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1.
J Vet Intern Med ; 32(1): 469-473, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29114956

ABSTRACT

BACKGROUND: Periodic lack of availability and high cost of commercially produced isotonic fluids for intravenous (IV) use in horses have increasingly led to use of home-made or commercially compound fluids by veterinarians. Data regarding the quality control and safety of compounded fluids would be of benefit to equine veterinarians. OBJECTIVES: To compare electrolyte concentrations, sterility, and endotoxin contamination of commercially available fluids to 2 forms of compounded isotonic crystalloid fluids intended for IV use in horses. METHODS: Prospective study. Two methods of preparing compounded crystalloids formulated to replicate commercial Plasma-Lyte A (Abbott, Chicago, IL) were compared. One formulation was prepared by a hand-mixed method involving chlorinated drinking water commonly employed by equine practitioners, and the other was prepared by means of ingredients obtained from a commercial compounding pharmacy. The variables for comparison were electrolyte concentrations, sterility, and presence of endotoxin contamination. RESULTS: Electrolyte concentrations were consistent within each product but different between types of fluids (P < 0.0001). Hand-mixed fluids had significantly more bacterial contamination compared to commercial Plasma-Lyte A (P = 0.0014). One of the hand-mixed fluid samples had detectable endotoxin contamination. CONCLUSIONS AND CLINICAL IMPORTANCE: Chlorinated drinking water is not an acceptable source of water to compound isotonic fluids for IV administration. Equine practitioners should be aware of this risk and obtain the informed consent of their clients.


Subject(s)
Drug Compounding/veterinary , Electrolytes/standards , Horses , Infusions, Intravenous/veterinary , Isotonic Solutions/pharmacology , Quality Control , Animals , Crystalloid Solutions , Drug Compounding/methods , Drug Contamination , Endotoxins/analysis , Infusions, Intravenous/standards , Isotonic Solutions/chemistry , Water/chemistry
2.
Vet Comp Oncol ; 15(3): 706-709, 2017 Sep.
Article in English | MEDLINE | ID: mdl-27028306

ABSTRACT

Compounding of drugs for use in veterinary oncology is becoming increasingly common. We obtained 15 mg cyclophosphamide capsules from five different compounding pharmacies and performed potency analyses at two time points, as well as stability at 60 days. Potency results for four out of five and zero out of five (4/10) samples analysed were inadequate. Stability at 60 days was acceptable for all but one sample. This pilot study raises several important points of concern when compounding chemotherapy in dogs and cats. Further studies are necessary to solidify this data. Collaboration between pharmacists, veterinarians and regulatory bodies is needed to ensure safe and accurate delivery of compounded drugs to client-owned animals.


Subject(s)
Antineoplastic Agents, Alkylating/chemistry , Cyclophosphamide/chemistry , Drug Compounding/veterinary , Animals , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/therapeutic use , Capsules , Cat Diseases/drug therapy , Cats , Cyclophosphamide/administration & dosage , Cyclophosphamide/therapeutic use , Dog Diseases/drug therapy , Dogs , Drug Stability , Neoplasms/drug therapy , Neoplasms/veterinary , Pilot Projects
3.
Mol Psychiatry ; 18(11): 1218-24, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23089632

ABSTRACT

Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10(-8), inflation-corrected P=9.4 × 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2) 0.95), have previously been associated with risk for bipolar disorder.


Subject(s)
Alcoholism/genetics , Chromosomes, Human, Pair 15/genetics , Genome-Wide Association Study , Open Reading Frames/genetics , Symptom Assessment , Alcoholism/diagnosis , Diagnostic and Statistical Manual of Mental Disorders , Endophenotypes , Female , Genetic Predisposition to Disease/genetics , Genotype , Humans , Male , Pedigree , Polymorphism, Single Nucleotide
4.
Biochem Biophys Res Commun ; 411(3): 501-5, 2011 Aug 05.
Article in English | MEDLINE | ID: mdl-21741357

ABSTRACT

Autoimmune rippling muscle disease (ARMD) is an autoimmune neuromuscular disease associated with myasthenia gravis (MG). Past studies in our laboratory recognized a very high molecular weight skeletal muscle protein antigen identified by ARMD patient antisera as the titin isoform. These past studies used antisera from ARMD and MG patients as probes to screen a human skeletal muscle cDNA library and several pBluescript clones revealed supporting expression of immunoreactive peptides. This study characterizes the products of subcloning the titin immunoreactive domain into pGEX-3X and the subsequent fusion protein. Sequence analysis of the fusion gene indicates the cloned titin domain (GenBank ID: EU428784) is in frame and is derived from a sequence of N2-A spanning the exons 248-250 an area that encodes the fibronectin III domain. PCR and EcoR1 restriction mapping studies have demonstrated that the inserted cDNA is of a size that is predicted by bioinformatics analysis of the subclone. Expression of the fusion protein result in the isolation of a polypeptide of 52 kDa consistent with the predicted inferred amino acid sequence. Immunoblot experiments of the fusion protein, using rippling muscle/myasthenia gravis antisera, demonstrate that only the titin domain is immunoreactive.


Subject(s)
Autoimmune Diseases/immunology , Muscle Proteins/immunology , Muscular Diseases/immunology , Protein Kinases/immunology , Amino Acid Sequence , Autoimmune Diseases/genetics , Connectin , DNA, Complementary/genetics , Exons , Humans , Immunodominant Epitopes/genetics , Immunodominant Epitopes/immunology , Molecular Sequence Data , Muscle Proteins/genetics , Muscular Diseases/genetics , Protein Kinases/genetics , Protein Structure, Tertiary
5.
Mol Psychiatry ; 14(5): 501-10, 2009 May.
Article in English | MEDLINE | ID: mdl-18414406

ABSTRACT

Alcohol dependence frequently co-occurs with cigarette smoking, another common addictive behavior. Evidence from genetic studies demonstrates that alcohol dependence and smoking cluster in families and have shared genetic vulnerability. Recently a candidate gene study in nicotine dependent cases and nondependent smoking controls reported strong associations between a missense mutation (rs16969968) in exon 5 of the CHRNA5 gene and a variant in the 3'-UTR of the CHRNA3 gene and nicotine dependence. In this study we performed a comprehensive association analysis of the CHRNA5-CHRNA3-CHRNB4 gene cluster in the Collaborative Study on the Genetics of Alcoholism (COGA) families to investigate the role of genetic variants in risk for alcohol dependence. Using the family-based association test, we observed that a different group of polymorphisms, spanning CHRNA5-CHRNA3, demonstrate association with alcohol dependence defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV) criteria. Using logistic regression we replicated this finding in an independent case-control series from the family study of cocaine dependence. These variants show low linkage disequilibrium with the SNPs previously reported to be associated with nicotine dependence and therefore represent an independent observation. Functional studies in human brain reveal that the variants associated with alcohol dependence are also associated with altered steady-state levels of CHRNA5 mRNA.


Subject(s)
Alcoholism/genetics , Brain/metabolism , Genetic Predisposition to Disease , Nerve Tissue Proteins/genetics , Polymorphism, Single Nucleotide/genetics , RNA, Messenger/metabolism , Receptors, Nicotinic/genetics , Alcoholism/pathology , Brain/pathology , Cluster Analysis , Cocaine-Related Disorders/genetics , Diagnostic and Statistical Manual of Mental Disorders , Family Health , Gene Frequency , Genome-Wide Association Study/methods , Genotype , Humans , Linkage Disequilibrium , Logistic Models , Risk
6.
Allergy ; 61(5): 640-7, 2006 May.
Article in English | MEDLINE | ID: mdl-16629797

ABSTRACT

BACKGROUND: Low sensitization rates to common allergens have been observed in farm children, which might be due to high exposure to microbial agents. It is not known how microbial agents modify the association between specific allergen exposure and sensitization. OBJECTIVE: To examine the relations between house dust mite allergen exposure and mite sensitization in farm and nonfarm children and to assess the effects of microbial agents levels on this association. METHODS: Major mite allergens of Dermatophagoides pteronyssinus (Der p 1) and Dermatophagoides farinae (Der f 1), endotoxin, beta(1,3)-glucans and fungal extracellular polysaccharides were measured in mattress dust of 402 children participating in a cross-sectional study in five European countries. Mite allergen (Der p 1 + Der f 1) levels were divided into tertiles with cut-offs 1.4 and 10.4 microg/g. Sensitization was assessed by measurement of allergen-specific immunoglobulin E against house dust mite. RESULTS: Prevalence ratios of mite sensitization for medium and high when compared with low mite allergen levels were 3.1 [1.7-5.7] and 1.4 [0.7-2.8] respectively. Highest mite sensitization rates at intermediate exposure levels were consistently observed across country (except for Sweden) and in both farm and nonfarm children. The shape of the dose-response curve was similar for above and below median mattress microbial agent levels, but the 'sensitization peak' appeared to be lower for above median levels. CONCLUSIONS: Our data suggest a bell-shaped dose-response relationship between mite allergen exposure and sensitization to mite allergens. In populations with high microbial agent levels and low sensitization rates, the curve is shifted down.


Subject(s)
Allergens/immunology , Hypersensitivity/epidemiology , Nonlinear Dynamics , Pyroglyphidae/immunology , Adolescent , Air Pollution, Indoor/statistics & numerical data , Allergens/analysis , Child , Cross-Sectional Studies , Dose-Response Relationship, Immunologic , Europe/epidemiology , Female , Humans , Hypersensitivity/immunology , Immunoenzyme Techniques , Immunoglobulin E/immunology , Male , Prevalence , Risk Factors , Rural Population , Urban Population
7.
Allergy ; 61(4): 414-21, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16512802

ABSTRACT

BACKGROUND: The prevalence of allergic diseases has increased rapidly in recent decades, particularly in children. For adequate prevention it is important not only to identify risk factors, but also possible protective factors. The aim of this study was to compare the prevalence of allergic diseases and sensitization between farm children, children in anthroposophic families, and reference children, with the aim to identify factors that may protect against allergic disease. METHODS: The study was of cross-sectional design and included 14,893 children, aged 5-13 years, from farm families, anthroposophic families (recruited from Steiner schools) and reference children in Austria, Germany, The Netherlands, Sweden and Switzerland. A detailed questionnaire was completed and allergen-specific IgE was measured in blood. RESULTS: Growing up on a farm was found to have a protective effect against all outcomes studied, both self-reported, such as rhinoconjunctivitis, wheezing, atopic eczema and asthma and sensitization (allergen specific IgE > or = 0.35 kU/l). The adjusted odds ratio (OR) for current rhinoconjunctivitis symptoms was 0.50 (95% confidence interval (CI) 0.38-0.65) and for atopic sensitization 0.53 (95% CI 0.42-0.67) for the farm children compared to their references. The prevalence of allergic symptoms and sensitization was also lower among Steiner school children compared to reference children, but the difference was less pronounced and not as consistent between countries, adjusted OR for current rhinoconjunctivitis symptoms was 0.69 (95% CI 0.56-0.86) and for atopic sensitization 0.73 (95% CI 0.58-0.92). CONCLUSIONS: This study indicates that growing up on a farm, and to a lesser extent leading an anthroposophic life style may confer protection from both sensitization and allergic diseases in childhood.


Subject(s)
Agriculture , Anthroposophy , Hypersensitivity/prevention & control , Life Style , Adolescent , Child , Child, Preschool , Conjunctivitis/prevention & control , Cross-Sectional Studies , Female , Humans , Hypersensitivity/epidemiology , Male , Odds Ratio , Prevalence , Rhinitis/prevention & control
8.
Allergy ; 60(5): 611-8, 2005 May.
Article in English | MEDLINE | ID: mdl-15813805

ABSTRACT

BACKGROUND: Growing up on a farm and an anthroposophic lifestyle are associated with a lower prevalence of allergic diseases in childhood. It has been suggested that the enhanced exposure to endotoxin is an important protective factor of farm environments. Little is known about exposure to other microbial components on farms and exposure in anthroposophic families. OBJECTIVE: To assess the levels and determinants of bacterial endotoxin, mould beta(1,3)-glucans and fungal extracellular polysaccharides (EPS) in house dust of farm children, Steiner school children and reference children. METHODS: Mattress and living room dust was collected in the homes of 229 farm children, 122 Steiner children and 60 and 67 of their respective reference children in five European countries. Stable dust was collected as well. All samples were analysed in one central laboratory. Determinants were assessed by questionnaire. RESULTS: Levels of endotoxin, EPS and glucans per gram of house dust in farm homes were 1.2- to 3.2-fold higher than levels in reference homes. For Steiner children, 1.1- to 1.6-fold higher levels were observed compared with their reference children. These differences were consistently found across countries, although mean levels varied considerably. Differences between groups and between countries were also significant after adjustment for home and family characteristics. CONCLUSION: Farm children are not only consistently exposed to higher levels of endotoxin, but also to higher levels of mould components. Steiner school children may also be exposed to higher levels of microbial agents, but differences with reference children are much less pronounced than for farm children. Further analyses are, however, required to assess the association between exposure to these various microbial agents and allergic and airway diseases in the PARSIFAL population.


Subject(s)
Agriculture , Dust/analysis , Endotoxins/analysis , Fungal Structures/isolation & purification , Life Style , Schools , Child , Cross-Sectional Studies , Europe , Extracellular Fluid/chemistry , Humans , Multivariate Analysis , Polysaccharides/analysis , beta-Glucans/analysis
10.
Circulation ; 104(12 Suppl 1): I296-302, 2001 Sep 18.
Article in English | MEDLINE | ID: mdl-11568072

ABSTRACT

BACKGROUND: The advantages of blood cardioplegia include the oxygen-carrying capacity, superior oncotic and buffering properties, and endogenous antioxidants contained in blood. However, the partial dilution of blood in 4:1 (blood:crystalloid) cardioplegic solutions may nullify these advantages and progressively dilute blood during continuous retrograde delivery. This study tested the hypothesis that all-blood (66:1) cardioplegia provides superior myocardial protection compared with dilute (4:1) cardioplegia delivered in a continuous retrograde modality during surgical reperfusion of evolving myocardial infarction. METHODS AND RESULTS: After 60 minutes of left anterior descending coronary artery (LAD) occlusion, anesthetized canines were placed on cardiopulmonary bypass and randomized to either all-blood cardioplegia (AB group) or dilute blood cardioplegia (Dil group). After cross clamping, arrest was induced with 5 minutes of tepid (30 degrees C) antegrade potassium all-blood or dilute blood cardioplegia and maintained with tepid retrograde coronary sinus cardioplegia for a total of 1 hour. The LAD was released after 30 minutes of arrest, simulating revascularization. The cardioplegia hematocrit for the Dil group was lower than that for the AB group (7+/-1% versus 12+/-2%, P<0.05); at the end of bypass, systemic hematocrit was lower in the Dil group than in the Ab group (15+/-1% versus 20+/-1%, P<0.05). Infarct size (triphenyltetrazolium chloride staining) was comparable between the AB and Dil groups (29.6+/-2.9% versus 30.3+/-3.9% of area at risk), and there was no difference in area-at-risk myocardium systolic shortening (by sonomicrometry, -0.3+/-1% versus -0.4+/-1%). Tissue edema after bypass tended to be greater in the Dil group compared with the AB group in the heart (82+/-0% versus 81+/-1%), lung (79+/-1% versus 78+/-1%), liver (75+/-1% versus 74+/-0%), and skeletal muscle (76+/-1% versus 73+/-2%) and was significantly greater in the duodenum (80+/-1% versus 79+/-1%, P<0.05) and kidney (82+/-1% versus 79+/-1%, P<0.05). Postexperimental endothelial function (relaxation of acetylcholine) was impaired in LADs of the AB group versus the Dil group (59+/-6% versus 77+/-5%, P<0.05). CONCLUSIONS: Both all-blood cardioplegia and dilute cardioplegia have disadvantages, but these do not have an impact on the pathogenesis of infarct size or recovery of regional contractile function.


Subject(s)
Blood , Cardioplegic Solutions/pharmacology , Heart Arrest, Induced/methods , Myocardial Infarction/surgery , Myocardial Revascularization/methods , Animals , Body Water/drug effects , Cardioplegic Solutions/chemistry , Coronary Vessels/drug effects , Coronary Vessels/pathology , Creatine Kinase/blood , Disease Models, Animal , Disease Progression , Dogs , Endothelium, Vascular/metabolism , Female , Heart/drug effects , Hemodynamics/drug effects , Male , Myocardial Contraction/drug effects , Myocardial Infarction/enzymology , Myocardial Infarction/pathology , Myocardium/enzymology , Myocardium/pathology , Peroxidase/metabolism , Potassium Compounds/chemistry , Potassium Compounds/pharmacology , Recovery of Function/drug effects , Vasoconstrictor Agents/pharmacology , Vasodilation/drug effects , Vasodilator Agents/pharmacology
11.
Ann Thorac Surg ; 72(3): 679-87, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11565641

ABSTRACT

BACKGROUND: Aortic cross-clamping is contraindicated in patients with severe atherosclerosis of the ascending aorta, and administration of chemical cardioplegia may be cumbersome in these patients. In this study, we demonstrate an alternative method of achieving cardioplegia by electrical stimulation of the vagus nerve. METHODS: In anesthetized canines, the left anterior descending coronary artery was reversibly ligated for 90 minutes, followed by cardiopulmonary bypass (CPB) and randomization to three groups (n = 8 each): (1) BCP group: 1 hour of intermittent hypothermic (4 degrees C) blood cardioplegia infusion; (2) CPB group: 1 hour of CPB alone; (3) EP group (group receiving electroplegia): 1 hour of intermittent vagal stimulation (total of 60 20-second electrical stimuli at 40 Hz, 6 to 10 V) with adjunctive pyridostigmine (0.5 mg/kg), verapamil (50 microg/kg), and propranolol (80 microg/kg) to potentiate hyperpolarization and suppress ectopic escape beats. RESULTS: The EP group achieved consistent intervals of arrest with 3.8 +/- 1.2 escape beats per 20-second stimulation period. After 2 hours of reperfusion off CPB, the left anterior descending coronary artery segmental shortening was reduced from baseline in all groups, but the segmental shortening recovered to a greater extent in the EP group than in either the CPB or BCP group (2.4% +/- 1.4% versus -1.3% +/- 1.3% versus -4.0% +/- 0.8%, p < 0.05). Infarct size (TTC stain, percentage of area at risk) was comparable among groups (EP: 20.9% +/- 4.7%; CPB: 29.6% +/- 3.2%; BCP: 25.1% +/- 5.7%). Postischemic left anterior descending coronary artery endothelial function (percent maximum relaxation to acetylcholine) was depressed in the EP group (68.6% +/- 7.6% versus 102.3% +/- 6.4%, p < 0.05), but was comparable versus nonischemic circumflex function in the BCP group (77.1% +/- 11.9% versus 100.4% +/- 10.0%, p = 0.15) and the CPB group (93.8% +/- 6.6% versus 93.3% +/- 6.6%). CONCLUSIONS: Electroplegia achieves elective intermittent cardiac arrest, avoids hypothermia, chemical cardioplegia, and aortic cross-clamping, with physiological outcomes comparable to blood cardioplegia.


Subject(s)
Cardiac Surgical Procedures , Cardiopulmonary Bypass , Electric Stimulation , Heart Arrest, Induced/methods , Vagus Nerve/physiology , Acetylcholine/pharmacology , Animals , Anti-Arrhythmia Agents/administration & dosage , Blood , Blood Pressure , Body Water/metabolism , Coronary Vessels/drug effects , Coronary Vessels/physiopathology , Creatine Kinase/blood , Dogs , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiopathology , Heart Rate , Myocardial Contraction , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardial Reperfusion , Myocardium/metabolism , Peroxidase/metabolism , Propranolol/administration & dosage , Pyridostigmine Bromide/administration & dosage , Vasodilator Agents/pharmacology , Verapamil/administration & dosage
12.
Ann Thorac Surg ; 72(1): 197-202, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11465178

ABSTRACT

BACKGROUND: Factors determining predictability of response to thymectomy for myasthenia gravis (MG) vary in the literature. METHODS: A 25-year retrospective review (1974 to 1999) of all thymectomies performed at a single institution was undertaken. RESULTS: In 113 consecutive thymectomies for MG, women comprised 79% (89 of 113 patients), and mean age was 40+/-15 years. Complications occurred in 14% of patients (16 of 113). In-hospital mortality was 0, but 90-day hospital mortality was 0.88% (1 of 113 patients). Follow-up was obtained in 81% (92 of 113 patients) at a mean of 51+/-59 months postoperatively. Complete remission was achieved in 21% of patients (19 of 92), and marked improvement of MG in 54% (50 of 92), for a total benefit rate of 75%. Fourteen percent (13 of 92) were unchanged, and 11% (10 of 92) were worse. Using univariate analysis, sex, age, and pathology correlated significantly with outcome (p < 0.05): 80% of women (57 of 70) benefited from the procedure, versus 57% of men (12 of 21). Eighty percent (57 of 70) of patients less than 51 years of age were improved or in remission, versus 57% (12 of 22) older than 50. Twenty-three percent (5 of 22) of patients with thymoma deteriorated, versus 7.1% (5 of 70) without thymoma. Sex did not significantly correlate in the multivariate model. CONCLUSIONS: Sex, age, and thymic pathology are potential predictors of outcome in thymectomy for MG, and may shape treatment decisions and target higher-risk patients.


Subject(s)
Myasthenia Gravis/surgery , Postoperative Complications/diagnosis , Thymectomy , Thymoma/surgery , Thymus Neoplasms/surgery , Adult , Disease Progression , Female , Follow-Up Studies , Humans , Male , Middle Aged , Myasthenia Gravis/diagnosis , Myasthenia Gravis/mortality , Postoperative Complications/mortality , Retrospective Studies , Survival Rate , Thymoma/diagnosis , Thymoma/mortality , Thymus Neoplasms/diagnosis , Thymus Neoplasms/mortality , Treatment Outcome
13.
J Thorac Cardiovasc Surg ; 121(3): 570-9, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11241093

ABSTRACT

OBJECTIVE: Although beating heart coronary artery bypass grafting has recently gained popularity, it eliminates the protective strategies (ie, cardioplegia) developed for use in conventional cardiac operations. We recently introduced the technique of perfusion-assisted direct coronary artery bypass to perfuse the grafted vessels during multivessel off-pump coronary artery bypass grafting. In the present study we tested the hypothesis that intracoronary reperfusion with the cardioprotective agent adenosine during simulated perfusion-assisted direct coronary artery bypass attenuates reperfusion injury. METHODS: In anesthetized dogs the heart was exposed, and the left anterior descending coronary artery was ligated for 75 minutes. Reperfusion was achieved through a catheter in the left anterior descending coronary artery by means of a computer-controlled pump. Intracoronary left anterior descending coronary artery perfusion pressure was continuously matched to mean arterial blood pressure. In one group (adenosine group) 10 micromol/L adenosine was added to the blood during the first 30 minutes of reperfusion, whereas another group (vehicle group) received a comparable volume of saline solution. RESULTS: During the first 30 minutes of reperfusion, blood flow through the left anterior descending coronary artery was significantly greater (P <.05) in the adenosine group than in the vehicle group (150.6 +/- 21.9 vs 50.2 +/- 11.3 mL/min at 15 minutes of reperfusion). Although there were no group differences in postischemic wall motion, infarct size was significantly smaller in the adenosine group than in the vehicle group (11.1% +/- 3.0% vs. 28.0% +/- 4.0% of area at risk, P <.05). Myeloperoxidase activity in the necrotic tissue, an index of neutrophil accumulation, tended to be lower in the adenosine group than in the vehicle group (58.6 +/- 14.2 vs. 91.0 +/- 21.6 DeltaAbs Units x min(-1) x g(-1) tissue). In isolated postischemic left anterior descending coronary artery rings, the maximal relaxation response to the endothelium-dependent vasodilator acetylcholine was significantly greater in the adenosine group than in the vehicle group (97.9% +/- 5.6% vs. 64.7% +/- 6.5%, P<.05). CONCLUSION: This novel reperfusion strategy for off-pump coronary artery bypass grafting can be used not only in cases requiring multiple grafting but also to attenuate necrosis and endothelial dysfunction in acute evolving infarction.


Subject(s)
Adenosine/therapeutic use , Coronary Artery Bypass/methods , Myocardial Reperfusion Injury/prevention & control , Myocardial Reperfusion/methods , Vasodilator Agents/therapeutic use , Animals , Coronary Vessels/physiology , Dogs , Hemodynamics , Regional Blood Flow
14.
J Mol Cell Cardiol ; 33(1): 57-68, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11133223

ABSTRACT

This study tests the hypothesis that infarct reduction with adenosine (Ado) is associated with inhibition of apoptotic cell death by modulating expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax proteins and reducing neutrophil accumulation. In three groups of dogs, the left anterior descending coronary artery was occluded for 60 min and reperfused for 6 h. Either saline (Control, n=8), Ado (140 microg/kg/min, n=8) or CGS21680, an adenosine A2A receptor analogue, (0.2 microg/kg/min, n=7) were infused during the first 2 h of reperfusion. Myocardial apoptosis was detected by histological TUNEL staining and DNA laddering. Expression of Bcl-2 and Bax proteins was analyzed using Western blot assay. Neutrophil localization was detected by immunohistochemistry with monoclonal anti-neutrophil CD18 antibody. There was no group difference in collateral blood flow (colored microspheres) during ischemia. Intra-left atrial administration of Ado and CGS21680 significantly decreased infarct size from 26+/-2% in Control to 13+/-1%* and 16+/-3%*, respectively. TUNEL positive cells in the peri-necrotic zone of the ischemic myocardium were also significantly reduced from 16+/-2% in Control group to 9+/-1%* and 10+/-2%*, respectively, consistent with the absence of DNA laddering in these two groups. Densitometrically, Ado and CGS21680 at reperfusion significantly increased the expression (% of normal myocardium) of downregulated Bcl-2 from 45+/-6% in Control group to 78+/-12%* and 69+/-10%*, respectively, and attenuated expression of upregulated Bax from 198+/-16% in Control group to 148+/-10%* and 158+/-12%*, respectively. Furthermore, the number of positive CD18 cells (mm(2) myocardium), which was significantly correlated with TUNEL positive cells in peri-necrotic zone, was significantly reduced from 403+/-42 in Control group to 142+/-18* in Ado group and 153+/-20%* in CGS21680 group, respectively. In conclusion, the present study suggests that inhibition of apoptosis by Ado at reperfusion involves alterations in anti-apoptotic Bcl-2 and pro-apoptotic Bax proteins and neutrophil accumulation, primarily mediated by an adenosine A2A receptor. * P<0.05 v Control group.


Subject(s)
Adenosine/analogs & derivatives , Adenosine/therapeutic use , Apoptosis/drug effects , Gene Expression Regulation/drug effects , Genes, bcl-2 , Myocardial Reperfusion Injury/prevention & control , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Proto-Oncogene Proteins/biosynthesis , Adenosine/administration & dosage , Adenosine/pharmacology , Animals , Blotting, Western , CD18 Antigens/analysis , Coronary Circulation/drug effects , DNA Fragmentation , Dogs , Drug Evaluation, Preclinical , Female , Hemodynamics/drug effects , Injections, Intra-Arterial , Male , Myocardial Infarction/pathology , Myocardial Ischemia/complications , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/pathology , Necrosis , Neutrophils/pathology , Phenethylamines/pharmacology , Phenethylamines/therapeutic use , Proto-Oncogene Proteins/genetics , Receptors, Purinergic P1/drug effects , Receptors, Purinergic P1/physiology , bcl-2-Associated X Protein
15.
Ann Thorac Surg ; 72(6): 1977-84, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11789780

ABSTRACT

BACKGROUND: Radial artery bypass conduits are prone to early vasospasm or "string sign" with use of vasopressor therapy intraoperatively and postoperatively, causing increased resistance in coronary artery grafts. Current intraoperative treatment with papaverine fails to provide sustained inhibition of vasoconstriction. We tested the hypothesis that a 30-minute pretreatment of radial artery segments with the alpha-adrenergic antagonist phenoxybenzamine (PB) or the putative protein phosphatase 2,3-butadione monoxime (BDM) attenuates vasoconstriction induced by the vasopressors phenylephrine or norepinephrine for as long as 48 hours compared with papaverine. METHODS: Canine radial arteries were harvested, incubated in control buffer or solutions of papaverine 10(-6) M, BDM 10(-6) M or phenoxybenzamine 10(-6) M for 30 minutes, washed, and stored in drug-free culture medium for 2, 24, or 48 hours. After storage, constriction was induced by norepinephrine at incremental concentrations ranging from 0.7 to 3.5 micromol/L or by phenylephrine (0.300 to 1.5 micromol/L) with or without the inhibitors, and the degree of vasoconstriction was quantified in organ chambers. Responses to norepinephrine or phenylephrine were compared to constriction with receptor-independent potassium chloride KC1 (30 mmol/L). RESULTS: Maximum responses to phenylephrine and norepinephrine were comparable at 2, 24, and 48 hours after harvest in the control group (phenylephrine: 67% +/- 4%, 62% +/- 6%, 65% +/- 6% of KC1 response; norepinephrine: 75% +/- 4%, 62% +/- 1%, 58% +/- 7%, respectively). Papaverine failed to attenuate constriction to phenylephrine and norepinephrine 2, 24, or 48 hours posttreatment. Pretreatment with BDM did not reduce vasoconstriction responses to phenylephrine or norepinephrine 2 hours after incubation but did reduce constriction responses thereafter. In contrast, phenoxybenzamine completely attenuated constriction to both phenylephrine (19% +/- 8%, 1% +/- 4%, -12% +/- 4%) and norepinephrine (7.1% +/- 1%, -5% +/- 5%, -20% +/- 5%) at 2, 24, and 48 hours posttreatment, respectively. Phenoxybenzamine did not alter endothelial function relative to controls at any time point. CONCLUSIONS: Thirty-minute pretreatment of RA conduits with 10(-6) M phenoxybenzamine completely inhibits vasoconstriction to phenylephrine and norepinephrine for as long as 48 hours. Soaking radial artery grafts briefly in phenoxybenzamine solution before implantation may be effective in preventing postoperative vasospasm caused by two common alpha-adrenergic agonists used in postoperative hemodynamic management.


Subject(s)
Arteries/transplantation , Coronary Artery Bypass , Phenoxybenzamine/pharmacology , Vasoconstriction/drug effects , Animals , Dogs , Dose-Response Relationship, Drug , Papaverine/pharmacology , Radial Artery/transplantation , Tissue Preservation , Vasoconstrictor Agents/pharmacology
16.
Cardiovasc Res ; 47(2): 294-305, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10946066

ABSTRACT

OBJECTIVE: The purpose of this study was to compare protective effects of AMP579 and adenosine (Ado) at reperfusion (R) on inhibition of polymorphonuclear neutrophil (PMN) activation, PMN-mediated injury to coronary artery endothelium, and final infarct size. METHODS: In anesthetized dogs, 1 h of left anterior descending coronary artery occlusion was followed by 24 h R and drugs were administered at R. Control (n=8, saline control), AMPI (n=7, AMP579, 50 microg/kg i.v. bolus followed by 3 microg/kg/min for 2 h), AMPII (n=7, AMP579, 50 microg/kg i.v. bolus), AMPIII (n=7, AMP579, 3 microg/kg/min i.v. for 2 h), and Ado (n=7, adenosine, 140 microg/kg/min i.v. for 2 h). RESULTS: AMP579 in vitro directly inhibited superoxide radical (O(-)(2)) generation (nM/5x10(6) PMNs) from PMNs dose-dependently (from 17+/-1* at 10 nM to 2+/-0.2* at 10 microM vs. activated 30+/-2). However, inhibition of O(-)(2) generation by Ado at each concentration was significantly less than for AMP579. The IC(50) value for AMP579 (0.09+/-0.02 microM) on O(-)(2) generation was significantly less than that of Ado (3.9+/-1. 1 microM). Adherence of unstimulated PMN to postischemic coronary artery endothelium (PMNs/mm(2)) was attenuated in AMPI and AMPIII vs. Control (60+/-3* and 58+/-3* vs. Control 110+/-4), while Ado partially attenuated PMN adherence (98+/-3*). Accordingly, endothelial-dependent vascular relaxation was significantly greater in AMPI and AMPIII vs. Ado. At 24 h R, myocardial blood flow (MBF, ml/min/g) in the area at risk (AAR), confirmed by colored microspheres, in AMPI and AMPIII was significantly improved (0.8+/-0. 1* and 0.7+/-0.1* vs. Control 0.3+/-0.04). Infarct size (IS, TTC staining) in AMPI and AMPIII was significantly reduced from 38+/-3% in Control to 21+/-4%* and 22+/-3%*, respectively, confirmed by lower plasma creatine kinase activity (I.U./g protein) in these two groups (27+/-6* and 32+/-2* vs. 49+/-3). Cardiac myeloperoxidase activity (MPO, Abs/min) in the AAR was significantly reduced in AMPI and AMPIII vs. Control (36+/-11* and 35+/-10* vs. 89+/-10). However, changes in MBF, IS and MPO were not significantly altered by Ado. CONCLUSIONS: These data suggest that continuous infusion of AMP579 at R is more potent than adenosine in attenuating R injury, and AMP579-induced cardioprotection involves inhibition of PMN-induced vascular and myocardial tissue injury. *P<0.05 vs. Control.


Subject(s)
Adenosine/therapeutic use , Imidazoles/therapeutic use , Pyridines/therapeutic use , Receptors, Purinergic P1/drug effects , Reperfusion Injury/prevention & control , Analysis of Variance , Animals , Cell Adhesion , Cells, Cultured , Creatine Kinase/blood , Dogs , Dose-Response Relationship, Drug , Endothelium, Vascular/pathology , Female , Male , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/physiopathology , Myocardial Reperfusion Injury/prevention & control , Myocardium/enzymology , Myocardium/metabolism , Neutrophils/metabolism , Neutrophils/pathology , Peroxidase/metabolism , Random Allocation , Regional Blood Flow/drug effects , Reperfusion Injury/metabolism , Reperfusion Injury/physiopathology , Superoxides/metabolism , Time Factors , Water/metabolism
17.
World J Surg ; 24(4): 421-9, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10706914

ABSTRACT

This collective review includes all available case reports and series of smooth muscle (stromal) tumors of the small intestine in the world literature from 1881 to 1996. We identified 1074 patients with leiomyoma (LM) and 1689 with leiomyosarcoma (LMS). Our purpose was to update our previous review, which encompassed case reports and series from 1881 to 1959, which included 350 LMs and 257 LMSs. The peak incidence of smooth muscle tumors in the small intestine in both male and female patients was between the ages of 50 and 59. Most commonly, the presenting complaint was gastrointestinal bleeding. Computed tomography was found to detect LM and LMS most successfully and had the additional advantage of locating metastatic disease. The jejunum contained the highest numbers of smooth muscle tumors, followed by the ileum and then the duodenum, with malignant lesions in all locations typically attaining larger diameters than benign tumors. The overall rate of metastatic spread of LMS ranged from 24% to 50%, with the liver being most commonly involved. Unlike other sarcomas, both hematogenous and lymphatic spread were common. The 5-year survival of 705 patients with LMS from 22 series was 27. 8%. For both benign and malignant smooth muscle tumors of the small intestine, surgery remains the treatment of choice, with little efficacy reported for irradiation, chemotherapy, or both.


Subject(s)
Intestinal Neoplasms/classification , Intestine, Small/pathology , Leiomyoma/classification , Leiomyosarcoma/classification , Age Factors , Female , Gastrointestinal Hemorrhage/physiopathology , Humans , Incidence , Intestinal Neoplasms/physiopathology , Intestinal Neoplasms/surgery , Intestine, Small/surgery , Leiomyoma/physiopathology , Leiomyoma/surgery , Leiomyosarcoma/physiopathology , Leiomyosarcoma/secondary , Leiomyosarcoma/surgery , Lymphatic Metastasis , Male , Middle Aged , Sex Factors , Survival Rate , Tomography, X-Ray Computed
18.
Pediatr Res ; 46(5): 553-61, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10541318

ABSTRACT

Diamond-Blackfan anemia (DBA) is a constitutional disease characterized by a specific maturation defect in cells of erythroid lineage. We have assembled a registry of 229 DBA patients, which includes 151 patients from France, 70 from Germany, and eight from other countries. Presence of malformations was significantly and independently associated with familial history of DBA, short stature at presentation (before any steroid therapy), and absence of hypotrophy at birth. Two hundred twenty-two patients were available for long-term follow-up analysis (median, 111.5 mo). Of these individuals, 62.6% initially responded to steroid therapy. Initial steroid responsiveness was found significantly and independently associated with older age at presentation, familial history of DBA, and a normal platelet count at the time of diagnosis. Severe evolution of the disease (transfusion dependence or death) was significantly and independently associated with a younger age at presentation and with a history of premature birth. In contrast, patients with a familial history of the disease experienced a better outcome. Outcome analysis revealed the benefit of reassessing steroid responsiveness during the course of the disease for initially nonresponsive patients. Bone marrow transplantation was successful in 11/13 cases; HLA typing of probands and siblings should be performed early if patients are transfusion dependent, and cord blood should be preserved. Incidence of DBA (assessed for France over a 13-y period) is 7.3 cases per million live births without effect of seasonality on incidence of the disease or on malformative status. Similarly, no parental imprinting effect or anticipation phenomenon could be documented in families with dominant inheritance.


Subject(s)
Abnormalities, Multiple/genetics , Fanconi Anemia/genetics , Abnormalities, Multiple/epidemiology , Fanconi Anemia/epidemiology , Female , Follow-Up Studies , France/epidemiology , Humans , Infant , Infant, Newborn , Male , Medical History Taking , Prevalence , Prognosis , Registries , Treatment Outcome
19.
Bioinformatics ; 15(5): 348-55, 1999 May.
Article in English | MEDLINE | ID: mdl-10366654

ABSTRACT

MOTIVATION: The sensitivity and specificity of branched DNA (bDNA) assays are derived in part through the judicious design of the capture and label extender probes. To minimize non-specific hybridization (NSH) events, which elevate assay background, candidate probes must be computer screened for complementarity with generic sequences present in the assay. RESULTS: We present a software application which allows for rapid and flexible design of bDNA probesets for novel targets. It includes an algorithm for estimating the magnitude of NSH contribution to background, a mechanism for removing probes with elevated contributions, a methodology for the simultaneous design of probesets for multiple targets, and a graphical user interface which guides the user through the design steps. AVAILABILITY: The program is available as a commercial package through the Pharmaceutical Drug Discovery program at Chiron Diagnostics.


Subject(s)
DNA Probes , DNA/analysis , Nucleic Acid Amplification Techniques , Nucleic Acid Hybridization/methods , Software , Animals , Electronic Data Processing , Humans
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