A comparison of the pharmacological and mechanical properties in vitro of large and small pulmonary arteries of the rat.

1. The mechanical and pharmacological properties of small pulmonary arteries (100-300 microns normalized lumen diameter) were directly compared with those of the left main pulmonary artery (1-2 mm) from the rat. The active and passive length-tension characteristics and responses to a variety of agonists and antagonists were dependent on arterial diameter. 2. Maximum contractile function was obtained in both groups of vessels when stretched so as to give an equivalent transmural pressure of 30 mmHg. This is substantially lower than that found for systemic vessels, and reflects the normal low pulmonary arterial pressure. 3. Noradrenaline was a powerful vasoconstrictor in large but not small pulmonary arteries (P less than 0.001). In contrast, bradykinin produced a significantly greater response in the small arteries (P less than 0.001). In comparison with large pulmonary arteries, small arteries were more sensitive to noradrenaline (P less than 0.05) and 5-hydroxytryptamine (P less than 0.001), less sensitive to endothelin-1 (P less than 0.001) and had the same sensitivity to prostaglandin F2 alpha. 4. The mechanism that maintains the low arterial tone of the pulmonary circulation is unknown, but it may involve the release of relaxing factors from the endothelium. In this preparation, basal resting tone could not be demonstrated in either large or small arteries. 5. Acetylcholine-induced relaxation of pre-contracted pulmonary arteries was reduced or absent in the small artery, despite histological evidence of an intact endothelium. In large arteries pre-contracted with prostaglandin F2 alpha, acetylcholine (100 mumol/l) caused 88.2% relaxation compared with 25.2% in the small artery.(ABSTRACT TRUNCATED AT 250 WORDS)     

A markedly diminished pleiotropic response to phenobarbital and structurally-related xenobiotics in Zucker rats in comparison with F344/NCr or DA rats.

Phenobarbital (PB) and certain structurally-related compounds induce a variety of hepatic drug-metabolizing enzymes in many strains of rats. Thus, following administration of PB (300, 500 ppm), barbital (BB, 1500 ppm) or 5-ethyl-5-phenylhydantoin (EPH, 500 ppm), CYP2B1-mediated benzyloxyresorufin O-dealkylase activity and epoxide hydrolase activity were profoundly induced in female DA and F344/NCr rats. In contrast, outbred female lean and obese Zucker rats showed markedly reduced CYP2B1 responses (less than 15% and less than 5% of those observed in the female DA or F344/NCr rat) to PB (doses less than or equal to 300 ppm), BB (1500 ppm) or EPH (500 ppm). In parallel studies, profound increases in RNA levels coding for CYP2B1, glutathione S-transferases Ya/Yc (alpha subclass), or epoxide hydrolase were detected in the female F344/NCr rat following treatment with PB (300 ppm), BB (1500 ppm) or EPH (500 ppm). In contrast, lean Zucker rats showed a strong response only to the highest dose of PB (500 ppm), implying that the diminished response in the Zucker rats may occur at some pretranslational level. Similar studies with lower doses of PB, EPH or BB in male lean Zucker rats showed a decreased response, relative to that in male F344/NCr rats. However, this insensitivity was not as profound as that observed in the female Zucker rats. In fact, the response to PB-type inducers in male or female Zucker rats is probably most clearly explained as a shift of the dose-response curve sharply to the right (decreased responsiveness, compared to F344/NCr or DA rats of the same sex). This decreased responsiveness of female lean Zucker rats to induction of CYP2B1, relative to that of F344/NCr rats, was also observed with the structurally-diverse PB-type inducers clonazepam, clotrimazole and 2-hexanone. In contrast, the female Zucker rat (obese or lean) displayed a pronounced response to induction of CYP1A-mediated ethoxyresorufin O-deethylase activity by beta-naphthoflavone, a prototype inducer of CYP1A1 and CYP1A2. The Zucker rat would thus appear to represent a potentially exploitable genetic model for examining the mechanism of enzyme induction by the myriad xenobiotics which induce a PB-type response.     

Balloon dilatation of the aortic valve: limited success and early restenosis.

Balloon dilatation of the aortic valve was attempted 16 times in 15 patients with severe aortic stenosis. None died but one had a transient stroke after the procedure. At dilatation the gradient across the aortic valve was reduced by greater than 30% in 69% of patients and the Gorlin valve area (calculated in 7/15 patients) increased by 30% in half. But a comparison of Doppler gradients measured before and one to two days after dilatation in 11 patients showed a greater than 30% reduction in the simultaneously measured gradient in only four. Doppler gradient was the most accurate predictor of symptomatic benefit and a fall in Doppler gradient persisted mainly in patients whose peak to peak gradient fell by at least 40% at the time of the procedure. Balloon dilatation of the aortic valve is a relatively safe procedure but it is less successful than previous reports suggest, perhaps because of early restenosis. Some forms of aortic stenosis may be more amenable to this procedure than others.     

Ureteral obstruction following aortobifemoral bypass: management by endoscopic balloon dilation.

A 71-year-old man presented with left hydronephrosis 1 year after aortofemoral bypass. Hydronephrosis was due to extrinsic compression of the ureter between the graft anteriorly and the native iliac artery. Treatment by endoscopic transluminal balloon dilation resulted in complete resolution of the hydronephrosis.     

Alpha thalassaemia hydrops fetalis in the UK: the importance of screening pregnant women of Chinese, other South East Asian and Mediterranean extraction for alpha thalassaemia trait.

OBJECTIVE: Alpha zero (alpha 0 or alpha-1) thalassaemia is an important genetic risk for women originating from Hong Kong, Singapore, Vietnam, Thailand, the Philippines or South China. Cypriots are also at risk. Carriers of alpha zero thalassaemia trait can be detected by routine haemoglobinopathy screening. When a couple are both carriers, in each pregnancy there is a 25% risk that the fetus will have alpha thalassaemia hydrops fetalis; this is fatal for the fetus and carries serious obstetric and psychological risks for the mother. Most informed couples at risk request prenatal diagnosis and selective abortion. This study investigates the effectiveness of screening, counselling and prenatal diagnosis for alpha thalassaemia hydrops fetalis in the UK. DESIGN: Retrospective analysis of the notes. SUBJECTS: 18 couples attending University College Hospital London for prenatal diagnosis of alpha thalassaemia hydrops fetalis since 1982. RESULTS: The study shows underdiagnosis of both alpha zero thalassaemia trait and alpha thalassaemia hydrops fetalis leading to avoidable stillbirths and complications in pregnancy. CONCLUSION: We recommend early screening for alpha zero thalassaemia trait for all women of Southeast Asian or eastern Mediterranean origin and the offer of prenatal diagnosis when indicated. The diagnosis of alpha thalassaemia hydrops fetalis should be considered in women of the relevant ethnic origin who have a stillbirth, neonatal death, abnormal ultrasound findings at fetal anomaly scanning (especially a large placenta), or who develop pre-eclampsia.     

Discovery of potent and selective inhibitors of procollagen C-proteinase for the treatment of fibrotic disorders

Introduction   Fibrosis is a component of many tissue pathologies leading to loss of normal tissue function, primarily due to excessive collagen deposition. Collagen is deposited following cleavage of the C- and N- terminal peptides from the pro-collagen molecule. The cleavage of the globular C-peptide by PCP reduces solubility of the fibrillar collagen molecule, resulting in deposition of insoluble collagen. Increased insoluble collagen deposition is a feature of all organ fibroses, with inhibition of this process, a key potential anti-fibrotic mechanism. The aim of this work was to discover potent and selective PCP inhibitors as experimental, topically applied, anti-fibrotic drugs for clinical evaluation.
Materials and methods   PCP was cloned from human osteosarcoma cells and enzymatic activity demonstrated using a PCP-specific peptide cleavage assay. Activities were confirmed by measuring cleavage of [³H]C-peptide from type-I pro-collagen. A cell-based fibroplasias model was employed to demonstrate compound efficacy using collagen deposition, liberated C-peptide and histological endpoints. The activities of PCP inhibitors in fibroblast and epithelial in vitro cell proliferation and migration assays, and selectivity vs. a panel of MMPs were also determined.
Discussion   In summary, we have identified and characterized potent and selective inhibitors of PCP for progression to clinical studies for investigation as a treatment paradigm for fibrotic disease.  

  Results     

38.

American Society of Nuclear Cardiology review of the ACCF/ASNC appropriateness criteria for single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI)     

R. Parker Ward MD  Mouaz H. Al-Mallah MD  Gabriel B. Grossman MD  PhD  Christopher L. Hansen MD  Robert C. Hendel MD  Todd C. Kerwin MD  Benjamin D. McCallister Jr MD  Rupa Mehta MD  Donna M. Polk MD  MPH  Peter L. Tilkemeier MD  Aseem Vashist MD  Kim Allan Williams MD  David G. Wolinsky MD  Edward P. Ficaro PhD 《Journal of nuclear cardiology》2007,14(6):911-e38

     

39.

American Society of Nuclear Cardiology review of the ACCF/ASNC appropriateness criteria for single-photon emission computed tomograph myocardial perfusion imaging (SPECT MPI)     

R. Parker Ward  Mouaz H. Al-Mallah  Gabriel B. Grossman  Christopher L. Hansen  Robert C. Hendel  Todd C. Kerwin  Benjamin D. McCallister  Rupa Mehta  Donna M. Polk  Peter L. Tilkemeier  Aseem Vashist  Kim Allan Williams  David G. Wolinsky  Edward P. Ficaro 《Journal of nuclear cardiology》2007,14(6):e26-e38

Conclusion  The ACCF/ASNC AC for SPECT MPI provides recommendations for the appropriate use of SPECT MPI. After the publication of the AC document in 2005, the AC has been used by nuclear cardiology practices with many clinical studies evaluating the list of indications in routine clinical practice. From these data. ASNC recommends minor but important changes to the indication list, suggesting the addition of 6 new indications and the modification of the definitions for “chest pain syndrome” and “CHD high risk.”. An objective review of existing indications focused on only those indications that had significant variability among the reviewers (n=20). These indications were reviewed in the presence of existing and new evidence-based data, and ASNC recommends that the grades for 6 indications be re-evaluated. The AC for SPECT MPI will require periodic review as new evidence becomes available or as clinical practice evolves. ASNC recognizes the importance of these criteria to improve the quality of patient care, and it will continue to play a key role in assembling the information for this ongoing review. From the current summary of evidence, ASNC consensus opinions, and ASNC recommendations in this document, ASNC strongly recommends that the AC guidelines be reviewed Prepared by the American Society of Nuclear Cardiology Quality Assurance Subcommittee for Quality in Imaging Standards. Reviewed by members of the American Society of Nuclear Cardiology Quality Assurance Committee. Approved by the American Society of Nuclear Cardiology Board of Directors, September 6, 20.     

40.

A hypertensive response to exercise is associated with transient ischemic dilation on myocardial perfusion SPECT imaging.     

Matthew P Smelley  Daniel E Virnich  Kim A Williams  R Parker Ward 《Journal of nuclear cardiology》2007,14(4):537-543

BACKGROUND: A hypertensive response to exercise (HRE) is associated with false-positive stress echocardiograms and myocardial perfusion single photon emission computed tomography (myocardial perfusion imaging [MPI]) defects even in the absence of coronary artery disease (CAD). Transient ischemic dilation (TID) of the left ventricle on stress MPI is a marker of severe CAD and future cardiac events. This study evaluated the association between an HRE and TID. METHODS AND RESULTS: Blinded quantitative TID assessment was performed in 125 patients who had an HRE and a summed stress score (SSS) of less than 4, as well as 125 control patients with an SSS of less than 4 and without an HRE matched for age, gender, and resting systolic blood pressure. Cardiac comorbidities, pretest Framingham risk, and exercise results were recorded. TID was defined as a stress-to-rest volume ratio of 1.22 or greater. An HRE was associated with a high prevalence of TID and significantly more TID than no HRE (25.6% vs 11.2%; odds ratio, 3.00 [95% confidence interval, 1.41-6.38]). TID was more prevalent even in subgroups with a low pretest probability CAD, including those without diabetes mellitus or angina. On conditional logistic regression analysis, an HRE was found to be independently associated with TID after consideration of other clinical and exercise MPI variables (odds ratio, 2.72 [95% confidence interval, 1.01-7.31]). CONCLUSION: An HRE is associated with a high prevalence of TID in patients without other significant perfusion defects, possibly as a result of global subendocardial ischemia induced by the HRE.     

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American Society of Nuclear Cardiology review of the ACCF/ASNC appropriateness criteria for single-photon emission computed tomograph myocardial perfusion imaging (SPECT MPI)

Conclusion  The ACCF/ASNC AC for SPECT MPI provides recommendations for the appropriate use of SPECT MPI. After the publication of the AC document in 2005, the AC has been used by nuclear cardiology practices with many clinical studies evaluating the list of indications in routine clinical practice. From these data. ASNC recommends minor but important changes to the indication list, suggesting the addition of 6 new indications and the modification of the definitions for “chest pain syndrome” and “CHD high risk.”. An objective review of existing indications focused on only those indications that had significant variability among the reviewers (n=20). These indications were reviewed in the presence of existing and new evidence-based data, and ASNC recommends that the grades for 6 indications be re-evaluated. The AC for SPECT MPI will require periodic review as new evidence becomes available or as clinical practice evolves. ASNC recognizes the importance of these criteria to improve the quality of patient care, and it will continue to play a key role in assembling the information for this ongoing review. From the current summary of evidence, ASNC consensus opinions, and ASNC recommendations in this document, ASNC strongly recommends that the AC guidelines be reviewed Prepared by the American Society of Nuclear Cardiology Quality Assurance Subcommittee for Quality in Imaging Standards. Reviewed by members of the American Society of Nuclear Cardiology Quality Assurance Committee. Approved by the American Society of Nuclear Cardiology Board of Directors, September 6, 20.     

A hypertensive response to exercise is associated with transient ischemic dilation on myocardial perfusion SPECT imaging.

BACKGROUND: A hypertensive response to exercise (HRE) is associated with false-positive stress echocardiograms and myocardial perfusion single photon emission computed tomography (myocardial perfusion imaging [MPI]) defects even in the absence of coronary artery disease (CAD). Transient ischemic dilation (TID) of the left ventricle on stress MPI is a marker of severe CAD and future cardiac events. This study evaluated the association between an HRE and TID. METHODS AND RESULTS: Blinded quantitative TID assessment was performed in 125 patients who had an HRE and a summed stress score (SSS) of less than 4, as well as 125 control patients with an SSS of less than 4 and without an HRE matched for age, gender, and resting systolic blood pressure. Cardiac comorbidities, pretest Framingham risk, and exercise results were recorded. TID was defined as a stress-to-rest volume ratio of 1.22 or greater. An HRE was associated with a high prevalence of TID and significantly more TID than no HRE (25.6% vs 11.2%; odds ratio, 3.00 [95% confidence interval, 1.41-6.38]). TID was more prevalent even in subgroups with a low pretest probability CAD, including those without diabetes mellitus or angina. On conditional logistic regression analysis, an HRE was found to be independently associated with TID after consideration of other clinical and exercise MPI variables (odds ratio, 2.72 [95% confidence interval, 1.01-7.31]). CONCLUSION: An HRE is associated with a high prevalence of TID in patients without other significant perfusion defects, possibly as a result of global subendocardial ischemia induced by the HRE.