Does prophylactic sotalol and magnesium decrease the incidence of atrial fibrillation following coronary artery bypass surgery: a propensity-matched analysis

Background  

Atrial fibrillation can occur in up to 40% of patients undergoing coronary surgery.     

Retention of "safe" blood donors. The Retrovirus Epidemiology Donor Study

BACKGROUND: There are obvious advantages to increasing donor retention. However, for reasons of blood safety, certain donors may, in fact, be more desirable to retain than others. “Safe” donors are defined as those who provided a blood donation that was negative on all laboratory screening tests and who subsequently reported no behavioral risks in response to an anonymous survey. This study identifies the most important factors affecting the intention of “safe” donors to provide another donation. STUDY DESIGN AND METHODS: An anonymous survey asking about donation history, sexual history, injecting drug use, and recent donation experience was mailed to 50,162 randomly selected allogeneic donors (including directed donors) who gave blood from April through July or from October through December 1993 at one of the five United States blood centers participating in the Retrovirus Epidemiology Donor Study. Before mailing, questionnaires were coded to designate donors with nonreactive laboratory screening tests at their most recent donation. RESULTS: A total of 34,726 donors (69%) responded, with substantially higher response among repeat donors. According to reported intentions only, the vast majority of “safe” donors indicated a high likelihood of donating again within the next 12 months. Only 3.4 percent reported a low likelihood of donating again. A comparison of those likely to return and those unlikely to return reveals significant differences in demographics and in ratings of the donation experience. A higher proportion of those unlikely to return were first-time donors, minority-group donors, and donors with less education. The highest projected loss among “safe” donors was seen for those who gave a fair to poor assessment of their treatment by blood center staff or of their physical well-being during or after donating. CONCLUSION: These data suggest that efforts to improve donors' perceptions of their donation experience, as well as attention to the physical effects of blood donation, may aid in the retention of both repeat and first-time donors.     

The significance of the structural characteristics of the sphenoid sinuses in the development of sphenoiditis]

Medicolegal autopsies show a great incidence of sphenoiditides (63.3%) with a prevalent chronic atrophy (48%). Frontal and asymmetric presentation of the posterior cribrate cells about the sphenoid sinuses proved an unfavorable regional anatomic factor underlying dysfunction of the shunt drainage. Sphenoiditides are also promoted by digestions of the Vidian nerve canal producing harbours at the base of the sphenoid pterygoid process. Identification of anatomical factors of risk and characterization of the mucosal defects can be conducted at additional x-ray examination.     

Effects of atrial natriuretic peptide on DNA synthesis and NADPH diaphorase activity in epitheliocytes and smooth muscle cells of the respiratory tract in newborn albino rats

Newborn rats received single intraperitoneal injections of atrial natriuretic peptide (1-28) in a dose of 3.2×10_-8 mol/kg on day 6 of life. Autoradiography with ³H-thymidine showed that the peptide inhibited DNA synthesis in smooth muscle cells of the respiratory tract. Pretreatment with nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester attenuated, but did not abolish the effect of atrial natriuretic peptide (1-28). Histochemical assay for NADPH diaphorase showed that nitric oxide constitutively produced in the epithelium is involved in the growth-inhibitory effect of atrial natriuretic peptide (1-28) on proliferating smooth muscle cells.     

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.      

Engagement of the CD4 receptor inhibits the interleukin-2-dependent proliferation of human T cells transformed by Herpesvirus saimiri

Infection with Herpesvirus saimiri, a tumor virus of non-human primates, transformed human CD4⁺ T cell clones to permanent interleukin (IL)-2-dependent growth without need for restimulation with antigen and accessory cells. The IL-2-dependent proliferation of these cells was dramatically inhibited by soluble anti-CD4 whole antibodies, F(ab′)₂ and Fab fragments, and also by gp 120 of human immunodeficiency virus. The inhibition was not due to cell death and could be overcome by high concentrations of exogenous IL-2. Cell surface expression of CD4, and to a lesser degree the density of the IL-2 receptor α chain, were reduced upon anti-CD4 treatment. After long lasting (>12h) incubation with anti-CD4, abundance and activity of CD4-bound p56^lck were diminished while the free fraction of p56^lck remained unchanged. Since IL-2 binding to its receptor activated only the CD4-bound fraction of p56^lck, the IL-2-induced p56^lck activity was diminished after long-term CD4 ligation. Taken together, our results suggest a cross talk between CD4- and IL-2 receptor-mediated signaling via p56^lck.     

Use of electrographic method for detection of catheter position in the aorta

Electrographic method has permitted to detect the position of aorta catheter's end in 5 patients. This method is most available for intensive care departments of city hospital, because it doesn't require special equipment and additional staff, is easy to master, may be directly used during catheterisation, is safe for patients and staff and is cost effective.     

Engineered kinase activation reveals unique morphodynamic phenotypes and associated trafficking for Src family isoforms

The Src kinase family comprises nine homologous members whose distinct expression patterns and cellular distributions indicate that they have unique roles. These roles have not been determined because genetic manipulation has not produced clearly distinct phenotypes, and the kinases’ homology complicates generation of specific inhibitors. Through insertion of a modified FK506 binding protein (insertable FKBP12, iFKBP) into the protein kinase isoforms Fyn, Src, Lyn, and Yes, we engineered kinase analogs that can be activated within minutes in living cells (RapR analogs). Combining our RapR analogs with computational tools for quantifying and characterizing cellular dynamics, we demonstrate that Src family isoforms produce very different phenotypes, encompassing cell spreading, polarized motility, and production of long, thin cell extensions. Activation of Src and Fyn led to patterns of kinase translocation that correlated with morphological changes in temporally distinct stages. Phenotypes were dependent on N-terminal acylation, not on Src homology 3 (SH3) and Src homology 2 (SH2) domains, and correlated with movement between a perinuclear compartment, adhesions, and the plasma membrane.Since its discovery, c-Src (1) has been subject to intensive research into its cellular functions and regulation. Whereas c-Src is the best-studied protooncogene, less is known about the other, closely related Src family kinase (SFK) members. Their high degree of similarity in structure and regulation suggests that SFKs can partially compensate for each other in vivo. Indeed, knockout studies have shown that only mice deficient in all three genes (src, yes, and fyn) show embryonic lethality (2). Early studies demonstrated that disruption of Src or Fyn genes individually resulted only in subtle changes in function of a few cell types (e.g., osteoclasts for src^−/−, and T cells for fyn^−/−) (3, 4). Roche et al. provided strong evidence that Src, Yes, and Fyn substitute for each other during cell cycle progression (5). These studies suggested that there is a high degree of functional redundancy among Src family kinases.Nonetheless, emerging evidence indicates that Src and Fyn regulate distinct processes in the same cell. Down-regulation of Fyn expression enhances VEGF-stimulated migration of endothelial cells, whereas down-regulation of Src does not (6). Differences in the transforming capacity of SFKs are thought to depend on their affinity for cholesterol-enriched membrane microdomains, which is determined in part by their N-terminal lipid modifications (7, 8). Src has higher tumorigenic potential than Fyn in prostate epithelium, and this is differently affected by alterations in N-terminal palmitoylation (9). Previous studies have shown that Src localizes to perinuclear endosomal compartments and translocates to the plasma membrane upon activation (10–12), whereas Fyn localizes to the plasma membrane regardless of its activity (13, 14). Although these studies suggest that localization is important in differentiating the actions of the two kinases, they do not identify specific roles associated with particular subcellular locations.Various techniques have been applied to elucidate the differences in signaling specificity of SFKs. Kinase–substrate interactions have been examined using purified substrates (15). Mutated kinases with selectivity for radiolabeled ATP analogs have identified directly phosphorylated substrates of Src (16). These methods were restricted to cell lysates or purified proteins, and so were unable to address the role of cellular localization in substrate specificity.To dissect the unique role of different SFK isoforms (2–4, 17, 18) in living cells, we engineered regulatable analogs of Fyn, Yes, and LynA kinases using our rapamycin-regulated activation (RapR) strategy, which has been developed using Src as a prototype (19, 20). Insertable FKBP12 (iFKBP, a truncated form of FKBP) was inserted into the catalytic domain of each SFK, which abolished their kinase activity. Activity was rescued by treating cells with rapamycin in the presence of the FKBP12-rapamycin binding domain (FRB) (Fig. 1A). Molecular dynamics studies have indicated that heterodimerization of the inserted iFKBP with FRB likely reduces the conformational mobility of the kinase G loop, restoring ATP binding (3, 21).Open in a separate windowFig. 1.Design of RapR kinases. (A) Schematic representation of the approach used to regulate catalytic activity of SFKs. The insertion of iFKBP at a highly conserved site in the catalytic domain of each kinase resulted in loss of kinase activity. Catalytic activity was restored by rapamycin, which induced binding of iFKBP and coexpressed FRB. (B) Sequence alignment of SFKs shows that there is a well-defined loop where iFKBP is inserted (blue). It is linked to the G loop (red) through a β-sheet in each SFK.These analogs enabled activation of each isoform specifically, within minutes, resulting in clear phenotypic differences. Unlike genetic modifications of cell populations, there was little time for the cell to compensate for kinase activation before observation. The induced cell behaviors occurred in a succession of stages, associated with changes in the subcellular distribution of each kinase. We focused on Src and Fyn, developing quantitative tools to carefully characterize the kinetics of induced behaviors and associated localization dynamics. Our results indicated that Src’s unique ability to induce polarized movement shortly after kinase activation results from its localization in a perinuclear compartment, where it phosphorylates substrates that traffic on microtubules to the cell perimeter. Both the localization dynamics and phenotype differences between Src and Fyn were dependent on N-terminal lipid modifications, and not on SH2 and SH3 domain interactions.