Transesophageal dipyridamole echocardiography for diagnosis of coronary artery disease.

The value of transthoracic dipyridamole echocardiography has been extensively documented. However, in some patients, because of a poor acoustic window, the rest transthoracic examination is not always feasible and the transesophageal approach is more convenient. Therefore, transesophageal echocardiography with high dose dipyridamole (up to 0.84 mg/kg body weight over 10 min) was performed in 32 patients in whom the transthoracic dipyridamole test either was not feasible (n = 29) or yielded ambiguous results (n = 3). The transesophageal echocardiographic test results were considered abnormal when new dipyridamole-induced regional wall motion abnormalities were observed. All 32 patients underwent coronary angiography; significant coronary artery disease was defined as greater than or equal to 70% lumen diameter narrowing in at least one major vessel. All patients also performed a bicycle exercise test 1 day before transesophageal dipyridamole echocardiography. Transesophageal stress studies were completed in all patients, with a maximal imaging time (in tests with a negative result) of 20 min. No side effects or intolerance to drug or transducer was observed. The left ventricle was always visualized in the four-chamber and transgastric short-axis views. High quality two-dimensional echocardiographic images were obtained in all patients both at rest and at peak dipyridamole infusion and were digitally analyzed in a quad-screen format. Coronary angiography showed coronary artery obstruction in 24 patients: 6 had single-, 9 double- and 9 triple-vessel disease. The transesophageal dipyridamole test showed a specificity of 100% and an overall sensitivity of 92%. The sensitivity of this test for single-, double- and triple-vessel disease was 67%, 100% and 100%, respectivel

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

Ethics for the Living World Alternative Methods and New Strategies for The Protection of Nonhuman Animals

The use of animals in laboratories is a controversial issue involving much dispute between the researchers who support animal experimentation and those who are in favor of its abolishment. The former, whilst criticizing the emotional behavior of those who oppose it, consider experimentation on animals unavoidable, whereas the latter criticize animal experiments and the underlying logic as erroneous considering its methods unscientific and therefore misleading. This paper stems from the idea of researching into possible ways of developing or improving new alternative strategies for animal experimentation by finding adequate solutions beyond dogmatic opposition in the context of the current European Directive 2010/63/EU (the main reference point for the experimentation on animals) for the protection of animals used for scientific purposes. More specifically the paper aims at offering the readers a working proposal, while duly respecting the protocol for the post mortem donation of their own corpses for the purposes of study and research. As we believe diseases need to be cured and not only treated, we are advocating post mortem studies on organs which could lead to the discovery of the causes of unknown etiological pathologies. The commitment to the implementation of constantly new and innovative alternatives concerning animal experimentation is right and proper, especially in the light of the enormous debt which the Italian National Bioethics Committee stated that mankind has towards nonhuman living beings

Lost in Translation: the Need for Better Tools

although for most pharmaceutical compounds the final aim is improving human health, almost almost the methods used to identify and purse therapeutic targets and to obtain new potential drugs have traditionally focused on animal model

Commitment of Italian academic LARF-DIMES for teaching and training in alternative approach to animal testing

To underline the importance of both the ethical issues of alternative approaches to animal testing and the life sciences in the 21st century, LARF-DIMES, at the University of Genova (Italy), is engaged since 2008 in organization of training courses for dissemination of international resources using the over twenty years of experience of its staff in various fields of experimental pathology and teaching which demonstrates the greater effectiveness of animal-free testing. Moreover LARF team organizes stages for graduated and graduating students of Medicine, Biology, Biotechnology, Pharmacy degrees, PhD courses, and 2nd level Master on Reach regulations. The courses, focused on practical part and demonstration/lessons of specialist(s) working in the field, provide basic knowledge or improve existing expertise, on alternative methods. In each course, the participants get an update on innovative in vitro models with particular emphasis on 3D models. The organization plan foresees a substantial practice to allow everybody to set up cytotoxicity tests, according to OECD guidelines, and other emerging alternative in vitro models. These at least 2 days training courses are opened to 24 participants and include already experts of in vitro methods as well undergraduating students. The participants came from all over Italy, and the interest has been so high that courses are consistently oversubscribed, with unlucky participants asking to be registered on future courses to secure a place. On 2013 LARF team was one of the winners of international Lush Prize for Training category.All training modules were carried out by LARF staff and specialists from leading companies in in vitro research and models, such MatTek, ETT, Lonza, Biopredict, IvTech and others. Dissemination of 3R-knowledge ensures best possible practice for a predictive and reliable toxicology, by performing and optimizing 2D/3D in vitro models based on human cells to evaluate the health hazard

Break with tradition: donating cadavers for scientific purposes and reducing the use of sentient beings

In recent years, the development of research and the increased awareness of our moral duties beyond the human species have pushed the scientific community to revise widely-accepted ontological reductionist views that regard non-human animals as mere things. The new horizons offered by the development of advanced research methods therefore require an on-going commitment to new perspectives able to find the right balance between the need for scientific knowledge on one hand and the respect for animal life on the other. This is in line with increasing attention to animal welfare and expansion of the \u201c3Rs model\u201d: replacement, reduction, refinement. With the view of promoting the adoption of alternative methods, human body donation for research can contribute not only to the acquisition of important information for human health and for doctors\u2019 training, but also can reduce significantly the number of animals sacrificed. By investigating the scientific and ethical reasons that may encourage cadaver donation, the authors aim to promote the adoption of the practice in Italy following other European experiences

Allestimento di metodica in vitro: linee cellulari stabilizzate umane di origine cutanea per la valutazione del potenziale tossico e irritante di materie prime e prodotti finiti ad uso topico

La complementarit\ue0 del test in vitro rispetto alle valutazioni in vivo risiede nel fatto di poter arricchire il test in vivo di parametri quantitativi, sensibili, precoci e spesso unici perch\ue9 non esplorabili direttamente sull\u201fuomo. Il test in vitro pu\uf2 impiegare sistemi biologici semplificati (colture cellulari) o sofisticati (organi e tessuti ricostruiti) e sono perci\uf2 alternativi alla sperimentazione animale. La valutazione dell\u201feffetto irritante, studiato tramite l\u201fuso di cheratinociti umani, \ue8 stata gi\ue0 applicata anche in ambito cosmetologico. Dall\u201fanalisi comparativa dei dati ottenuti dai test in vitro con quelli ottenuti dai test in vivo sembra emergere una buona correlazione sia per quanto riguarda l\u201feffetto della sostanza utilizzata sia per quanto riguarda i dati di previsione del potenziale d\u201firritazione. Il modello proposto \ue8 basato sulla possibilit\ue0 di considerare i livelli di citochine infiammatorie come parametro di potenziale irritativo/infiammatorio in quanto le citochine possono avere un\u201fazione pro/anti-infiamatoria e possono agire in sinergia e/o antagonismo, a seconda dello stimolo. In questa ottica i test in vitro che implicano l\u201fanalisi di citochine, potrebbero essere usati anche per classificare le sostanze chimiche in base al potenziale di sensibilizzazione o irritante, con lo scopo di ridurre il numero dei test fatti su animali.I risultati ottenuti consentono di fare due considerazioni di rilievo: entrambe le citochine testate rispondono in tempi di esposizione precoce; \ue8 evidente l\u201finfluenza dei trattamenti con molecole potenzialmente irritanti sull\u201fespressione e sulla modulazione della LIF nei cheratinociti NCTC 2544. I dati sull\u201fespressione delle citochine durante esposizione a diverse concentrazioni dei composti in esame hanno mostrato una buona correlazione con quelli ottenuti dagli indici di tossicit\ue0 basale sui cheratinociti. L\u201futilizzo della metodica in ambito cosmetologico, per esempio nella fase di pre-screening di componenti di ingredienti cosmetici, pu\uf2 ridurre drasticamente i potenziali effetti irritativi, intervenendo a monte della consueta fase delle prove \u201cpatch test\u201d condotte sui volontari

4-Hydroxybenzoic Acid as an Antiviral Product from Alkaline Autoxidation of Catechinic Acid: A Fact to Be Reviewed

The dark brown mixture resulting from the autooxidation of catechinic acid (CA) (AOCA) has been reported to possess antiviral activity against Herpes Simplex Virus 1 and 2 (HSV-1 and HSV-2). Unfortunately, the constituents of AOCA were not separated or identified and the compound(s) responsible for AOCA’s antiviral activity remained unknown until recently. Colorless 4-hydroxy benzoic acid (4-HBA) has been reported as the main constituent (75%) of AOCA, and as being responsible for its antiviral activity. The findings seemed not to be reliable because of the existence in the literature of very different findings, because of the high concentration that was attributed to the supposed 4-HBA in the dark mixture, and because of the absence of essential analytical experiments to confirm 4-HBA in AOCA. Particularly, the AOCA chromatograms highlighting a peak attributable to 4-HBA, using commercial 4-HBA as a standard, is missing, as well as investigations concerning the antiviral activity of marketed 4-HBA. Therefore, in this study, to verify the exactness of the recent reports, we prepared CA from catechin and AOCA from CA, and the absence of 4-HBA in the mixture was first established by thin-layer chromatography (TLC), and then was confirmed by UHPLC–MS/MS, UV–Vis, and ATR–FTIR analyses. For further confirmation, the ATR–FTIR spectral data were processed by principal components analysis (PCA), which unequivocally established strong structural differences between 4-HBA and AOCA. Finally, while the antiviral effects of AOCA against HSV-2 were confirmed, a commercial sample of 4-HBA was completely inactive

Assessment of left ventricular dyssynergy by color kinesis

Color kinesis is a new echocardiographic technique based on acoustic quantification. It has been developed to facilitate the ability to identify contraction abnormalities and has been incorporated into a commercialy available ultrasound imaging system. The potential of this technique to improve the qualitative and quantitative assessment of wall motion abnormalities is described. Evaluation of color-encoded images allows detection of decreased amplitude of endocardial motion in abnormally contracting segments as well as a shorter time of endocardial excursion in segments with severely decreased motion. Compared with off-line quantitative studies, color kinesis has the advantage to be used on-line, without time-consuming manual tracing of endocardial boundaries. In addition, a single end-systolic color image contains the entire picture of spatial and temporal contraction and can be digitally scored and retrieved. Ire patients with proven coronary artery disease, color kinesis had a sensitivity of 88%, a specificity of 77%, and an overall accuracy of 86% in identifying the presence of segmental dysfunction. The practical application of color kinesis might be to improve our ability to distinguish normal from hypokinesis, something that has always been difficult in clinical echocardiography. Segmental analysis of color kinesis images allows objective detection of dobutamine-induced regional wall motion abnormalities in agreement with conventional visual interpretation of the corresponding 2-dimensional views. A method for objective assessment of wall dynamics during dobutamine stress echocardiography would be of particular clinical value, because these images are even more difficult to interpret than conventional echocardiograms. Quantitative assessment of diastolic function may allow objective evaluation of segmental relaxation abnormalities, especially under conditions of pharmacologic stress testing. Acquisition of color kinesis images during dobutamine stress echocardiography, both transthoracic and transesophageal, may facilitate the assessment of hybernating but viable myocardium and enhance the sensitivity in the detection of coronary artery disease. (C) 1998 by Excerpta Medica, Inc