Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines as Selective,Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors

相似文献   

Cytogenetic studies in non-African Burkitt lymphoma

A particular translocation between chromosomes 8 and 14 has been found repeatedly in cytogenetic studies of Burkitt lymphoma, both of African and non-African origin. We report here our findings in cytogenetic studies of direct tumor preparations from 18 non-African Burkitt lymphoma patients, 9 of whom also had cell lines available for study. A t(8;14) was found in direct tumor material in 10 of the 18 patients. Seven of the 9 cell lines had a t(8;14). A total of 15 patients had either a t(8;14) or a 14q+ present in tumor material and/or cell lines. In addition, 8 patients had a peculiar marker chromosome 1. The t(8;14) was not found in every malignant cell and, where present, it was rarely the sole karyotypic abnormality. The relationship of the t(8;14) to the evolution of the tumor is discussed.     

Definition of pulmonary embolism‐related death and classification of the cause of death in venous thromboembolism studies: Communication from the SSC of the ISTH

Pulmonary embolism (PE)‐related death is often a component of the primary outcome in venous thromboembolism (VTE) clinical studies. Definitions for PE‐related death vary widely, which may lead to biased risk estimates of clinical outcomes, thereby affecting both internal and external validity of study results. We here provide a standardized definition of PE‐related death and propose guidance for classification and reporting of the cause of death for clinical studies in VTE. The proposal was developed in a four‐step process, including a systematic review of definitions used for PE‐related death in previous studies, two subsequent surveys with VTE experts, and meetings held within the Scientific and Standardization Committee (SSC) working group until consensus on the proposal was reached. The proposed classification comprises three categories: Category A: PE‐related death, category B: undetermined cause of death, and category C: cause of death other than PE. Category A includes A1: autopsy‐confirmed PE in the absence of another more likely cause of death; A2: objectively confirmed PE before death in the absence of another more likely cause of death; and A3: PE is not objectively confirmed, but is most likely the main cause of death. Category B includes B1: cause of death is undetermined, despite available information; and B2: insufficient clinical information available to determine the cause of death. The use of the proposed definition will hopefully improve the accuracy of study outcomes, between‐study comparisons, meta‐analyses, and validity of future clinical VTE studies.     

The use of 7-amino actinomycin D in identifying apoptosis: simplicity of use and broad spectrum of application compared with other techniques

The detection and quantitation of apoptotic cells is becoming increasingly important in the investigation of the role of apoptosis in cellular proliferation and differentiation. The pathogenesis of hematologic disorders such as aplastic anemia and the development of neoplasia are believed to involve dysregulation of apoptosis. To quantitate accurately the proportion of apoptosis cells within different cell types of a heterogeneous cell population such as blood or bone marrow, a method is required that combines the analysis of large numbers of cells with concurrent immunophenotyping of cell surface antigens. In this study, we have evaluated such a method using the fluorescent DNA binding agent, 7-amino actinomycin D (7AAD), to stain three diverse human cell lines, induced to undergo apoptosis by three different stimuli. Flow cytometric analysis defines three populations on the basis of 7AAD fluorescence and forward light scatter. We have shown by cell sorting and subsequent morphological assessment and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling that the populations defined by 7AAD represent live, apoptotic, and late-apoptotic/dead cells. This method is quick, simple, reproducible, and cheap and will be a valuable tool in the investigation of the role of apoptosis in normal physiology and in disease states.     

Serum protein profile alterations in hemodialysis patients

BACKGROUND: Serum protein profiling patterns can reflect the pathological state of a patient and therefore may be useful for clinical diagnostics. Here, we present results from a pilot study of proteomic expression patterns in hemodialysis patients designed to evaluate the range of serum proteomic alterations in this population. METHODS: Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) was used to analyze serum obtained from patients on periodic hemodialysis treatment and healthy controls. Serum samples from patients and controls were first fractionated into six eluants on a strong anion exchange column, followed by application to four array chemistries representing cation exchange, anion exchange, metal affinity and hydrophobic surfaces. A total of 144 SELDI-TOF-MS spectra were obtained from each serum sample. RESULTS: The overall profiles of the patient and control samples were consistent and reproducible. However, 30 well-defined protein differences were observed; 15 proteins were elevated and 15 were decreased in patients compared to controls. Serum from 1 patient exhibited novel protein peaks suggesting possible additional changes due to a secondary disease process. CONCLUSION: SELDI-TOF-MS demonstrated consistent serum protein profile differences between patients and controls. Similarity in protein profiles among dialysis patients suggests that patient physiological responses to end-stage renal disease and/or dialysis therapy have a major effect on serum protein profiles.     

Ruptured anterior communicating artery aneurysm. Therapeutic options in 119 consecutive cases

BACKGROUND AND PURPOSE: The respective roles of endovascular and surgical treatment must be clearly defined in the management of ruptured anterior communicating artery (AcoA) aneurysm. The aim of our study was to report our results, using the aneurysm direction as the main morphological argument to choose between microsurgery and endovascular embolization. Morbidity and mortality, causes of unfavorable outcome and morphological results were also assessed. PATIENTS AND METHODS: Our prospective study included 119 patients: 89 treated by microsurgery and 30 undergoing embolization with Guglielmi Detachable Coils (GDC). When the aneurysm had an anterior direction (fundus of the aneurysm in front of the pericallosal arteries), we attempted microsurgery. If the fundus of the aneurysm was behind the pericallosal arteries, we selected the most adapted procedure after discussion with the neurovascular team, taking into account the physiological status, treatment risk and neck size. Preoperative status of the patients was assessed according to the Hunt and Hess (HH) classification. Cerebral CT-scan and angiograms were routinely performed after treatment to determine causes of unfavorable outcome (GOS>1) and the morphological results. RESULT: Overall clinical outcome was excellent (GOS1) for 63.0% of patients, good (GOS2) for 10.1%, fair (GOS3) for 13.4%, poor (GOS4) for 2.5%. The mortality rate was 10.9%. Among the 82 patients in good preoperative grade (HHIII), 8 (21.6%) achieved an excellent outcome. However permanent morbidity or death occurred in 15 patients (78.4%). Permanent disability and death were related to initial subarachnoid hemorrhage and were observed 21.3% of patients in the microsurgical group and 30.0% in the endovascular group [Fisher's Exact Test; p=0.33]. Procedure-related permanent disability and death rates were 9.0% for the microsurgical group and 23.3% for the endovascular group (p=0.06) respectively. In the microsurgical group, the only morphologic characteristic which significantly correlated with the occurrence of vessel occlusion was the fundus direction (p=0.03). The difference between endovascular and microsurgical procedures in the achievement of complete occlusion was considered significant (p=0.04). CONCLUSION: In our experience, the direction of the aneurysm was the main morphological criterion in choosing between microsurgery or endovascular procedure for the treatment of AcoA aneurysm. We propose that microsurgical clipping should be preferred for AcoA aneurysms with anterior direction, and depending on morphological criteria, endovascular packing for those with posterior direction.     

Does the intensity of the inflammatory reaction in a bruise depend on its proximity to the site of trauma?

Whole blood was withdrawn by tail vessel puncture from anesthetized adult male Sprague–Dawley rats and 0.1 ml was re-injected subcutaneously at each of two sites on their abdominal wall. In addition, two adjacent sites were injected with 0.1 ml of sterile saline, and two more sites were only punctured using an injecting needle. In the second part of the study anesthetized adult male Sprague–Dawley rats had two sites on the abdominal wall pinched using a small pair of forceps, two adjacent sites received an injection of 0.1 ml of whole blood obtained by tail vessel puncture, and two more sites were both pinched and injected with 0.1 ml of whole blood. At intervals of 3, 6, 12 h, 1, 2, 3, 5, and 7 days the animals were euthanized and the skin of the abdomen was processed for histological assessment. Hemosiderin staining in tissues from the first part of the study was assessed qualitatively by scoring sections as 0, 1, 2, or 3 (representing no staining, mild staining, moderate staining, and intense staining) and semi quantitatively using a Nanozoomer Digital Pathology Scanner (NDP Scan U10074-01, Hamamatsu Photonics K.K., Japan). No inflammatory reaction was observed at the sites subjected to needle puncture only. At the sites of saline injection a mild reaction occurred. At the sites where the blood had been injected an intense inflammatory cell response occurred centrally, but not toward the periphery where blood had tracked. In the second experiment the most intense inflammation was also observed in the sites where there had been a pinch and injection of blood. Again, this was maximal centrally with reduced inflammation peripherally. Perls’ staining of hemosiderin was comparable in both models, with iron first observed at day 1 at the region of the injection site. At the sites of injection only, and the sites of injection plus pinch, blood had spread laterally. Hemosiderin staining appeared first and more intensely at the site of injection/trauma. The intensity of the inflammatory response in this animal model of bruising was, therefore, directly related to the proximity to the site of trauma; the appearance and intensity of hemosiderin staining was also influenced by the location within the bruises. This study has shown that histological changes that may be utilized to date bruises may be significantly influenced by the site of the biopsy.