A Novel Preclinical Model for Chronic Thrombo-Embolic Pulmonary Hypertension development, validation and characterization

Since the disease chronic thrombo-embolic pulmonary hypertension (CTEPH), which is caused by an abnormal increase in blood pressure in the lungs due to obstructions, is still incompletely understood, therapeutic interventions are limited, and a curative medicine is still not available for CTEPH, we aim to unravel some mechanisms of this disease in this dissertation. To establish this, we developed a large animal model for CTEPH in which chronic catheters in and around the heart enable serial and awake measurements of blood pressures, cardiac output and oxygen metabolism both at rest and during exercise. The research in this thesis provides an insight in some of the underlying mechanisms which cause remodeling of the pulmonary vasculature and the heart in this disease. Our results indicate that specific research in global signaling pathways such as the vasodilator nitric oxide, the vasoconstrictor endothelin and Rho-kinase are very important for the development of more effective CTEPH treatment. In addition, we show the importance of exercise testing in PH, especially in the early stages to provide earlier diagnosis. All together we provided a lot of information on the pathophysiology of CTEPH with the help of a novel large animal model. Although we gathered all this information, future studies need to be conducted before the ideal, curative therapy will reach the patient

Зведений словопокажчик української лексики

У статті обґрунтовано доцільність створення "Зведеного словопокажчика української лексики" (далі – ЗС), підкреслено його реєстраційно-довідковий характер і важливість не тільки для лексикографії, а й для мовознавства в цілому. Викладено деякі положення, що стосуються завдань та принципів укладання ЗС, а також уточнень і доповнень до Інструкції. Стаття містить перелік словників-джерел Зведеного словопокажчика зі скороченням їхніх назв

Reaching the hydrodynamic regime in a Bose-Einstein condensate by suppression of avalanche

We report the realization of a Bose-Einstein condensate (BEC) in the hydrodynamic regime. The hydrodynamic regime is reached by evaporative cooling at a relative low density suppressing the effect of avalanches. With the suppression of avalanches a BEC containing 120.10^6 atoms is produced. The collisional opacity can be tuned from the collisionless regime to a collisional opacity of more than 3 by compressing the trap after condensation. In the collisional opaque regime a significant heating of the cloud at time scales shorter than half of the radial trap period is measured. This is direct proof that the BEC is hydrodynamic.Comment: Article submitted for Phys. Rev. Letters, 6 figure

Cross-linguistic views of gesture usage

People have stereotypes about gesture usage. For instance, speakers in East Asia are not supposed to gesticulate, and it is believed that Italians gesticulate more than the British. Despite the prevalence of such views, studies that investigate these stereotypes are scarce. The present study examined peopleÕs views on spontaneous gestures by collecting data from five different countries. A total of 363 undergraduate students from five countries (France, Italy, Japan, the Netherlands and USA) participated in this study. Data were collected through a two-part questionnaire. Part 1 asked participants to rate two characteristics of gesture: frequency and size of gesture for 13 different languages. Part 2 asked them about their views on factors that might affect the production of gestures. The results showed that most participants in this study believe that Italian, Spanish, and American English speakers produce larger gestures more frequently than other language speakers. They also showed that each culture group, even within Europe, put weight on a slightly different aspect of gestures

The genetic basis of chronic myelogenous and acute lymphoblastic leukemia

The Ph' chromosome is a cardinal feature of chronic myelogenous leukemia (CML). Originally described by Nowell and Hungerford (1960) as a small chromosome 22 it was later demonstrated by de Klein and co-workers(1982) to typically result from a reciprocal translocation t(9;22)(q34.1;q11.2). In approximately 5 percent of patients, the Ph' chromosome results from anomalous complex translocation. Detailed studies using in situ hybridization have demonstrated that chromosomes 9 and 22 are usually involved in such translocations. Translocations between chromosome 22 and a chromosome other than 9 rarely occur.The human c-abl sequences represent the cellular homologue of the transforming gene of Abelson Murine Leukemia Virus (A-MuLV). This retrovirus is a recombinant between Moloney Murine Leukemia virus and mouse cellular c-abl sequences (Goff et al., 1980). A-MuLV induces lymphoid tumors following invivo inoculation of the mouse (Potter, 1983; Prekumar et al., 1975). Southern blot analysis of a series of somatic cell hybrids demonstrated that the human c-abl gene is localized on chromosome 9 (Heisterkamp et al., 1982). The finding that a small region of chromosome 9 is translocated to chromosome 22 in CML prompted studies to elucidate whether the abl gene was involved in this disease (de Klein et al., 1982). Bartram and colleagues (1983) first reported that the c-abl gene is translocated in Ph' positive but not in Ph' negative patients while Heisterkamp and co-workers (1983) reported a CML patient with a breakpoint 14 kb 5' of the c-abl sequences homologous to v-abl. This data suggested a role for c- abl in CML, a theory supported by the presence of an abnormally sized abl messenger RNA (Collins et al., 1984; Gale and Canaani, 1984) and abl protein in the CML, cell line K562 (Konopka et al., 1984).The region of chromosome 22 involved in the translocation has also been identified. Cloning of a chimeric breakpoint fragment from a CML, patient (Heisterkamp et al., 1983) enabled the use of a chromosome 22 specific probe. Subsequent Southern blot analysis of the DNA of a number of CML, patients showed that chromosome 22 breakpoints map to a stretch of 5.8 kb of DNA (Groffen, et al., 1984). This area on chromosome 22 was designated breakpoint cluster region or bcr.The investigation described in this thesis was undertaken to gain further insight into the genetic organization of the c-abl gene on the Ph' chromosome and the consequence of the Ph' translocation at the transcription and translation level. Chapter 2 is an extensive review of the genetic basis of CML, and acute lymphoblastic leukemia (All). Discussed is the cytogenetic and molecular aspects of CML, and ALL and the activation of the c-abl protein kinases as a consequence of the Ph' translocation. In Chapter 3, we show that the breakpoint cluster region on chromosome 22 is part of a gene, called phl . Molecular characterization demonstrates that phl . is a large gene oriented with its 5' end towards the centromere and with its 3' end toward the telomere of chromosome 22. As a consequence of the Ph' translocation the 3' end of this gene is translocated to chromosome 9, whereas the S' sequences remain on the Ph' chromosome. Following translocation, the remaining phl sequences become fused to the c-abl gene in a head to tail fashion on chromosome 22. We hypothesized that this genomicconfiguration could result in the transcription of a chimeric mRNA consisting of 5' phl and 3' abl sequences. In the study presented in Chapter 4, we analyzed the RNA of CML patients and found strong evidence for this model. Direct proof for the hypothesis was provided by cloning of a chimeric phl /c- abl cDNA in the CML cell line K562, described in Chapter 5. The experiments described herein have also contributed to more information about the genomic organization of the phl. and c-abl genes on the Ph' chromosome.Reports by Konopka et al. (1985) showing the presence of a larger 210K c- abl protein in the leukemic cells of CML patients initiated the studies described in Chapter 6. We demonstrate that this abnormal c- abl protein is a fusion protein containing amino terminal phl and carboxy terminal abl sequences. This phl /c- abl protein has an elevated tyrosine kinase activity when compared to the normal c- abl protein. In addition, we show in this chapter that the normal phl. gene encodes for a 160 K phosphoprotein exhibiting an associated kinase activity.A better understanding of the Ph' chromosome at the molecular level has allowed us to develop a probe for the detection of the Ph' translocation. In Chapter 7, we report the results of the clinical trials done at seven medical centers involving more than 400 clinical samples. In this report we demonstrate that the use of DNA probe analysis in the CML diagnostics has several advantages over cytogenetic methods