The role of asymmetric dimethylarginine and arginine in the failing heart and its vasculature

Nitric oxide (NO) is formed from arginine by the enzyme nitric oxide synthase (NOS). Asymmetric dimethylarginine (ADMA) can inhibit NO production by competing with arginine for NOS binding. Therefore, the net amount of NO might be indicated by the arginine/ADMA ratio. In turn, arginine can be metabolized by the enzyme arginase, and ADMA by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). While ADMA has been implicated as a cardiovascular risk factor, arginine supplementation has been indicated as a treatment in cardiac diseases. This review discusses the roles of ADMA and arginine in the failing heart and its vasculature. Furthermore, it proposes nutritional therapies to improve NO availability.     

Effects of mechanical left ventricular unloading by impella on left ventricular dynamics in high‐risk and primary percutaneous coronary intervention patients

Objectives : We studied online left ventricular (LV) dynamic effects of mechanical LV unloading directly after percutaneous coronary intervention (PCI). Background : Limited clinical information is available on the direct LV dynamic consequences of LV unloading in patients undergoing high‐risk PCI and primary PCI for acute ST‐elevation myocardial infarction. Methods : The effects of the Impella LP2.5 device on LV dynamics were studied in 11 patients (elective high‐risk PCI, n = 6; primary PCI, n = 5). LV pressure and volume were continuously assessed by a pressure‐conductance catheter at 4 different support levels of the Impella, from 0 L/min at baseline to 2.5 L/min at maximal support. Results : The response to increased LV unloading was not different between both groups of patients. The pooled data showed no change on global and systolic LV function during increased LV unloading, while diastolic function showed improvement as indicated by an increased LV compliance in all patients. There was a decrease in end‐diastolic pressure from 22 ± 12 to 13 ± 9 mm Hg (P = 0.0001), in end‐diastolic elastance from 0.134 ± 0.060 to 0.091 ± 0.064 mm Hg/mL (P = 0.009), and in end‐diastolic wall stress from 84 ± 50 to 47 ± 39 mm Hg (P = 0.004). Conclusions : LV unloading decreases end‐diastolic wall stress and improves diastolic compliance dose‐dependently. Our results indicate beneficial LV unloading effects of Impella during high‐risk and primary PCI. © 2009 Wiley‐Liss, Inc.     

Relationship between myocardial performance index and aortic distensibility in patients with essential hypertension

We aimed to investigate the association between aortic distensibility (AD) and left ventricle myocardial performance index (MPI) in patients with newly diagnosed hypertension (HT). We studied 49 patients with HT and 24 healthy control subjects. AD was calculated from the echocardiographically derived ascending aorta diameters. The MPI was calculated from both conventional flow Doppler echocardiography and tissue Doppler echocardiography recordings. Conventional Doppler E/A and tissue Doppler derived Ea/Aa were determined for all the subjects. Aortic distensibility was lower, and both conventional and tissue Doppler MPI values were higher (p<0.001 for all) in patient group compared with control group. AD was correlated with systolic blood pressure (SBP) (beta=-0.436, p=0.037), Ea/Aa (beta=0.228, p=0.038) and tissue derived MPI (beta=-0.302, p=0.043) in multiple linear regression analysis. Aortic distensibility was independently related to tissue derived MPI and Ea/Aa besides SBP.     

Functional MRI evidence for language plasticity in adult epileptic patients: Preliminary results

The present fMRI study explores the cerebral reorganisation of language in patients with temporal lobe epilepsy, according to the age of seizures onset (early or late) and the hippocampal sclerosis (associated or not). Seven right-handed control volunteers and seven preoperative adult epileptic patients performed a rhyme decision (language condition) and a visual detection (control condition) tasks in visually presented words and unreadable characters, respectively. All patients were left hemisphere dominant for language. Appropriate statistical analyses provided the following preliminary results: (1) patients compared with healthy subjects showed lower degree of hemispheric lateralization with supplementary involvement of the right hemisphere; (2) the degree of hemispheric specialization depends on the considered region; (3) patients with early seizures show signs of temporal and parietal reorganization more frequently than patients with late onset of seizures; (4) patients with early seizures show a tendency for intra-hemispheric frontal reorganisation; (5) associated hippocampal sclerosis facilitates the inter-hemispheric shift of temporal activation. Although our patients were left hemisphere predominant for language, the statistical analyses indicated that the degree of lateralization was significantly lower than in healthy subjects. This result has been considered as the indication of atypical lateralization of language.     

Integration of in vitro neurotoxicity data with biokinetic modelling for the estimation of in vivo neurotoxicity

Risk assessment of neurotoxicity is mainly based on in vivo exposure, followed by tests on behaviour, physiology and pathology. In this study, an attempt to estimate lowest observed neurotoxic doses after single or repeated dose exposure was performed. Differentiated human neuroblastoma SH-SY5Y cells were exposed to acrylamide, lindane, parathion, paraoxon, phenytoin, diazepam or caffeine for 72 hours. The effects on protein synthesis and intracellular free Ca2+ concentration were studied as physiological endpoints. Voltage operated Ca2+ channel function, acetylcholine receptor function and neurite degenerative effects were investigated as neurospecific endpoints for excitability, cholinergic signal transduction and axonopathy, respectively. The general cytotoxicity, determined as the total cellular protein levels after the 72 hours exposure period, was used for comparison to the specific endpoints and for estimation of acute lethality. The lowest concentration that induced 20% effect (EC20) obtained for each compound, was used as a surrogate for the lowest neurotoxic level (LOEL) at the target site in vivo. The LOELs were integrated with data on adsorption, distribution, metabolism and excretion of the compounds in physiologically-based biokinetic (PBBK) models of the rat and the lowest observed effective doses (LOEDs) were estimated for the test compounds. A good correlation was observed between the estimated LOEDs and experimental LOEDs found in literature for rat for all test compounds, except for diazepam. However, when using in vitro data from the literature on diazepam's effect on gamma-amino butyric acid (GABA)A receptor function for the estimation of LOED, the correlation between the estimated and experimental LOEDs was improved from a 10,000-fold to a 10-fold difference. Our results indicate that it is possible to estimate LOEDs by integrating in vitro toxicity data as surrogates for lowest observed target tissue levels with PBBK models, provided that some knowledge about toxic mechanisms is known.     

Influence of different atropine therapy strategies on fenthion-induced organ dysfunction in rats

We studied the influence of dose and timing of atropine therapy on fenthion-induced organ dysfunction. Thirty-six rats were randomized into six groups. All rats in the five groups except the control group were intoxicated with fenthion. The high-dose atropine group received 2 mg/kg of atropine, whereas the low-dose group received 100 microg/kg of atropine every hour for 24 hr. One group received 2 mg/kg of atropine in the first 4 hr of intoxication while the other group received 2 mg/kg of atropine in the last 4 hr before killed, which for all rats was 24 hr after intoxication. Pseudocholinesterase and aspartate aminotransferase and alanine aminotransferase levels and histopathological markers of lung, brain and liver were studied. None of our atropine therapy strategies in this study totally prevented harm on the three organs. Although the high dose of atropine administered for 24 hr had the least harmful markers for lung, it also had the most harmful markers for brain and liver. We did not succeed in finding a unique therapy strategy in our models beneficial for all studied organs in fenthion intoxication in rats. Atropine administration strategy should be oriented for the most affected organ pathology in fenthion intoxication.     

Butyrophilins: an emerging family of immune regulators

Butyrophilins (Btns) and butyrophilin-like (Btnl) molecules are emerging as novel regulators of immune responses in mice and humans. Several clues point to their probable importance: many of the genes are located within the MHC; they are structurally related to B7-co-stimulatory molecules; they are functionally implicated in T cell inhibition and in the modulation of epithelial cell-T cell interactions; and they are genetically associated with inflammatory diseases. Nonetheless, initial immersion into the current literature can uncover confusion over even basic information such as gene names and expression patterns, and seemingly conflicting data regarding the biological activities of different family members. This review addresses each of these issues, concluding with the attractive potential of Btn and Btnl molecules to act as specific attenuators of tissue-associated inflammatory responses.     

Effect of ginkgo biloba on the pharmacokinetics of raltegravir in healthy volunteers

Medicinal herbs may cause clinically relevant drug interactions with antiretroviral agents. Ginkgo biloba extract is a popular herbal product among HIV-infected patients because of its positive effects on cognitive function. Raltegravir, an HIV integrase inhibitor, is increasingly being used as part of combined antiretroviral therapy. Clinical data on the potential inhibitory or inductive effect of ginkgo biloba on the pharmacokinetics of raltegravir were lacking, and concomitant use was not recommended. We studied the effect of ginkgo biloba extract on the pharmacokinetics of raltegravir in an open-label, randomized, two-period, crossover phase I trial in 18 healthy volunteers. Subjects were randomly assigned to a regimen of 120 mg of ginkgo biloba twice daily for 15 days plus a single dose of raltegravir (400 mg) on day 15, a washout period, and 400 mg of raltegravir on day 36 or the test and reference treatments in reverse order. Pharmacokinetic sampling of raltegravir was performed up to 12 h after intake on an empty stomach. All subjects (9 male) completed the trial, and no serious adverse events were reported. Geometric mean ratios (90% confidence intervals) of the area under the plasma concentration-time curve from dosing to infinity (AUC(0-∞)) and the maximum plasma concentration (C(max)) of raltegravir with ginkgo biloba versus raltegravir alone were 1.21 (0.93 to 1.58) and 1.44 (1.03 to 2.02). Ginkgo biloba did not reduce raltegravir exposure. The potential increase in the C(max) of raltegravir is probably of minor importance, given the large intersubject variability of raltegravir pharmacokinetics and its reported safety profile.     

Artifact reduction strategies for prosthetic heart valve CT imaging

Multislice CT evaluation of prosthetic heart valves (PHV) is limited by PHV-related artifacts. We assessed the influence of different kV settings, a metal artifact reduction filter (MARF) and an iterative reconstruction algorithm (IR) on PHV-induced artifacts in an in vitro model. A Medtronic-Hall tilting disc and St Jude bileafet PHV were imaged using a 64-slice scanner with 100 kV/165 mAs, 120 kV/100 mAs, 140 kV/67 mAs at an equal CTDI_vol. Images were reconstructed with (1) filtered back projection (FBP), (2) IR, (3) MARF and (4) MARF and IR. Hypo- and hyperdense artifacts volumes (mean mm³ ± SD) were quantified with 2 thresholds (≤?50 and ≥175 Hounsfield Units). Image noise was measured and the presence of secondary artifacts was scored by 2 observers independently. Mean hypodense artifacts for the Medtronic-Hall/St Jude valve (FBP) were 966 ± 23/1,738 ± 21 at 100 kV, 610 ± 13/991 ± 12 at 120 kV, and 420 ± 9/634 ± 9 at 140 kV. Compared to FBP, hypodense artifact reductions for IR were 9/8 %, 10/7 % and 12/6 % respectively, for MARF 92 %/84 %, 89/81 % and 86/77 % respectively; for MARF + IR 94/85 %, 92/82 %, and 90/79 % respectively. Mean hyperdense artifacts for the Medtronic-Hall/St Jude valve were 5,530 ± 48/6,940 ± 70 at 100 kV, 5,120 ± 42/6,250 ± 53 at 120 kV, and 5,011 ± 52/6,000 ± 0 at 140 kV. Reductions for IR were 2/2 %, 2/3 % and 3/4 % respectively, for MARF were 9/30 %, 0/25 %, 5/22 % respectively, MARF + IR 12/32 %, 4/27 % and 7/25 % respectively. Secondary artifacts were found in all MARF images. Image noise was reduced in the IR images. In vitro PHV-related artifacts can be reduced by increasing kV despite maintaining identical CTDI_vol. Although MARF is more effective than IR, it induces secondary artifacts.