tbuckley/cabot-search huggingface dataset:
Abstract 1377: PHLPP, a Novel Akt Phosphatase, Expressed and is Regulated in Cardiomyocytes
Authors: Shigeki Miyamoto, Tianyan Gao, Alexandra C Newton, Joan Heller Brown
Journal: Circulation (2006)

Akt is known to be a strong survival signaling in various cell types including the heart. Although activation of Akt by PI3K, PDK-1 and a putative PDK-2 has been extensively studied, signals terminating Akt activation have only recently been discovered. Studies by the Newton laboratory identified a novel protein phosphatase, PH domain Leucine-rich repeat Protein Phosphatase, PHLPP, that specifically dephosphorylates the ser-473 site, but not the thr-308 site on Akt. PHLPP expression markedly diminished Akt kinase activity and triggered apoptosis, while PHLPP downregulation selectively increased Akt phoshorylation at ser-473 and prevented apoptosis. The possibility that PHLPP is regulated and contributes to the activation of Akt in cardiomyocytes has not yet been explored. Two isoforms of PHLPP, PHLPP-1 and -2 have been identified and PHLPP-1 mRNA is strongly expressed, while PHLPP-2 shows lower expression in adult mouse ventricular myocytes (AMVMs). Western blotting revealed PHLPP-1 expression in both AMVMs and neonatal rat ventricular myocytes (NRVMs). Immunostaining demonstrated that PHLPP-1 was located not only in the cytosol but also in the nucleus implying that PHLPP-1 can regulate Akt signaling in multiple cellular components. Studies were then carried out to determine whether PHLPP expression was regulated when Akt activity was chronically altered. We found that PHLPP-1 protein was upregulated 2–3 fold in NRVMs treated for 48 hrs with leukemia inhibitory factor an efficacious activator of Akt. Conversely treatment with rapamycin, an mTOR inhibitor for 48 hrs, significantly decreased PHLPP expression, consistent with a postulated role of mTOR in regulating Akt activation state. PHLPP was also downregulated in both ES cells and cardiomyocytes from PDK-1 knock out (KO) mice in which Akt activation was severely limited. These data demonstrate that PHLPP expression is regulated to compensate for chronic changes in Akt activity and suggest a potential role for PHLPP in regulating cardiomyocyte survival. Studies are currently in progress using PHLPP-1 adenovirus and PHLPP-1 KO mice to examine the functional importance of PHLPP in regulation of Akt and cardiomyocyte survival in vitro and in response to pathophysiological interventions in vivo.
Abstract 16712: Focal Adhesion Kinase: A Putative Therapeutic Target for the Treatment of Pulmonary Arterial Hypertension
Authors: Roxane Paulin, Jolyane Meloche, Audrey Courboulin, Caroline Lambert, Evangelos Michelakis, Sebastien Bonnet
Journal: Circulation (2011)

Background: Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary artery smooth muscle cells (PASMC) proliferation, migration and suppressed apoptosis. This phenotype is attributed in part to the sustained activation of the neoplasic axis c-Src/STAT3. In cancer, c-Src enhances focal adhesion kinase activation (FAK), a signaling hub implicated in the sustainability of cell proliferation, survival and motility, in part by potently inducing STAT family of proteins activation. Recently FAK inhibition has been proposed as a new therapeutic intervention in cancer. We hypothesized that FAK inhibition in PAH will decrease the activation of STAT3 axis decreasing PASMC proliferation, migration and resistance to apoptosis. Methods/Results: Using immunoblots (n=3 p&lt;0.05) we showed activation of both c-Src and FAK (phosphorylation on Y416 and Y397 respectively) in human PAH-PASMCs resulting in cSrc/FAK complex formation (FAK phosphorylation on Y576) promoting STAT3 activation (phosphorylation on Y705). All these results were inhibited by 1) Src inhibitor PP2, 2) FAK siRNA. The Src/FAK-dependent activation of STAT3 accounts for 1) PAH-PASMCs mitochondrial hyperpolarization (TMRM n=150 p&lt;0.05), increasing resistance to apoptosis (n=150 p&lt;0.05 TUNEL) 2) increases proliferation by 30% (PCNA &amp; Ki67) 3) increases cell migration (transwell assay, n=3 p&lt;0.05) and invasion (Scratch test n=5 p&lt;0.05) by 25% compared to controls. All these findings were similarly reversed by either Src, FAK and STAT3 inhibitors. Finally, in vivo FAK-siRNA nebulization improves monocrotaline-PAH (n=10 in each group p&lt;0.05) measured by PA pressure, PA wall thickness, right ventricular hypertrophy (Echo &amp; catheterization). Conclusion: FAK inhibition represents a new therapeutic target for PAH. Currently new FAK inhibitors have been moved to clinic trials to treat cancer. Our findings suggest that these compounds could be useful for the treatment of PAH as well.
Abstract 13611: Negative Prognostic Impact of Late Gadolinium Enhancement on Cardiac Magnetic Resonance Images in Heart Transplant Patients
Authors: Patrizia Pedrotti, Claudia Vittori, Stefano Pedretti, Santo Dellegrottaglie, Angela Milazzo, Manlio Cipriani, Maria Frigerio, Francesco Mauri, Alberto Roghi
Journal: Circulation (2010)
Anger attacks in unipolar depression, Part 1: Clinical correlates and response to fluoxetine treatment
Authors: M Fava, J F Rosenbaum, J A Pava, M K McCarthy, R J Steingard, E Bouffides
Journal: American Journal of Psychiatry (1993)

Anger attacks are sudden, intense spells of anger associated with a surge of autonomic arousal including such symptoms as tachycardia, sweating, flushing, and a feeling of being out of control. The purpose of this study was to determine whether depressed patients with and without anger attacks exhibit distinct psychological characteristics and whether these attacks respond to treatment with fluoxetine.The Anger Attacks Questionnaire, the Hamilton Rating Scale for Depression, the Symptom Questionnaire, and the Cook-Medley Hostility Scale were among the scales administered at the Depression Research Program of the Clinical Psychopharmacology Unit at the Massachusetts General Hospital to 127 medication-free outpatients with major depression and to 85 of these patients after 8 weeks of open treatment with a fixed dose (20 mg/day) of fluoxetine.At baseline, 44% of the depressed outpatients reported having anger attacks; these patients had significantly higher scores on measures of anxiety, somatization, and state and trait hostility than did the subjects who did not exhibit such attacks. After treatment, there were significant reductions in these measures, and the anger attacks disappeared in the majority (71%) of the patients who had previously reported them. There was a trend toward greater overall clinical improvement for patients with anger attacks than for patients without them.This study identified a subgroup of highly irritable and hostile depressed patients who report the presence of anger attacks and have a psychological profile distinct from that of depressed patients without anger attacks. Furthermore, fluoxetine treatment appears to be beneficial in reducing anger and hostility in these patients.
Dissociative phenomena in women with borderline personality disorder
Authors: S L Shearer
Journal: American Journal of Psychiatry (1994)

This study was conducted to determine whether trauma variables and certain behavioral correlates are differentially prevalent in borderline personality disorder patients with greater and those with lesser dissociative experience.Subjects were 62 female inpatients, all meeting DSM-III-R criteria for borderline personality disorder, 14 of whom also had a concomitant dissociative disorder diagnosis. Structured interviews and published scales were used to collect data addressing a priori hypotheses.Univariate analyses supported hypotheses that patients with borderline personality disorder and greater dissociative experience are characterized by more self-reported traumatic experiences, posttraumatic symptoms, behavioral dyscontrol, self-injurious behavior, and alcohol abuse. Multivariate analyses suggested that scores on the Dissociative Experiences Scale were predicted particularly by adult sexual assault, behavioral dyscontrol, and both sexual and physical abuse in childhood.These results support the use of the Dissociative Experience Scale as a brief screening instrument to aid in the identification of borderline personality disorder patients with prominent posttraumatic and dissociative disorders. Patients with borderline personality disorder seem to be characterized by somewhat different life experiences, treatment histories, and behavioral presentations depending on their level of dissociative experience, even though they meet the same DSM-III-R criteria. Neither extreme view of the overlap in diagnostic populations was supported.
Abstract 3719: Deletion of Angiotensin II type 2 Receptor Accelerates Adipogenesis in Murine Mesenchymal Stem Cells with Wnt 10b/beta-catenin Signaling: Potential Link to Obesity and Metabolic Syndrome
Authors: Kenichi Matsushita, Yaojiong Wu, Hao Wang, Richard E Pratt, Victor J Dzau
Journal: Circulation (2008)

Recent evidence suggests that the reninangiotensin system (RAS) plays a vital role in adipocyte biology and the pathophysiology of metabolic syndrome. Obesity is a major risk factor and mesenchymal stem cells (MSCs) are suggested to be an important source of new fat cells. Previously we reported that MSCs have all the components of the RAS and that angiotensin II (Ang II) can influence adipocyte differentiation. However, the effect of Ang II type 2 receptor (AT2R) deletion on adipogenesis in mouse model is unknown. Accordingly, we employed AT2R-null mice and examined the role of AT2R in the differentiation of MSCs to adipocytes. Methods and Results: Murine MSCs were isolated from AT2R-null mice and wildtype littermates (WT). Confluent MSCs were differentiated into adipocytes by the established protocol. Adipogenesis was quantitated by assessing lipid droplet accumulation using 2 different methods. Using the fluorescent dye which binds to lipid droplets (AdipoRed), AT2R-null group showed significantly increased total fluorescence (261.6 ± 49.6 % vs. WT) on day 7. Oil red O staining, followed by extraction of the absorbed dye and measurement of the absorbance on day 14, also exhibited that AT2R-null group showed significantly increased lipid droplet accumulation (202.7 ± 14.1 % vs. WT). We next examined the expression of adipocyte-specific genes by real-time RT-PCR. AT2R-null group exhibited a significantly increased expression of PPARγ, fatty acid synthase, and adiponectin (vs. WT). Since Wnt 10b/beta-catenin signaling is reported to play an important role to inhibit adipogenesis, we further examined it by real-time RT-PCR and immunoblotting. The AT2R-null group exhibited significantly decreased Wnt 10b expression accompanied by a decrease of cellular beta-catenin (vs. WT). Conclusion: Our results demonstrate that the AT2 receptor has an inhibitory effect on adipogenic differentiation in murine mesenchymal stem cells. Moreover, this inhibitory effect is associated with Wnt 10b/beta-catenin signaling which plays an important role to inhibit adipogenesis. These results provide important insights into the pathophysiology of obesity and obesity related consequences such as metabolic syndrome and may identify potential therapeutic targets.
Abstract 4428: Similar Response to Spironolactone in Whites and African American Patients with Resistant Hypertension
Authors: Saima Husain, Mari K Nishizaka, Eduardo Pimenta, Krishna K Gaddam, Suzanne Oparil, David A Calhoun
Journal: Circulation (2008)

Primary aldosteronism (PA) is a common cause of resistant hypertension with a prevalence of approximately 20%. Spironolactone is the drug of choice for the medical management of patients with PA. Blacks have been reported to have low-renin HTN and respond better to diuretics and calcium channel blockers. Racial differences in response to spironolactone in patients with resistant hypertension have not been previously described. Consecutive subjects referred to the University of Alabama at Birmingham hypertension clinic for resistant hypertension had been evaluated with a plasma aldosterone concentration (PAC), plasma renin activity (PRA), and a 24-hr urine collection for aldosterone, sodium, and potassium during the patient’s usual diet. The BP response to spironolactone was compared retrospectively in patients. For clinical reasons, subjects had been treated with a median dose of 25 mg of spironolactone and the BP response at 6 weeks, 3 and 6 months was compared retrospectively. A total of 117 patients with resistant hypertension were included in the analysis, including 59 white and 58 black subjects. Both groups had a similar number of antihypertensive medications at baseline. PAC, PRA, U-aldo and serum potassium levels were also similar. BP reduction at 6-weeks, 3- and 6-months after treatment with spironolactone was similar in black and white subjects. At 3 months, the mean reduction in systolic BP was −19.5±19.0 and −23.2±20.0 for blacks and whites, respectively (p= 0.321). These data indicate that African American and white subjects with resistant hypertension respond equally well to spironolactone.
Clinical implications of benzodiazepine pharmacokinetics
Authors: R I Shader, D J Greenblatt
Journal: American Journal of Psychiatry (1977)

Pharmacokinetic research has shown that clear differences exist among benzodiazepines in rate and route of elimination and in the presence or absence of pharmacologically active metabolites. These findings and other results of pharmacokinetic research have clinical implications in terms of dosage schedules, drug accumulation during long-term therapy, antianxiety therapy in the elderly, drug interactions, pharmacotherapy in specific disease states, and the influence of route of administration on drug action.
Choosing the right antibiotic
Authors: D. Bihari, M. H Wilcox, J. Sandoe
Journal: BMJ (1999)

Editor—Leibovici et al make a fundamental point about the prescription of antimicrobial drugs—the right antibiotic at the right time saves lives1—and we should not forget it. Yet as the various commentators point out, it is not always easy to choose the right antimicrobial since we know that all drugs have side effects, some are expensive, and some are more poisonous than others.

In intensive care, many patients present with septic shock, and we usually only get “one bite” at the cherry. I try to teach our residents a few of the “see-saw” principles of antimicrobial prescribing that I have learnt along the way.

Firstly, the right drug in the right dose (big) at the right time does save lives. Surprisingly to some, antibiotics do work and you need to get it right from the start. Secondly, there is not much point in saving your “best” antibiotic for the postmortem room. Next, we treat patients, not fevers, white cell counts, chest radiographs, or cultures. But on the other hand, just because the laboratory cannot grow something does not mean that there are no germs there causing trouble. And it does not mean that you should not consult them. You should. Finally, try to avoid poisoning the patient but always remember (and keep telling the managers) that saving lives costs money. There is nothing cheaper than a quick death.
Ruptured Cornual Pregnancy
Authors: Munawar Hussain, Haleema Yasmeen, Khursheed Noorani
Journal: New England Journal of Medicine (1974)

A case of ruptured cornual pregnancy is presented here. The patient presented with history of 30 weeks gestational amenorrhoea and pain in the lower abdomen and epigastrium for the last seven days. Ultrasound revealed a 29 weeks abdominal pregnancy with blood in the pelvic cavity. On laparotomy, there was a ruptured right cornual pregnancy, treated cornual resection and uterine repair. An alive male baby of one kg weight was delivered from the resected cornua of the uterus.
Abstract 16998: Impact of Annual Operator Volume on Percutaneous Coronary Intervention Outcomes: A United States Experience From 2,243,209 procedures
Authors: Nileshkumar J Patel, Peeyush M Grover, Neeraj Shah, Kathan Mehta, Ankit Chothani, Shilpkumar Arora, Vikas Singh, Ghanshyambhai T Savani, Nilay Patel, Abhishek Deshmukh, Ankit Rathod, Tushar Tuliani, Sidakpal P Panaich, Dhaval Khalpada, Vipulkumar Bhalara, Narendrasinh G Parmar, Apurva O Badheka, Jawahar L Mehta, James Lafferty, William O'Neill, Eduardo de Marchena, Mauricio G Cohen
Journal: Circulation (2013)

Introduction: Percutaneous coronary intervention (PCI) volume is often used as a surrogate to define quality and maintain proficiency (> 75 PCI/year). Currently there lacks definite evidence to sup...
Abstract 1905: Restoration of Normoglycemia Re-Establishes the Infarct-Sparing Effect of Postconditioning in Diabetic Mice
Authors: Karin Przyklenk, Michelle Maynard, Dale L Greiner, Peter Whittaker
Journal: Circulation (2008)

Relief of ischemia in a stuttering manner (postconditioning: PostC) reduces infarct size in healthy adult populations, due in part to activation of ERK 1/2 during the early minutes of reflow. However, emerging evidence suggests that PostC fails to limit ischemia-reperfusion injury in the setting of diabetes. Our current aim was to establish whether this loss in efficacy of PostC reflects a permanent diabetes-associated defect in cardioprotective signaling, or whether therapy to restore normoglycemia can re-establish the PostC phenotype. To address this issue, isolated buffer-perfused hearts were obtained from 4 cohorts of C57BL/6J mice: healthy adults; animals injected 2 or 4 wks earlier with streptozotocin (STZ) to induce diabetes; and mice injected 4 wks earlier with STZ that, at 2 wks after being rendered diabetic, received islet cell transplantation (ICT). All hearts underwent 30 min global ischemia and, within each cohort, were assigned to receive either complete, abrupt reperfusion (controls) or PostC with 3 10-sec cycles of stuttered reflow. In hearts from healthy mice: (i) PostC was cardioprotective (infarct size [delineated by tetrazolium staining] was 27±3% vs 50±3% of the LV in PostC hearts vs controls; p&lt;.05); (ii) PostC-induced protection was associated with significant, &gt;2-fold increases in expression of phospho-MEK, phospho-ERK and downstream targets of ERK; and (iii) the benefits of PostC were abrogated by the MEK inhibitor PD98059. At both 2 and 4 weeks post-STZ injection, mice displayed: (i) low plasma insulin levels (0.18±0.08 and 0.07±0.02 vs 1.40±0.20 ng/ml) and hyperglycemia (blood glucose: 556±15 and 558±10 vs 178±7 mg/dl in healthy C57 mice); (ii) no up-regulation of ERK signaling in response to stuttered reflow; and (iii) no infarct-sparing effect of PostC (mean infarct sizes: 62– 63% in STZ-PostC groups vs 58 – 63% in STZ-controls). In contrast, ICT: (i) restored normal insulin and blood glucose levels (1.33±0.09 ng/ml; 189±7 mg/dl) and, most notably (ii) reinstated the up-regulation in ERK signaling and infarct-sparing effect of PostC (infarct size: 31±3% vs 51±5% in STZ±ICT controls; p&lt;0.05). Thus, therapeutic control of insulin and blood glucose re-establishes the protective PostC phenotype in this mouse model of diabetes.
Abstract 191: Mechanical Postconditioning with Chest Compression Pauses at the Initiation of CPR Prevents Neurological Dysfunction at 24 Hours in Pigs After 15 Minutes of Untreated Ventricular Fibrillation
Authors: Demetris Yannopoulos, Nicolas Segal, Emily Caldwell, Scott McKnite, Santiago Garcia, Lance Becker, Tom P Aufderheide, Keith G Lurie
Journal: Circulation (2011)

Background: Mechanical post conditioning (PC) with intermittent initiation of flow (“stutter” reperfusion) has been shown to decrease infarction size in ST elevation infarction and decrease ischemic stroke size in animals. We hypothesize that when using sodium nitroprusside-enhanced cardiopulmonary resuscitation (SNPeCPR) mechanical post conditioning with stutter CPR (20-second CPR pauses), begun immediately on SNPeCPR initiation, will improve 24-hour cerebral function compared to 12 hours of therapeutic hypothermia (TH) post resuscitation. Methods: 14 anesthetized and intubated pigs underwent 15 minutes of untreated VF followed by 5 minutes of SNPeCPR comprised of active compression decompression CPR plus an inspiratory impedance threshold device combined with abdominal binding. 2 mg of sodium nitroprusside (SNP) were given IV at minute 1 and 1 mg at minute 3 of CPR. All animals received in addition 0.5 mg of epinephrine at minute 5, 30 seconds before the first defibrillation attempt. Six animals (PC group), were treated with 40 seconds of SNPeCPR and the first dose of SNP, then followed by 20-second pauses (cessation of perfusion) and 20 seconds of SNPeCPR with a total of 4 cycles for up to 3 minutes. After that, animals had uninterrupted SNPeCPR until defibrillation at minute 5. The other 8 animals (TH group) had SNPeCPR for a total of 5 minutes without interruptions. The TH group received 12 hours of TH (core temp=33°C). The PC group received no TH. Cerebral performance category (CPC) was scored at 24 hours by a veterinarian blinded to the treatment group. Results: During SNPeCPR, there were no hemodynamic differences except for a significantly higher aortic pressure response to epinephrine at min 5 (SBP/DBP; 148±12/78±7 in the PC group versus 110±9/62±5 mmHg in the TH group, p&lt;0.05). Both groups had 100% return of spontaneous circulation rates and 24-hour survival. CPC was significantly lower in the PC group (1±0 = normal) versus the TH group (2.4±0.8 = mild to moderate disability), p&lt;0.01. Conclusion: In this porcine model of cardiac arrest and SNPeCPR, mechanical PC with pauses in compressions at the initiation of the resuscitation efforts prevented 24-hour neurological dysfunction after 15 minutes of untreated VF and was superior to TH.
Abstract 434: Prolyl 4-Hydroxylase 2 Gene Silencing Attenuates Post-Ischemic Injury and Proinflammatory Chemokine Generation in Murine Hearts
Authors: Fadi N Salloum, Ramesh Natarajan, Evan D Ownby, Bernard J Fisher, Julia A Messina, Alpha A Fowler, Rakesh C Kukreja
Journal: Circulation (2006)

Background: Hypoxia Inducible Factor-1 (HIF-1) activates genes modulating inflammation (e.g., eNOS, iNOS, and HO-1). We recently showed that in vivo silencing of prolyl 4-hydroxylase 2 (P4HA2) acti...