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Publication Record


Echocardiographic Detection of Occult Diastolic Dysfunction in Pulmonary Hypertension After Fluid Challenge.
Agrawal V, D'Alto M, Naeije R, Romeo E, Xu M, Assad TR, Robbins IM, Newman JH, Pugh ME, Hemnes AR, Brittain EL
(2019) J Am Heart Assoc 8: e012504
MeSH Terms: Adult, Aged, Cardiac Catheterization, Diastole, Echocardiography, Doppler, Female, Heart Failure, Hemodynamics, Humans, Hypertension, Pulmonary, Infusions, Parenteral, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Reproducibility of Results, Retrospective Studies, Saline Solution, Ventricular Dysfunction, Left, Ventricular Function, Left
Show Abstract · Added March 8, 2020
Background Identification of occult diastolic dysfunction often requires invasive right heart catheterization with provocative maneuvers such as fluid challenge. Non-invasive predictors of occult diastolic dysfunction have not been identified. We hypothesized that echocardiographic measures of diastolic function are associated with occult diastolic dysfunction identified at catheterization. Methods and Results We retrospectively examined hemodynamic and echocardiographic data from consecutive patients referred for right heart catheterization with fluid challenge from 2009 to 2017. A replication cohort of 52 patients who prospectively underwent simultaneous echocardiography and right heart catheterization before and after fluid challenge at Monaldi Hospital, Naples, Italy. In the retrospective cohort of 126 patients (83% female, 56+14 years), 27/126 (21%) had occult diastolic dysfunction. After adjusting for tricuspid regurgitant velocity and left atrial volume index, E velocity (odds ratio 1.8, 95% CI 1.1-2.9, P=0.01) and E/e' (odds ratio 1.9, 95% CI 1.1-3, P=0.005) were associated with occult diastolic dysfunction with an optimal threshold of E/e' >8.6 for occult diastolic dysfunction (sensitivity 70%, specificity 64%). In the prospective cohort, 5/52 (10%) patients had diastolic dysfunction after fluid challenge. Resting E/e' (odds ratio 8.75, 95% CI 2.3-33, P=0.001) and E velocity (odds ratio 7.7, 95% CI 2-29, P=0.003) remained associated with occult diastolic dysfunction with optimal threshold of E/e' >8 (sensitivity 73%, specificity 90%). Conclusions Among patients referred for right heart catheterization with fluid challenge, E velocity and E/e' are associated with occult diastolic dysfunction after fluid challenge. These findings suggest that routine echocardiographic measurements may help identify patients like to have occult diastolic dysfunction non-invasively.
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20 MeSH Terms
Parenteral Prostanoid Use at a Tertiary Referral Center: A Retrospective Cohort Study.
Hay BR, Pugh ME, Robbins IM, Hemnes AR
(2016) Chest 149: 660-6
MeSH Terms: Adult, Cause of Death, Cohort Studies, Comorbidity, Connective Tissue Diseases, Death, Sudden, Endothelin Receptor Antagonists, Familial Primary Pulmonary Hypertension, Female, Guideline Adherence, HIV Infections, Heart Defects, Congenital, Heart Failure, Humans, Hypertension, Pulmonary, Infusions, Parenteral, Male, Middle Aged, Patient Selection, Phosphodiesterase 5 Inhibitors, Practice Guidelines as Topic, Prostaglandins, Quality Improvement, Retrospective Studies, Severity of Illness Index, Tertiary Care Centers
Show Abstract · Added March 8, 2020
BACKGROUND - Evidence-based guidelines recommend the use of parenteral prostaglandin (PP) therapy in patients with advanced pulmonary arterial hypertension (PAH). Despite this, many patients with PAH die without PP therapy. We sought to examine the frequency of PP use at a large referral center and characterize patients with PAH who died without receiving PP.
METHODS - We conducted a single-center retrospective cohort analysis of consecutive patients with PAH between 2008 and 2012. Clinical data and cause of death were compared between patients with PAH treated with PP (PAH-PP) and those who were not but were not documented as poor PP candidates (PAH-nonPP).
RESULTS - Of the 101 patients who received a diagnosis of PAH and died, 61 received PP therapy. Of the 40 patients not treated with PP, 10 did not have documented evaluations for PP therapy (PAH-nonPP) whereas 30 were not considered candidates or refused PP therapy. Compared with PAH-PP, PAH-nonPP had a longer 6-min walk distance, had a longer duration between time of diagnosis and date of worse functional class visit, were less likely to be diagnosed as functional class IV, and had significantly lower right atrial pressure. None of the PAH-nonPP died of progressive PAH.
CONCLUSIONS - We found that most patients who die with PAH are evaluated for PP therapy at a large referral center and the small minority of PAH-nonPP tended to have less severe disease and die of non-PAH-related causes. Our data suggest that at large pulmonary hypertension (PH) centers, the vast majority of patients who are appropriate candidates receive PP therapy.
Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Frequency of peripherally inserted central catheter complications in children.
Barrier A, Williams DJ, Connelly M, Creech CB
(2012) Pediatr Infect Dis J 31: 519-21
MeSH Terms: Anti-Bacterial Agents, Catheter-Related Infections, Catheterization, Central Venous, Catheterization, Peripheral, Child, Child, Preschool, Female, Humans, Immunocompetence, Infant, Infusions, Parenteral, Male, Risk Factors, Thrombosis
Show Abstract · Added February 3, 2014
This study examined the frequency and types of complications with peripherally inserted central catheters (PICCs) placed in immunocompetent pediatric patients for parenteral antimicrobial therapy. It also sought to determine risk factors associated with those complications. Complications occurred at a frequency of 19.3/1000 PICC days, and greater than 30% of PICCs developed at least one complication. Risk factors for complication include double-lumen PICCs, PICCs placed in the femoral vein, younger age, and greater number of daily doses.
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14 MeSH Terms
Hypocretin 1/orexin A in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration.
España RA, Melchior JR, Roberts DC, Jones SR
(2011) Psychopharmacology (Berl) 214: 415-26
MeSH Terms: Analysis of Variance, Animals, Behavior, Addictive, Behavior, Animal, Central Nervous System Stimulants, Cocaine, Dopamine, Infusions, Parenteral, Injections, Intravenous, Intracellular Signaling Peptides and Proteins, Male, Microdialysis, Motivation, Neuropeptides, Orexins, Potentiometry, Rats, Rats, Sprague-Dawley, Reinforcement, Psychology, Reward, Self Administration, Signal Transduction, Time Factors, Ventral Tegmental Area
Show Abstract · Added March 30, 2020
RATIONALE - Recent evidence indicates that the hypocretin/orexin system participates in the regulation of reinforcement and addiction processes. For example, manipulations that decrease hypocretin neurotransmission result in disruptions of neurochemical and behavioral responses to cocaine.
OBJECTIVES - To further assess the relationship between the hypocretin system and cocaine reinforcement, the current studies used microdialysis and in vivo voltammetry to examine the effects of hypocretin 1 on cocaine-induced enhancement of dopamine signaling in the nucleus accumbens core. Fixed ratio, discrete trials, and progressive ratio self-administration procedures were also used to assess whether hypocretin 1 promotes cocaine self-administration behavior.
RESULTS - Infusions of hypocretin 1 into the ventral tegmental area increased the effects of cocaine on tonic and phasic dopamine signaling and increased the motivation to self-administer cocaine on the discrete trials and progressive ratio schedules.
CONCLUSIONS - Together with previous observations demonstrating that a hypocretin 1 receptor antagonist disrupts dopamine signaling and reduces self-administration of cocaine, the current observations further indicate that the hypocretin system participates in reinforcement processes likely through modulation of the mesolimbic dopamine system.
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MeSH Terms
Portal infusion of amino acids is more efficient than peripheral infusion in stimulating liver protein synthesis at the same hepatic amino acid load in dogs.
Dardevet D, Kimball SR, Jefferson LS, Cherrington AD, Rémond D, DiCostanzo CA, Moore MC
(2008) Am J Clin Nutr 88: 986-96
MeSH Terms: Amino Acids, Animals, Blood Glucose, Carbon Isotopes, Catheterization, Peripheral, Cross-Over Studies, Dogs, Glucagon, Infusions, Intravenous, Infusions, Parenteral, Insulin, Liver, Male, Mechanistic Target of Rapamycin Complex 1, Multiprotein Complexes, Portal Vein, Protein Biosynthesis, Proteins, Random Allocation, Somatostatin, TOR Serine-Threonine Kinases, Transcription Factors
Show Abstract · Added June 2, 2014
BACKGROUND - Hepatic glucose uptake is enhanced by the portal delivery of glucose, which creates a negative arterioportal substrate gradient. Hepatic amino acid (AA) utilization may be regulated by the same phenomenon, but this has not been proven.
OBJECTIVE - We aimed to assess hepatic AA balance and protein synthesis with or without a negative arterioportal AA gradient.
DESIGN - Somatostatin was infused intravenously, and insulin and glucagon were replaced intraportally at 4- and 3-fold basal rates, respectively, in 3 groups (n = 9 each) of conscious dogs with catheters for hepatic balance measurement. Arterial glucose concentrations were clamped at 9 mmol/L. An AA mixture was infused intravenously to maintain basal concentrations (EuAA), intraportally to mimic the postmeal AA increase (PoAA), or intravenously (PeAA) to match the hepatic AA load in PoAA. Protein synthesis was assessed with a primed, continuous [(14)C]leucine infusion.
RESULTS - Net hepatic glucose uptake in the PoAA condition was < or =50% of that in the EuAA and PeAA conditions (P < 0.05). In the PoAA and PeAA conditions, hepatic intracellular leucine concentrations were 2- to 2.5-fold those in the EuAA condition (P < 0.05); net hepatic leucine uptake and [(14)C]leucine utilization were approximately 2-fold greater (P < 0.05) and albumin synthesis was 30% greater (P < 0.05) in the PoAA condition than in the EuAA and PeAA conditions. Phosphorylation of ribosomal protein S6 [downstream of the mammalian target of Rapamycin complex 1 (mTORC1)] was significantly higher in the PoAA, but not PeAA, condition than in the EuAA condition.
CONCLUSIONS - Portal, but not peripheral, AA delivery significantly enhanced hepatic protein synthesis under conditions in which AAs, glucose, insulin, and glucagon did not differ at the liver, an effect apparently mediated by mTORC1 signaling.
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22 MeSH Terms
Defects in postabsorptive plasma homeostasis of fatty acids in sickle cell disease.
Buchowski MS, Swift LL, Akohoue SA, Shankar SM, Flakoll PJ, Abumrad N
(2007) JPEN J Parenter Enteral Nutr 31: 263-8
MeSH Terms: Adolescent, Adult, Anemia, Sickle Cell, Case-Control Studies, Erythrocyte Membrane, Fasting, Fatty Acids, Nonesterified, Female, Humans, Infusions, Parenteral, Lipid Metabolism, Male, Middle Aged, Phospholipids, Postprandial Period, Triglycerides
Show Abstract · Added December 10, 2013
BACKGROUND - The chronic hemolytic anemia experienced by sickle cell disease (SCD) patients leads to adverse effects on oxygen transport by the blood and to a decrease in oxygen availability for peripheral tissues. Limited tissue oxygen availability has the potential to modify events of intracellular metabolism and, thus, alter lipid homeostasis.
METHODS - The impact of SCD on plasma fatty acid homeostasis was determined in 8 African American SCD patients and in 6 healthy African American control subjects under postabsorptive conditions and during a 3-hour IV infusion of a nutrient solution containing lipid, glucose, and amino acids.
RESULTS - SCD patients had higher fasting levels of plasma nonesterified fatty acids (NEFA), triglycerides, and phospholipids than healthy controls. Similarly, SCD patients had higher fasting levels of fatty acids in plasma triglycerides and phospholipids than healthy controls. Infusion of nutrients resulted in equivalent plasma NEFA profiles, total NEFA, and triglycerides in SCD patients and controls. However, the plasma phospholipid concentrations and fatty acid composition of plasma triglycerides and phospholipids were significantly higher in SCD patients; in particular, plasma pools of oleic acid were consistently increased in SCD. Plasma free oleic acid levels were elevated basally, leading to increased oleic acid content in triglycerides and phospholipids both post absorptively and during nutrient infusion.
CONCLUSIONS - There is an underlying defect in lipid metabolism associated with SCD best manifested during the fasting state. This abnormality in lipid homeostasis has the potential to alter red blood cell (RBC) membrane fluidity and function in SCD patients.
1 Communities
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16 MeSH Terms
Serum leptin level is a regulator of bone mass.
Elefteriou F, Takeda S, Ebihara K, Magre J, Patano N, Kim CA, Ogawa Y, Liu X, Ware SM, Craigen WJ, Robert JJ, Vinson C, Nakao K, Capeau J, Karsenty G
(2004) Proc Natl Acad Sci U S A 101: 3258-63
MeSH Terms: Animals, Bone Density, Brain, Cerebral Ventricles, Homeostasis, Humans, Infusions, Parenteral, Leptin, Lipodystrophy, Mice, Mice, Obese, Mice, Transgenic
Show Abstract · Added November 14, 2013
Leptin is a powerful inhibitor of bone formation in vivo. This antiosteogenic function involves leptin binding to its receptors on ventromedial hypothalamic neurons, the autonomous nervous system and beta-adrenergic receptors on osteoblasts. However, the mechanisms whereby leptin controls the function of ventromedial hypothalamic antiosteogenic neurons remain unclear. In this study, we compared the ability of leptin to regulate body weight and bone mass and show that leptin antiosteogenic and anorexigenic functions are affected by similar amounts of leptin. Using a knock-in of LacZ in the leptin locus, we failed to detect any leptin synthesis in the central nervous system. However, increasing serum leptin level, even dramatically, reduced bone mass. Conversely, reducing serum-free leptin level by overexpressing a soluble receptor for leptin increased bone mass. Congruent with these results, the high bone mass of lipodystrophic mice could be corrected by restoring serum leptin level, suggesting that leptin is an adipocyte product both necessary and sufficient to control bone mass. Consistent with the high bone mass phenotype of lipodystrophic mice, we observed an advanced bone age, an indirect reflection of premature bone formation, in lipodystrophic patients. Taken together, these results indicate that adipocyte-derived circulating leptin is a determinant of bone formation and suggests that leptin antiosteogenic function is conserved in vertebrates.
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12 MeSH Terms
Evaluation of low-dose intraperitoneal interferon-alpha for palliation of ascites in patients with non-ovarian gynecologic malignancies.
Khabele D, Runowicz CD, Fields AL, Anderson PS, Goldberg GL
(2003) Gynecol Oncol 89: 420-3
MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Ascites, Dose-Response Relationship, Drug, Female, Genital Neoplasms, Female, Humans, Infusions, Parenteral, Interferon-alpha, Middle Aged, Neoplasm Staging, Retrospective Studies
Show Abstract · Added March 5, 2014
OBJECTIVE - Intraperitoneal interferon-alpha (IP-IFNalpha) has shown some benefit in the treatment of patients with ovarian cancer. Our goal was to evaluate the use of low-dose IP-IFNalpha for the palliative control of ascites in non-ovarian gynecologic malignancies, including primary peritoneal and uterine papillary serous carcinomas.
METHODS - Fifteen patients with non-ovarian gynecologic malignancies received one or two doses of 10 MU (10 x 10(6) U/m(2)) of IP-IFNalpha via single-use drum catheter for the symptomatic control of ascites. The median age for this patient group was 61 years (range 40-84). Histopathologic diagnoses were confirmed on all patients. Eleven of 15 (73%) patients had uterine cancers. Four of 15 (27%) patients had papillary serous primary peritoneal carcinomas. Thirteen of 15 (87%) patients had Stage III disease or more. All patients had been heavily pretreated with chemotherapy and all had progressive disease.
RESULTS - Specific parameters used to evaluate IP-IFNalpha were (1) median survival; (2) number of days to recurrent ascites; (3) number of subsequent paracenteses required for symptomatic relief; and (4) symptomatology and side effects. Median overall survival was 3 months (range 0.5-13). Seven of 15 (47%) patients survived >3 months. Twelve of 15 (80%) patients had recurrent ascites within 30 days of treatment. However, 3/15 (20%) patients had a prolonged, >30-day period, without symptomatic ascites. One patient (6%) had a 270-day response with no ascites. Toxicity was minimal from IP-IFNalpha infusion. The most common side effect was fever in 6/15 (40%) patients.
CONCLUSION - IP-IFNalpha was well tolerated and may have some benefit in a subset of patients. Although 80% of patients had recurrent ascites within 30 days, 20% had a prolonged, >30-day response. Further study is warranted to determine the role of immune modulators, such as IP-IFNalpha, in the palliative management of patients with non-ovarian gynecologic malignancies that cause ascites.
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14 MeSH Terms
Parenteral N,N-diethyldithiocarbamate produces segmental demyelination in the rat that is not dependent on cysteine carbamylation.
Tonkin EG, Valentine HL, Zimmerman LJ, Valentine WM
(2003) Toxicol Appl Pharmacol 189: 139-50
MeSH Terms: Animals, Body Weight, Chelating Agents, Chromatography, High Pressure Liquid, Cysteine, Demyelinating Diseases, Ditiocarb, Globins, Infusion Pumps, Implantable, Infusions, Parenteral, Male, Neurofilament Proteins, Peripheral Nerves, Rats, Rats, Sprague-Dawley
Show Abstract · Added May 27, 2014
Disulfiram, a dithiocarbamate drug used in alcohol aversion therapy, produces a peripheral neuropathy characterized in rats as segmental demyelination accompanied by generation of S-(diethylaminocarbonyl)cysteine (DETC-Cys) adducts. N,N-Diethyldithiocarbamate (DEDC) is a major metabolite of disulfiram that can undergo methylation and oxidation to S-methyl-N,N-diethylthiocarbamate (MeDETC) sulfoxide and sulfone, thought to be responsible for carbamylation of sulfhydryl functions by disulfiram. To assess the role of cysteine carbamylation in disulfiram toxicity, DEDC and MeDETC were administered parenterally to male Sprague-Dawley rats for 4 and 8 weeks. The roles of the disulfide linkage in disulfiram and of carbamylated glutathione metabolites were assessed by administering S-(diethylaminodithiocarbonyl)N-acetylcysteine (DS-NAC) and S-(diethylaminocarbonyl)-N-acetylcysteine (DETC-NAC), respectively, parenterally for 12 weeks. Following exposure, spinal cord-derived neurofilament preparations and hemoglobin were isolated and analyzed by RP-HPLC and LC/MS/MS for the presence of DETC-Cys adducts. Peripheral nerve sections were also obtained and examined by light and electron microscopy for morphological lesions. RP-HPLC analysis of globin preparations from DEDC-, MeDETC-, and DS-NAC-exposed animals demonstrated a late-eluting peak, identical to that reported for disulfiram-generated DETC-Cys adducts on the beta(3)-globin chain. DETC-NAC exposure did not result in detectable globin modification by RP-HPLC. The quantity of DETC-Cys adducts produced on globin and neurofilament preparations determined by LC/MS/MS was twofold greater for MeDETC than DEDC following equimolar doses of each compound. Primary myelin lesions consisting of demyelinated axons and myelin splitting were observed in peripheral nerves following exposure to DEDC for 8 weeks. No lesions were detected following exposure to MeDETC, DS-NAC, or DETC-NAC at any time point or dose level. These results are consistent with DEDC, but not the other metabolites, being a demyelinating agent and thus a potential proximate toxic species for disulfiram-mediated demyelination. The production of significantly greater levels of DETC-Cys adducts by MeDETC relative to DEDC in the absence of neurotoxicity for MeDETC is consistent with cysteine carbamylation not contributing to the demyelination produced by disulfiram and DEDC.
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15 MeSH Terms
Intradialytic parenteral nutrition improves protein and energy homeostasis in chronic hemodialysis patients.
Pupim LB, Flakoll PJ, Brouillette JR, Levenhagen DK, Hakim RM, Ikizler TA
(2002) J Clin Invest 110: 483-92
MeSH Terms: Amino Acids, Cross-Over Studies, Energy Metabolism, Female, Forearm, Homeostasis, Humans, Infusions, Parenteral, Kidney Failure, Chronic, Leucine, Male, Middle Aged, Muscle, Skeletal, Oxidation-Reduction, Phenylalanine, Protein-Energy Malnutrition, Proteins, Renal Dialysis
Show Abstract · Added May 20, 2014
Decreased dietary protein intake and hemodialysis-associated protein catabolism are among several factors that predispose chronic hemodialysis (CHD) patients to protein calorie malnutrition. Since attempts to increase protein intake by dietary counseling are usually ineffective, intradialytic parenteral nutrition (IDPN) has been proposed as a potential therapeutic approach in malnourished CHD patients. In this study, we examined protein and energy homeostasis during hemodialysis in seven CHD patients at two separate hemodialysis sessions, with and without IDPN administration. Patients were studied 2 hours before, during, and 2 hours following a hemodialysis session, using a primed constant infusion of L-(1-(13)C) leucine and L-(ring-(2)H(5)) phenylalanine. Our results showed that IPDN promoted a large increase in whole-body protein synthesis and a significant decrease in whole-body proteolysis, along with a significant increase in forearm muscle protein synthesis. The net result was a change from an essentially catabolic state to a highly positive protein balance, both in whole-body and forearm muscle compartments. We conclude that the provision of calories and amino acids during hemodialysis with IDPN acutely reverses the net negative whole-body and forearm muscle protein balances, demonstrating a need for long-term clinical trials evaluating IDPN in malnourished CHD patients.
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18 MeSH Terms