptor is to sequester thrombin to the platelet surface and modulate cleavage of other platelet receptors such as the PAR4 thrombin receptor, which lacks a functional Hir sequence.

Amino Acid Sequence↗
PubMed2000

PAR1 thrombin receptor-G protein interactions. Separation of binding and coupling determinants in the galpha subunit.

Signal transfer between the protease-activated PAR1 thrombin receptor and membrane-associated heterotrimeric G proteins is mediated by protein-protein interactions. We constructed a yeast signaling system that resolves domain-specific functions of binding from coupling in the Galpha subunit. The endogenous yeast Galpha subunit, Gpa1, does not bind to PAR1 and served as a null structural template. N- and C-terminal portions of mammalian G(i2) and G(16) were substituted back into the Gpa1 template and gain-of-function assessed. The C-terminal third of G(16), but not of G(i2), provides sufficient interactions for coupling to occur with PAR1. The N-terminal two-thirds of G(i2) also contains sufficient determinants to bind and couple to PAR1 and overcome the otherwise negative or missing interactions supplied by the C-terminal third of Gpa1. Replacement of the N-terminal alpha-helix of G(i2), residues 1-34, with those of Gpa1 abolishes coupling but not binding to PAR1 or to betagamma subunits. These data support a model that the N-terminal alphaN helix of the Galpha subunit is physically interposed between PAR1 and the Gbeta subunit and directly assists in transferring the signal between agonist-activated receptor and G protein.

Amino Acid Sequence↗
PubMed1999

Plasmin desensitization of the PAR1 thrombin receptor: kinetics, sites of truncation, and implications for thrombolytic therapy.

It has been hypothesized that protease-activated receptors may be activated and attenuated by more than one protease. Here, we explore a desensitization mechanism of the PAR1 thrombin receptor by anticoagulant proteases and provide an explanation to the enigma of why plasmin/tissue plasminogen activator (t-PA) can both activate and deactivate platelets prior to thrombin treatment. By using a soluble N-terminal exodomain (TR78) as a model for the full-length receptor, we were able to unambiguously compare cleavage rates and specificities among the serum proteases. Thrombin cleaves TR78 at the R41-S42 peptide bond with a kcat of 120 s-1 and a KM of 16 microM to produce TR62 (residues 42-103). We found that, of the anticoagulant proteases, only plasmin can rapidly truncate the soluble exodomain at the R70/K76/K82 sites located on a linker region that tethers the ligand to the body of the receptor. Plasmin cleavage of the TR78 exodomain is nearly equivalent to that of thrombin cleavage at R41 with similar rates (kcat = 30 s-1) and affinity (KM = 18 microM). Specificity was demonstrated since there is no observed cleavage at the five other potential plasmin-cleavage sites. Plasmin also cleaves the TR78 exodomain at the R41 thrombin-cleavage site generating transiently activated exodomain. We directly demonstrated that plasmin cleaves these same sites in full-length membrane-embedded receptor expressed in yeast and COS7 fibroblasts. The rate of plasmin truncation is similar between the extensively glycosylated COS7-expressed receptor and the nonglycosylated yeast-produced receptor. Mutation of the R70/K76/K82 sites to A70/A76/A82 eliminates plasmin truncation and desensitization of thrombin-dependent Ca2+ signaling and converts PAR1 into a plasmin-activated receptor with full agonist activity for plasmin. Plasmin does not desensitize the Ca2+ response of platelets or COS7 cells to SFLLRN consistent with intermolecular ligand-binding sites being located to the C-terminal side of K82. Truncation of the wild-type receptor at the C-terminal plasmin-cleavage sites removes the N-terminal tethered ligand or preligand, thereby providing an effective pathway for PAR1 desensitization in vivo.

Amino Acid Sequence↗
PubMed1998

Quantification of human immunodeficiency virus type 1 RNA levels in plasma by using small-volume-format branched-DNA assays.

We have developed small-volume (50 or 250 microl)-format branched-DNA assays for human immunodeficiency virus type 1 (HIV-1) RNA for use with specimens in which the volume is limited and/or a high viral load is anticipated. These formats exhibited good correlation with the standard 1-ml format; high specificity, reproducibility, and linearity; and no significant difference in the quantification of HIV-1 subtypes.

Adolescent↗
PubMed1998

Medically induced gingival hyperplasia.

Gingival hyperplasia or gingival overgrowth is a common occurrence in patients taking phenytoin, cyclosporine, or calcium channel blockers. Speech, mastication, tooth eruption, and aesthetics may be altered. Controlling the inflammatory component through an appropriate oral hygiene program may benefit the patient by limiting the severity of the gingival overgrowth. In patients in whom gingival overgrowth is present or may be anticipated, recognition of this condition and referral to a general dentist or periodontist are appropriate steps to management. The physician's awareness of the potential for development of overgrowth and the dental practitioner's role in attempting to prevent or minimize this problem are important aspects. In this article, we discuss the medications associated with gingival hyperplasia and describe appropriate recommendations.

Anticonvulsants↗
PubMed1997

Microwave pressure chamber processing of a denture repair polymer.

Most denture base repairs are made using a chemically activated acrylic resin polymer for reasons of cost and expediency. Heat-activated polymers are not typically used because they require a custom split cast gypsum mold, longer polymerization time, and higher laboratory fees. Repairs made using a chemically activated polymer compared with a heat-activated polymer generally have reduced transverse strength, poorer color stability, increased water sorption, and weak bond strength to existing acrylic resin. A method of utilizing a microwave polymer in a commercially available microwave flask is described. This technique allows denture base repairs to be made with a heat-activated polymer in a manner similar to that of chemically activated repairs.

Acrylic Resins↗
PubMed1997

An evaluation of operator preference of diamond burs in coronal tooth preparation.

Three postgraduate prosthodontic students served as clinicians/evaluators in a study rating their preferences for three different diamond cutting instruments from three manufacturers. Each evaluator prepared the axial walls of complete veneer crowns on extracted molar teeth and then ranked their preference of the instruments. To prepare nine teeth, each of the three instruments was used in random order and without knowledge of the specific manufacturer. The methodology for analyzing the evaluators' preferences and the results are discussed.

Analysis of Variance↗
PubMed1996

Increased prevalence of the Taq I A1 allele of the dopamine receptor gene (DRD2) in obesity with comorbid substance use disorder: a preliminary report.

In order to investigate the prevalence of the Taq I A1 allele of the dopamine receptor gene (DRD2) in obesity with and without comorbid substance use disorder, a total of 40 patients, from an outpatient neuropsychiatric clinic in Princeton, New Jersey, were genotyped for presence or absence of the Taq I DRD2 A1 allele. The primary inclusion criterion for 40 obese subjects was a body mass index (BMI) equal to or over 25 (uncharacterized); 11 obese subjects had severe substance use disorder; 20 controls had a BMI below 25; and, 33 substance use disorder (less severe) patients had a BMI below 25. The data were statistically compared with three different sets of controls divided into three separate groups (Group I, n = 20; Group II, n = 286; Group III, n = 714). They differed according to screening criteria (drug, alcohol, nicotine abuse/dependence, BMI below 25 and other related behaviours including parental history of alcoholism or drug abuse and DSM IV, Axis I and Axis II diagnoses). Groups II and III were population controls derived from the literature. The prevalence of the Taq I A1D2 dopamine receptor (DRD2) alleles was determined in 40 Caucasian obese females and males. In this sample with a mean BMI of 32.35 +/- 1.02, the A1 allele of the DRD2 gene was present in 52.5% of these obese subjects. Furthermore, we found that in the 23 obese subjects possessing comorbid substance use disorder, the prevalence of the DRD2 A1 allele significantly increased compared to the 17 obese subjects without comorbid substance use disorder. The DRD2 A1 allele was present in 73.9% of the obese subjects with comorbid substance use disorder compared to 23.5% in obese subjects without comorbid substance use disorder. Moreover, when we assessed severity of substance usage (alcoholism, cocaine dependence, etc.) increasing severity of drug use increased the prevalence of the Taq I DRD2 A1 allele; where 66.67% (8/12) of less severe probands possessed the A1 allele compared to 82% (9/11) of the most severe cases. Linear trend analyses showed that increasing use of drugs was positively and significantly associated with A1 allelic classification (p < 0.00001). These preliminary data suggest that the presence of the DRD2 A1 allele confirms increased risk not only for obesity, but also for other related addictive behaviours (previously referred to as the Reward Deficiency Syndrome) and that a BMI over 25 by itself (without characterization of macroselection or comorbid substance use disorders) is not a sufficient criterion for association with the DRD2 A1 allele.

Adult↗
PubMed1996

The D2 dopamine receptor gene as a determinant of reward deficiency syndrome.

The dopaminergic system, and in particular the dopamine D2 receptor, has been profoundly implicated in reward mechanisms in the brain. Dysfunction of the D2 dopamine receptors leads to aberrant substance seeking behaviour (alcohol, drug, tobacco, and food) and other related behaviours (pathological gambling, Tourette's syndrome, and attention deficit hyperactivity disorder). We propose that variants of the D2 dopamine receptor gene are important common genetic determinants of the 'reward deficiency syndrome'.

Compulsive Behavior↗
PubMed1995

Rapid and precise quantification of HIV-1 RNA in plasma using a branched DNA signal amplification assay.

The level of human immunodeficiency virus type 1 (HIV-1) RNA in human plasma has been quantitated directly with use of a solid-phase nucleic acid hybridization assay, based on branched DNA (bDNA) signal amplification technology with chemiluminescent detection. Signal amplification is accomplished by the incorporation of sites for 1,755 alkaline phosphatase-labeled probes per genome of HIV-1, after successive hybridization of target-specific oligonucleotides and bDNA amplifier molecules. The assay is performed in microwells, much like an immunoassay, and is amenable to routine laboratory use. Reproducibility and specificity studies indicated that the bDNA method was precise and showed no reactivity with seronegative donors. HIV-1 RNA levels were quantitated for 348 seropositive specimens, with a detection rate of 83% for those specimens from patients with < 500 CD4+ T-cell counts. Plasma RNA levels were found to change with disease stage, and in response to antiviral therapy. Quantitation of HIV-1 RNA in the plasma of HIV-1-infected patients, with use of the bDNA assay, may be a useful method for monitoring HIV-1 disease progression and therapeutic response.

Acyclovir↗