Value of Impedance Cardiography during 6‐Minute Walk Test in Pulmonary Hypertension

Background

Methods that predict prognosis and response to therapy in pulmonary hypertension (PH) are lacking. We tested whether the noninvasive estimation of hemodynamic parameters during 6‐minute walk test (6MWT) in PH patients provides information that can improve the value of the test.

Methods

We estimated hemodynamic parameters during the 6MWT using a portable, signal‐morphology‐based, impedance cardiograph (PhysioFlow Enduro) with real‐time wireless monitoring via a bluetooth USB adapter.

Results

We recruited 48 subjects in the study (30 with PH and 18 healthy controls). PH patients had significantly lower maximum stroke volume (SV) and CI and slower cardiac output (CO) acceleration and decelerations slopes during the test when compared with healthy controls. In PH patients, CI change was associated with total distance walked (R = 0.62; P < 0.001) and percentage of predicted (R = 0.4, P = 0.03), HR recovery at 1 minute (0.57, P < 0.001), 2 minutes (0.65, P < 0.001), and 3 minutes (0.66, P < 0.001). Interestingly, in PH patients CO change during the test was predominantly related to an increase in SV instead of HR.

Conclusions

Estimation of hemodynamic parameters such as cardiac index during 6‐minute walk test is feasible and may provide useful information in patients with PH. Clin Trans Sci 2013; Volume #: 1–7     

Altered Immune Phenotype in Peripheral Blood Cells of Patients with Scleroderma‐Associated Pulmonary Hypertension

Pulmonary arterial hypertension is a common and fatal complication of scleroderma that may involve inflammatory and autoimmune mechanisms. Alterations in the gene expression of peripheral blood mononuclear cells have been previously described in patients with pulmonary arterial hypertension. Our goal is to identify differentially expressed genes in peripheral blood mononuclear cells in scleroderma patients with and without pulmonary hypertension as biomarkers of disease.Gene expression analysis was performed on a Microarray Cohort of scleroderma patients with (n= 10) and without (n= 10) pulmonary hypertension. Differentially expressed genes were confirmed in the Microarray Cohort and validated in a Validation Cohort of scleroderma patients with (n= 15) and without (n= 19) pulmonary hypertension by RT‐qPCR. We identified inflammatory and immune‐related genes including interleukin‐7 receptor (IL‐7R) and chemokine receptor 7 as differentially expressed in patients with scleroderma‐associated pulmonary hypertension. Flow cytometry confirmed decreased expression of IL‐7R on circulating CD4+ T‐cells from scleroderma patients with pulmonary hypertension.Differences exist in the expression of inflammatory and immune‐related genes in peripheral blood cells from patients with scleroderma‐related pulmonary hypertension compared to those with normal pulmonary artery pressures. These findings may have implications as biomarkers to screen at‐risk populations for early diagnosis and provide insight into mechanisms of scleroderma‐related pulmonary hypertension. Clin Trans Sci 2010; Volume 3: 210–218     

Bloodstream Infections in Patients With Pulmonary Arterial Hypertension Treated With Intravenous Prostanoids: Insights From the REVEAL REGISTRY(®)

ObjectiveTo evaluate the rate of and potential risk factors for bloodstream infections (BSIs) using data from the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension [PAH] Disease Management) REGISTRY^®, which provides current information about patients with PAH.Patients and MethodsPatients were enrolled from March 30, 2006, through December 8, 2009, and data on reported BSIs were collected through the third quarter of 2010. Bloodstream infection rates were calculated per 1000 patient-days of risk.ResultsOf 3518 patients enrolled, 1146 patients received intravenous (IV) prostanoid therapy for more than 1 day (no BSI, n=1023; ≥1 BSI, n=123; total BSI episodes, n=166). Bloodstream infections rates were significantly increased in patients receiving IV treprostinil vs IV epoprostenol (0.36 vs 0.12 per 1000 treatment days; P<.001), primarily due to gram-negative organisms (0.20 vs 0.03 per 1000 treatment days; P<.001). Multivariate analysis adjusting for age, causes of PAH, and year of BSI found that treatment with IV treprostinil was associated with a 3.08-fold increase (95% confidence interval, 2.05-4.62; P<.001) in BSIs of any type and a 6.86-fold increase (95% confidence interval, 3.60-13.07; P<.001) in gram-negative BSIs compared with treatment with IV epoprostenol.ConclusionCompared with IV epoprostenol therapy, treatment with IV treprostinil is associated with a significantly higher rate of gram-negative BSIs; observed differences in BSI rate did not seem to be due to any other analyzed factors.Trial Registrationclinicaltrials.gov Identifier: NCT00370214     

Efficiency of High‐Flux Hemodialysis in the Treatment of Valproic Acid Intoxication

Abstract

Recently, highly efficient (i.e., high volume) dialysis systems have been successfully introduced for the treatment of critically ill patients in the intensive care unit. They also can be a safer, more effective, and less costly alternative to traditional extracorporal techniques in the treatment of severe intoxication. This holds true even if the substance to be eliminated is believed to be a poor candidate for dialysis treatment. We report a case of successful treatment of potentially life‐threatening intoxication, with valproic acid (VPA) using a GENIUS^® batch dialysis system for combined standard and extended high‐volume hemodialysis therapy. Concentration of VPA in the total collected dialysate were measured.     

Short‐Term Treatment with High‐Dose Atorvastatin Reduces LDL Cholesterol but Shows no Anti‐Inflammatory Effects in Normolipidemic Subjects with Normal CRP Levels

The benefit in reducing cardiovascular risk with statins has been attributed both to cholesterol lowering and pleiotropic effects. These pleiotropic effects are thought to include attenuation of the inflammatory response due to reduced prenylation of proteins in the inflammatory cascade. We conducted studies in normolipidemic subjects to determine if treatment with high‐dose (80 mg) atorvastatin could reduce circulating levels of inflammatory markers. We also determined whether high‐dose atorvastatin affected the inflammatory response of monocytes stimulated with lipopolysaccharide (LPS) ex vivo. We found that treatment with atorvastatin rapidly and significantly reduced plasma low‐density lipoprotein (LDL) cholesterol levels in subjects treated for 2 weeks. However, statin treatment had no discernible effect on plasma levels of the inflammatory markers high‐sensitivity C‐reactive protein (hsCRP), tumor necrosis factor (TNF)‐α, or interleukin (IL‐6) and no effect on the cytokine response of monocytes following ex vivo stimulation with LPS. High‐dose atorvastatin treatment of normolipidemic subjects with normal C‐reactive protein levels has no effect on the inflammatory response assessed by monocyte stimulation with LPS ex vivo despite significant reductions in LDL cholesterol levels. Clin Trans Sci 2010; Volume 3: 140–146     

High β-Lactamase Levels Change the Pharmacodynamics of β-Lactam Antibiotics in Pseudomonas aeruginosa Biofilms

Resistance to β-lactam antibiotics is a frequent problem in Pseudomonas aeruginosa lung infection of cystic fibrosis (CF) patients. This resistance is mainly due to the hyperproduction of chromosomally encoded β-lactamase and biofilm formation. The purpose of this study was to investigate the role of β-lactamase in the pharmacokinetics (PK) and pharmacodynamics (PD) of ceftazidime and imipenem on P. aeruginosa biofilms. P. aeruginosa PAO1 and its corresponding β-lactamase-overproducing mutant, PAΔDDh2Dh3, were used in this study. Biofilms of these two strains in flow chambers, microtiter plates, and on alginate beads were treated with different concentrations of ceftazidime and imipenem. The kinetics of antibiotics on the biofilms was investigated in vitro by time-kill methods. Time-dependent killing of ceftazidime was observed in PAO1 biofilms, but concentration-dependent killing activity of ceftazidime was observed for β-lactamase-overproducing biofilms of P. aeruginosa in all three models. Ceftazidime showed time-dependent killing on planktonic PAO1 and PAΔDDh2Dh3. This difference is probably due to the special distribution and accumulation in the biofilm matrix of β-lactamase, which can hydrolyze the β-lactam antibiotics. The PK/PD indices of the AUC/MBIC and C_max/MBIC (AUC is the area under concentration-time curve, MBIC is the minimal biofilm-inhibitory concentration, and C_max is the maximum concentration of drug in serum) are probably the best parameters to describe the effect of ceftazidime in β-lactamase-overproducing P. aeruginosa biofilms. Meanwhile, imipenem showed time-dependent killing on both PAO1 and PAΔDDh2Dh3 biofilms. An inoculum effect of β-lactams was found for both planktonic and biofilm P. aeruginosa cells. The inoculum effect of ceftazidime for the β-lactamase-overproducing mutant PAΔDDh2Dh3 biofilms was more obvious than for PAO1 biofilms, with a requirement of higher antibiotic concentration and a longer period of treatment.     

Does Acute Volume Overloading in the Setting of Left Ventricular Dysfunction and Pulmonary Hypertension Affect the Defibrillation Threshold?

The impact of acute volume overload hemodynamics on the DFT with concurrent moderate left ventricular systolic dysfunction is unknown. Ten mongrel dogs (17.2 kg), using a crossover study design, each had baseline (study 1) hemodynamic, echocardiographic, and DFT measurements. These measurements were repeated after left ventricular dysfunction was induced using a norepinephrine (5 micrograms/kg per min) infusion (study 2). Hemodynamic and DFT parameters were obtained simulating acute heart failure by volume overload with an 0.9% normal saline infusion to an associated mean pulmonary capillary wedge pressure of > 19 mmHg (study 3). Numerous significant echocardiographic and hemodynamic parameters were noted when the animals from studies 1 and 2, 2 and 3, and 1 and 3 were compared. A significant difference in the DFT was observed only when study animals 1 and 3 were compared (P < 0.02). None of the dogs were hypoxemic at the time of the acute heart failure DFT. The mechanism of this finding remains unknown. This data would suggest that acute volume overload with associated left ventricular dysfunction does adversely affect the DFT in a canine model.     

A Pilot Metabolic Profiling Study in Serum of Patients with Chronic Kidney Disease Based on 1H‐NMR‐Spectroscopy

Background: Chronic kidney disease (CKD) is the end point of a number of renal and systemic diseases. The metabolomics with a highly multiplexed and efficient manner is a challenging goal in nephrology.Methods: A ¹H‐NMR based metabolomics approach was applied to establish a human CKD serum metabolic profile. Serum samples were obtained from CKD patients with four stages (N= 80) and healthy controls (N= 28). The data acquired by CMPG spectrum were further processed by pattern recognition (PR) analysis. Principal components analysis (PCA) and partial least‐squares‐discriminant analysis (PLS‐DA) was capable of clustering the disease groups and establishing disease‐specific metabolites profile.Results: The classification models could grade CKD patients with considerably high value of Q² and R². The significant endogenous metabolites that contributed to distinguish CKD in different stages included the products of glycolysis (glucose, lactate), amino acids (valine, alanine, glutamate, glycine), organic osmolytes (betaine, myo‐inositol, taurine, glycerophosphcholine), and so on. Based on these metabolites, the model for diagnosing patients with CKD achieved the sensitivity and specificity of 100%.Conclusion: The study illustrated that serum metabolic profile was altered in response to renal dysfunction and the progression of CKD. The identified metabolic biomarkers may provide useful information for the diagnosis of CKD, especially in early stages. Clin Trans Sci 2012; Volume 5: 379–385     

Feasibility of Neoadjuvant Ad‐REIC Gene Therapy in Patients with High‐Risk Localized Prostate Cancer Undergoing Radical Prostatectomy

In a phase I/IIa study of in situ gene therapy using an adenovirus vector carrying the human REIC/Dkk‐3 gene (Ad‐REIC), we assessed the inhibitory effects of cancer recurrence after radical prostatectomy (RP), in patients with high risk localized prostate cancer (PCa). After completing the therapeutic interventions with initially planned three escalating doses of 1.0 × 10¹⁰, 1.0 × 10¹¹, and 1.0 × 10¹² viral particles (VP) in 1.0–1.2 mL (n = 3, 3, and 6), an additional higher dose of 3.0 × 10¹² VP in 3.6 mL (n = 6) was further studied. Patients with recurrence probability of 35% or more within 5 years after RP as calculated by Kattan''s nomogram, were enrolled. They received two ultrasound‐guided intratumoral injections at 2‐week intervals, followed by RP 6 weeks after the second injection. Based on the findings of MRI and biopsy mapping, as a rule, one track injection to the most prominent cancer area was given to initial 12 patients and 3 track injections to multiple cancer areas in additional 6 patients. As compared to the former group, biochemical recurrence‐free survival of the latter showed a significantly favorable outcome. Neoadjuvant Ad‐REIC, mediating simultaneous induction of cancer selective apoptosis and augmentation of antitumor immunity, is a feasible approach in preventing cancer recurrence after RP. (199)     

Emergence of High Levels of Extended-Spectrum-β-Lactamase-Producing Gram-Negative Bacilli in the Asia-Pacific Region: Data from the Study for Monitoring Antimicrobial Resistance Trends (SMART) Program, 2007

Of 3,004 gram-negative bacilli collected from intra-abdominal infections in the Asia-Pacific region during 2007, 42.2% and 35.8% of Escherichia coli and Klebsiella spp., respectively, were extended-spectrum β-lactamase (ESBL) positive. Moreover ESBL rates in India for E. coli, Klebsiella pneumoniae, and Klebsiella oxytoca were 79.0%, 69.4%, and 100%, respectively. ESBL-positive E. coli rates were also relatively high in China (55.0%) and Thailand (50.8%). Ertapenem and imipenem were the most active drugs tested, inhibiting over 90% of all species, including ESBL-positive isolates with the exception of Pseudomonas aeruginosa isolates (<90% susceptible to all study drugs) and ESBL-positive Klebsiella pneumoniae isolates (<90% susceptible to all study drugs except imipenem). Quinolones achieved 90% inhibition levels only against ESBL-negative K. pneumoniae and ESBL-negative K. oxytoca. A decline in ampicillin-sulbactam activity was noted, with only 34.5% of all Enterobacteriaceae inhibited in this study.Gram-negative bacilli (GNB) continue to be an important cause of health care-associated infections (8, 15). They are a common cause of sepsis, pneumonia, urinary tract infection, postsurgical infections in acute care hospitals, and intra-abdominal infections (16). Antimicrobial resistance among these bacilli is increasing on a worldwide basis, especially resistance against β-lactam antibiotics due to the development of β-lactamase enzymes, which can hydrolyze the β-lactam ring of such antibiotics (1). Various types of β-lactamases can confer resistance to expanded-spectrum cephalosporins, including chromosomally mediated β-lactamases, extended-spectrum β-lactamases (ESBLs), metallo-β-lactamases, and KPCs. ESBLs are known to confer resistance to all β-lactam drugs, but organisms typically remain susceptible to carbapenems (4, 12).Large-scale surveillance studies demonstrate that the vast majority of ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates, among others, are susceptible to carbapenems (9, 11, 17). However, antibiotic resistance in GNB is evolving globally, with different levels of regional resistance that can vary significantly. It is therefore increasingly important to monitor susceptibility trends in various regions of the world over time to detect, define, track, and communicate those trends so that effective therapeutic measures can be determined and customized to meet local needs.The Study for Monitoring Antimicrobial Resistance Trends (SMART) program monitors the activity of ertapenem, imipenem, amikacin, cefepime, cefotaxime, cefoxitin, ceftazidime, ceftriaxone, ciprofloxacin, levofloxacin, ampicillin-sulbactam, and piperacillin-tazobactam against GNB from intra-abdominal infections (IAI). This program has been ongoing since 2002 in most regions of the world, with nearly 120 hospitals participating in 2008. This report reviews the most current data from the SMART program from the Asia-Pacific region for isolates collected throughout 2007.(Parts of this study were presented as posters at the joint 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious Diseases Society of America, 2008 [2] and at the 7th International Symposium on Antimicrobial Agents and Resistance, 2009 [3].)     

Collaborative Approach in the Development of High‐Performance Brain–Computer Interfaces for a Neuroprosthetic Arm: Translation from Animal Models to Human Control

Our research group recently demonstrated that a person with tetraplegia could use a brain–computer interface (BCI) to control a sophisticated anthropomorphic robotic arm with skill and speed approaching that of an able‐bodied person. This multiyear study exemplifies important principles in translating research from foundational theory and animal experiments into a clinical study. We present a roadmap that may serve as an example for other areas of clinical device research as well as an update on study results. Prior to conducting a multiyear clinical trial, years of animal research preceded BCI testing in an epilepsy monitoring unit, and then in a short‐term (28 days) clinical investigation. Scientists and engineers developed the necessary robotic and surgical hardware, software environment, data analysis techniques, and training paradigms. Coordination among researchers, funding institutes, and regulatory bodies ensured that the study would provide valuable scientific information in a safe environment for the study participant. Finally, clinicians from neurosurgery, anesthesiology, physiatry, psychology, and occupational therapy all worked in a multidisciplinary team along with the other researchers to conduct a multiyear BCI clinical study. This teamwork and coordination can be used as a model for others attempting to translate basic science into real‐world clinical situations.