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Gomberg-Maitland M.,University of Chicago | Dufton C.,Rubicon science | Oudiz R.J.,University of California at Los Angeles | Benza R.L.,Allegheny General Hospital
Journal of the American College of Cardiology | Year: 2011

Pulmonary arterial hypertension (PAH) is a rare and progressive disease of the pulmonary arterial circulation that is characterized by a progressive rise in pulmonary vascular resistance, eventually leading to right-heart failure and death. There are currently 3 classes of drugs approved for the treatment of PAH: prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. All of these therapies have been approved for use on the basis of relatively small, short-term studies, yet it is common for each to be administered (alone or in combination) over the lifetime of a patient with PAH. Very few prospective, well-controlled PAH studies have examined long-term clinical outcomes associated with current medical therapy. Therefore, data that support the long-term therapeutic benefits of these long-term PAH therapies are limited and derived primarily from uncontrolled, observational studies. In this perspective, the authors review the published research to assess the strengths and weaknesses of the data that support the long-term clinical benefit of current PAH therapies. The authors conclude that current medical therapies approved for the treatment of PAH can provide sustained benefits in hemodynamic function and exercise capacity. The cumulative evidence, in the form of meta-analysis and registry data, suggest that patients are living longer compared with untreated patients; the reasons are likely multifactorial. Although definitive evidence will require randomized and properly controlled long-term trials, the current evidence supports the long-term use of these drugs for the treatment of patients with PAH. © 2011 American College of Cardiology Foundation.


BACKGROUND: We have shown that glucagon-like peptide-1 (GLP-1[7-36] amide) stimulates myocardial glucose uptake in dilated cardiomyopathy (DCM) independent of an insulinotropic effect. The cellular mechanisms of GLP-1-induced myocardial glucose uptake are unknown. METHODS AND RESULTS: Myocardial substrates and glucoregulatory hormones were measured in conscious, chronically instrumented dogs at control (n=6), DCM (n=9) and DCM after treatment with a 48-hour infusion of GLP-1 (7-36) amide (n=9) or vehicle (n=6). GLP-1 receptors and cellular pathways implicated in myocardial glucose uptake were measured in sarcolemmal membranes harvested from the 4 groups. GLP-1 stimulated myocardial glucose uptake (DCM: 20+/-7 nmol/min/g; DCM+GLP-1: 61+/-12 nmol/min/g; P=0.001) independent of increased plasma insulin levels. The GLP-1 receptors were upregulated in the sarcolemmal membranes (control: 98+/-2 density units; DCM: 256+/-58 density units; P=0.046) and were expressed in their activated (65 kDa) form in DCM. The GLP-1-induced increases in myocardial glucose uptake did not involve adenylyl cyclase or Akt activation but was associated with marked increases in p38alpha MAP kinase activity (DCM+vehicle: 97+/-22 pmol ATP/mg/min; DCM+GLP-1: 170+/-36 pmol ATP/mg/min; P=0.051), induction of nitric oxide synthase 2 (DCM+vehicle: 151+/-13 density units; DCM+GLP-1: 306+/-12 density units; P=0.001), and GLUT-1 translocation (DCM+vehicle: 21+/-3% membrane bound; DCM+GLP-1: 39+/-3% membrane bound; P=0.005). The effects of GLP-1 on myocardial glucose uptake were blocked by pretreatment with the p38alpha MAP kinase inhibitor or the nonspecific nitric oxide synthase inhibitor nitro-l-arginine. CONCLUSIONS: GLP-1 stimulates myocardial glucose uptake through a non-Akt-1-dependent mechanism by activating cellular pathways that have been identified in mediating chronic hibernation and the late phase of ischemic preconditioning.


Lang I.M.,Medical University of Vienna | Benza R.,Allegheny General Hospital
European Heart Journal | Year: 2012

As can be seen by the mounting literature, there has been immense progress in the field of pulmonary hypertension (PH) over the last three decades, illustrated by several important milestones including improved understanding of disease pathogenesis, new classifications of disease, advances in screening and diagnostic techniques, and new rules for staging and follow-up, which have subsequently led to improvements in patient outcomes. The objectives of this manuscript are to not only highlight these very recent advances but also point out areas of deficiencies or gaps in our knowledge that may serve a focal point for future discussion and investigation. © 2011 The Author.


Post C.,Allegheny General Hospital
Advances in Oto-Rhino-Laryngology | Year: 2011

There is a growing body of evidence, both from animal and human studies, that host genetic factors can influence the risk of developing otitis media (OM). The role of genetics in OM has been elucidated through studies with monozygotic and dizygotic twins, analyses linking genetic polymorphisms to OM susceptibility, and genome scans. Several twin studies have shown a strong genetic component to middle ear effusion risk, with the estimate of the role of heredity for the proportion of time with middle ear effusions being around 0.7. Genetic polymorphisms in plasminogen activator inhibitor-1, interleukin-6, tumor necrosis factor-α, human leukocyte antigen, and mannose-binding lectin have been variously linked with OM and upper respiratory infection susceptibility. Several genome linkage studies have identified chromosomal regions associated with chronic OM, including 3p, 10q, 10q22.3, 17q12 and 19q. A number of candidate genes are associated with these sites. Given the current state of understanding of the role of genetics in OM, a family history of OM should be as certained for all patients. Children with a strong family history of OM should be considered as candidates for a more aggressive early treatment of OM, particularly if other risk factors are present. These children may be earlier candidates for the placement of tympanostomy tubes and/or adenoidectomy. Existing data do not support routine genetic testing to determine a child's susceptibility to OM; however, given the advances in whole genome sequencing, such testing may someday play a role in the management of the OM patient. Copyright © 2011 S. Karger AG, Basel.


Purpose: The purpose of this study was to evaluate the hemodynamic stability and efficacy of 3 different propofol-ketamine admixtures compared with a propofol-saline solution admixture for continuous- infusion intravenous general anesthesia in outpatient adult dentoalveolar surgery. Patients and Methods: This was a prospective, randomized, positive-controlled clinical trial between a propofol-saline solution admixture and 3 propofol-ketamine admixtures comprising 4 groups: group A (control), propofol and saline solution; group B, 10:1 propofol-ketamine ratio; group C, 5:1 propofolketamine ratio; and group D, 3:1 propofol-ketamine ratio. The bispectral index (BIS) was used to monitor all patients for time to induction (BIS <70) to recovery time (BIS >90). The outcome variables- noninvasive systolic, diastolic, and mean blood pressures; pulse; and BIS-were recorded at baseline and every 5 minutes during surgery. One-way analysis of variance and x 2 analysis were conducted on the groups to determine statistical significance, set at P < .05. Post hoc pair-wise comparisons with Bonferroni adjustments were conducted on statistically significant groups. Results: A total of 64 adult patients (37 men and 27 women; mean age, 27.3 years) who had dentoalveolar surgery under intravenous general anesthesia in an outpatient oral and maxillofacial surgery clinic setting were enrolled in this study. There were statistically significant differences between mean values of groups only for mean systolic blood pressure and mean blood pressure in groups A and D (127 mm Hg vs 146 mm Hg and 96 mm Hg vs 109 mm Hg, respectively). There were statistically significant differences in percent change from baseline measurements only between groups A and D for systolic blood pressure (-6.9% vs +1.3%), diastolic blood pressure (-5.4% vs +0.7), and mean arterial pressure (-0.5% vs +2.6%). All mean percent changes from baseline were within 20% of baseline. There were statistically significant differences between groups for number of boluses but not time to surgery start, movement on injection, or length of surgery. Statistically significant differences in recovery times were found between all groups except between groups A and C and groups C and D. There were no incidences of postoperative nausea or vomiting in the immediate postoperative period. Conclusions: Through maintenance of hemodynamic stability and faster recovery time, the group B admixture (10:1 propofol-ketamine ratio) provided the greatest benefit for continuous intravenous general anesthesia in adults undergoing dentoalveolar surgery in an outpatient clinic setting. © 2012 American Association of Oral and Maxillofacial Surgeons.

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