Fast-atom bombardment tandem mass spectrometry of cyclic nucleotide analogues used as site-selective activators of cyclic nucleotide-dependent protein kinases

The mass spectrometric behaviour of six cyclic nucleotide analogues which activate cyclic AMP-dependent protein kinase was studied by positive-ion fast-atom bombardment (FAB) and collision-induced dissociation (CID) mass-analysed ion kinetic energy (MIKE) spectrometry. The compounds studied were 1,N6-ethenoadenosine-3',5'-cyclic monophosphate, (epsilon-cyclic AMP) and 2'-aza-1,N6-ethenoadenosine-3',5'-cyclic monophosphate, which each activate both isoforms of cyclic AMP-dependent protein kinase and have similar affinity for both the 'fast' and the 'slow' regulatory site of each isoform, N6-phenyl-cyclic AMP, which is selective for the 'fast' regulatory site of each isoform, and 6-chloropurine riboside-3',5'-cyclic monophosphate, 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole-3',5'-cyclic monophosphate and 8-(4-chlorophenylthio)-adenosine-3',5'-cyclic monophosphate, which are each selective for the 'slow' regulatory site and preferentially activate isoform II. The FAB- and CID/MIKE spectra of the analogues are discussed in relation to their use in studies of the regulation of protein kinase activity by quantitative FAB mass spectrometry.     

Cardiovascular research support by the American Heart Association in Louisiana

The American Heart Association (AHA) was founded in 1924 by a group of physician-scientists to promote the exchange of research ideas in an era when the treatment of heart disease was extremely frustrating. The organization has evolved to include education and community service in its mission, but the support and promotion of quality research has remained at the AHA's core. Research support by the AHA has been responsible for major advances in cardiovascular medicine, including the development of diuretics, pacemakers, artificial heart valves, defibrillators, cardiopulmonary resuscitation, hypercholesterolemia therapy, and artificial surfactant. Working to ensure the efficient distribution of funds, the AHA has distributed nearly $1.4 billion in support of quality research for graduate and medical students, post-doctoral fellows, and beginning and established investigators. Such support has assisted in the career development of four Nobel Prize winners. While cardiovascular disease remains America's leading cause of death, the activities of the AHA continue to support advances in its diagnosis and treatment.     

Depressed electrical atrial activity in hypertrophic and dilated cardiomyopathies. An electrocardiographic, vectorcardiographic and echocardiographic study]

Myelodysplasia and the myeloproliferative disorders are clonal hematopoietic stem cell disorders with heterogeneous clinical presentations and prognoses. This review highlights some of the recent progress that has been made in these disorders. Specifically, a number of studies have enhanced our understanding of the pathogenesis of these disorders, and potentially useful animal models for primary myelofibrosis have been developed. New, clinically useful prognostic scoring systems have been devised for myelodysplasia and for primary myelofibrosis. New chemotherapeutic approaches and nonmyelosuppressive alternative therapies for myelodysplasia have been studied. Data on the use of interferon for polycythemia vera and the potential leukemogenesis of hydroxyurea have recently become available. Finally, continued progress has been made in the use of allogeneic (related and unrelated donor) and autologous stem cell transplantation for myelodysplasia.     

Angiomegaly

Evaluation of Cost-Effectiveness in Health Care considers the background, methodology and potential political influence of economic evaluation (EE) in health care, the following conclusions can be drawn: EE is not just about cost cutting--it considers both costs and outcomes. EE needs to be integrated with decision-making procedures at different levels, namely the macro (policy) level, the meso (management) level, and the micro (clinical) level. EE needs to be seen as a part of a broader effort in health technology assessment and in relation to parallel efforts, e.g. guidelines development, quality assurance, evidence-based medicine. EE needs to be methodologically sound, but is not always possible to undertake the perfect study due to constraints of resources, time, information availability. Ways of setting priorities for EE need to be developed; this means selecting relevant topics and researchable questions. EE needs to be locally relevant; this means taking into account the variations of setting--within and between countries--and differences between trials (efficacy) and regular practice (community effectiveness). Factors that either encourage or inhibit the adoption of study results, i.e. adequate dissemination, professional support, financial incentives or political will, have to be considered.     

Diversity and age of the four major mtDNA haplogroups, and their implications for the peopling of the New World

Despite considerable investigation, two main questions on the origin of Native Americans remain the topic of intense debate-namely, the number and time of the migration(s) into the Americas. Using the 720 available Amerindian mtDNA control-region sequences, we reanalyzed the nucleotide diversity found within each of the four major mtDNA haplogroups (A-D) thought to have been present in the colonization of the New World. We first verified whether the within-haplogroup sequence diversity could be used as a measure of the haplogroup's age. The pattern of shared polymorphism, the mismatch distribution, the phylogenetic trees, the value of Tajima's D, and the computer simulations all suggested that the four haplogroups underwent a bottleneck followed by a large population expansion. The four haplogroup diversities were very similar to each other, offering a strong support for their single origin. They suggested that the beginning of the Native Americans' ancestral-population differentiation occurred approximately 30,000-40,000 years before the present (ybp), with a 95%-confidence-interval lower bound of approximately 25,000 ybp. These values are in good agreement with the New World-settlement model that we have presented elsewhere, extending the results initially found for haplogroup A to the three other major groups of mtDNA sequences found in the Americas. These results put the peopling of the Americas clearly in an early, pre-Clovis time frame.     

Thrombotic microangiopathy in association with cytomegalovirus infection in a renal transplant patient: a new treatment strategy

BACKGROUND: Cytomegalovirus (CMV) associated with thrombotic microangiopathy (TMA) in transplant patients has not been extensively described. This case illustrates an association between CMV and TMA in a transplant patient with resolution of the latter after treatment of the CMV. METHODS AND RESULTS: At 6 weeks after renal transplantation, a 57-year-old woman presented with TMA. Cyclosporine was discontinued, and plasmapheresis was started. However, the patient continued to deteriorate and developed CMV pneumonitis. Plasmapheresis was discontinued, and intravenous ganciclovir was initiated. Both the TMA and the CMV resolved after initiation of the ganciclovir. CONCLUSION: This case identifies another potential etiological factor in the development of TMA after renal transplantation. It is the first reported case of TMA being cured with treatment of CMV.     

Protocols for wound management

After 7 months of extensive research, wound management protocols were successfully developed and implemented at a 500-bed chronic care facility. The protocols gave registered nurses the authority and autonomy to initiate both treatment and preventive measures when caring for patients with pressure ulcers. The purpose of the protocols was twofold: (1) to prevent intact skin from breaking down and (2) to increase the healing rate of present ulcers.     

Detection of subtle changes in the brains of infants and children via subvoxel registration and subtraction of serial MR images

PURPOSE: To compare conventional two-dimensional multisection images with registered three-dimensional volume and subtraction images for detecting subtle changes in the brains of infants and children. METHODS: Twenty-six patients (24 with hemorrhagic/ischemic lesions) and one each with perinatal infection and Sturge-Weber disease were examined on two or more occasions with conventional multisection T1- and T2-weighted sequences as well as with 3-D T1-weighted volume sequences. A registration program was used to match the volume images to subvoxel dimensions, and subtracted images (second volume set minus the first) were obtained. The multisection images were compared with the 3-D and subtracted images and graded for detection of changes in a variety of brain structures. RESULTS: In 16% to 33% of comparisons of different structures, the multisection images and the 3-D registered and subtracted images showed changes equally well. The 3-D registered and subtracted images were better than the multisection images in 67% to 84% of comparisons for detection of changes in the cerebral hemispheres, ventricles, brain stem, cerebellum, and in lesions. Statistically significant differences were found between the graded performance of the registered 3-D images and the conventional 2-D images in detecting cerebral infarction and hypoxic ischemic encephalopathy. In the late phase following neonatal cerebral infarction (1 to 11 months), the 3-D registered and subtracted images revealed growth of the brain at the margins of the lesions. CONCLUSION: Subvoxel registration of serial MR images may be of value in detecting subtle changes in the brains of infants and children.