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Three Japanese patients demonstrated plasma prekallikrein (PK) deficiency (PKD) after an examination of the proband family line named 'PKD Seki'. A molecular genetic analysis of these PK genes showed homozygous amino acid substitutions Gly104Arg and Asn124Ser in exon 5, which encodes part of the apple domain 2 (A2) of the heavy chain. This is the first case involving substitutions in the heavy chain of the PK gene which affected blood coagulation. Because the apple domains of PK bind to the C-terminal domain (D6(H)) of high-molecular weight kininogen (HMWK), the two substitutions in A2 may therefore be the main cause of PKD Seki. We subsequently investigated the effects of amino acid substitutions in A2 to elucidate the binding activity of PK to HMWK using mutant A2 proteins produced in Escherichia coli. We clearly demonstrated that the Gly104Arg-substitution with the Asn124Ser-substitution in A2 reduce the binding activity of A2 to HMWK. PKD Seki is the first significant case to show the amino acid substitutions in the A2 affecting the binding capacity of PK with HMWK. Our findings therefore suggest that the binding of PK to HMWK may play a crucial role in the first step of blood coagulation.

Background: Recent studies have suggested that cardiac troponin T (cTnT) and troponin I may detect ongoing myocardial damage involved in the progression of chronic heart failure (CHF). This study was prospectively designed to examine whether the combination of cTnT, a marker for ongoing myocardial damage, and B-type natriuretic peptide (BNP), a marker for left ventricular overload, would effectively stratify patients with CHF after initiation of treatment.

Background: Heart-type fatty acid-binding protein (H-FABP) is proposed as an early biomarker for acute myocardial infarction (AMI), but its prognostic value is unclear in acute coronary syndrome (ACS). We evaluated the prognostic value of the H-FABP concentration relative to cardiac troponin T (cTnT) in the early hours of ACS. Methods: Serum concentrations of H-FABP and cTnT were measured on admission in 328 consecutive patients hospitalized for ACS within 6 h after the onset of chest pain [AMI, 241 (73.5%) patients; ST-segment elevation myocardial infarction, 154 (47.0%) patients; and emergent coronary angiography within 24 h after admission, 287 (87.5%) patients]. Cardiac events, which were defined as cardiac death or subsequent nonfatal AMI, were monitored for 6 months after admission. Results: During the 6-month follow-up period, there were 25 cardiac events, including 15 cardiac deaths and 10 subsequent nonfatal AMIs. Stepwise multivariate analyses including clinical, electrocardiographic, and biochemical variables revealed that increased H-FABP (above the median of 9.8 g/L), but not increased cTnT (above the median of 0.02 g/L), was independently associated with

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A total of 12 VanA-type vancomycin-resistant enterococci, consisting of 10 Enterococcus faecium isolates and two Enterococcus avium isolates, were examined in detail. The vancomycin resistance conjugative plasmids pHT␣ (65.9 kbp), pHT␤ (63.7 kbp), and pHT␥ (66.5 kbp) were isolated from each of three different E. faecium strains. The plasmids transferred highly efficiently between enterococcus strains during broth mating and were homologous with pMG1 (Gm r ; 65.1 kb).Gene transfer systems are an essential requirement for the spread of drug resistance in microorganisms. In general, the systems of efficient plasmid transfer have not been well characterized for the gram-positive bacteria. However, enterococci possess potent and unique capabilities of transferring plasmids among themselves and to other genera (4,5,21,35). One type of enterococcal plasmid consists of the group of narrow-hostrange and pheromone-responsive plasmids (4,5,9). The other type consists of the broad-host-range pAM␤1 and pIP501 plasmids, which were originally isolated from Enterococcus faecalis (8,24) and Streptococcus agalactiae (13, 18), respectively, and transfer on a solid surface at low frequency (8,13,18,24,27,40).We have described the isolation of the pheromone-independent gentamicin resistance conjugative plasmid pMG1 (Gm r ; 65.1 kb) from an Enterococcus faecium clinical isolate in Japan (20). pMG1 transfers efficiently among enterococcus strains during broth mating. pMG1-like plasmids are widely disseminated in vancomycin-resistant E. faecium clinical isolates obtained from a hospital in the United States (39).In this report, we show that the VanA resistance encoded on a Tn1546-like transposon was mediated by a pMG1-like plasmid and that this vancomycin resistance pMG1-like plasmid was capable of highly efficient transfer among the enterococci.Drug resistance of VRE isolates and isolation of vancomycin resistance conjugative plasmids. The laboratory strains and plasmids used in this study are listed in Table 1. A total of 12 isolates of vancomycin-resistant enterococci (VRE) were used in this study ( Table 2). The vancomycin resistance of each strain transferred to E. faecium BM4105RF at a frequency of about 10 Ϫ5 per donor cell by mating in broth for 4 h at 37°C.The transconjugants of each strain acquired only vancomycin and teicoplanin resistance, indicating that the glycopeptide resistance was transferred during broth mating. Analysis of agarose gel electrophoresis of restriction fragments of plasmid DNAs of each strain showed many DNA bands, indicating that each of the strains harbored several plasmids (Fig. 1, A1). The conjugative vancomycin resistance plasmid pHT␣ was identified from the transconjugant of E. faecium FH1 by repeated transfer experiments between E. faecium BM4105 strains. The plasmids isolated from each of the strains were classified into three types, ␣, ␤, and ␥, with respect to the restriction profiles that hybridized to the type ␣ plasmid pHT␣ (Fig. 1, A2) ( Table 2). The pHT␤ and pHT␥ plasmids, which were typ...

The response of human acute myelogenous leukemia (AML) cells to four different hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 ␤ (IL-1␤), interleukin-3 (IL-3), and stem cell factor (SCF)) and the relationship of the proliferative response of the AML cells to treatment outcome were studied. Proliferative responses were analyzed in 79 patients with de novo AML and 19 patients with AML arising from myelodysplastic syndrome (MDS). In de novo AML, a positive proliferative response (stimulation index Ͼ2) was seen in 65 to 75% of cases. AML cells arising from MDS had a much higher incidence of proliferative response to each growth factor (79 to 90%) and a much higher level of 3 H-TdR incorporation. The relationship to treatment outcome was evaluated in 79 patients with de novo AML. The patients whose leukemic cells had a positive proliferative response to any growth factor, especially IL-3 and SCF, had a poorer outcome, ie a lower complete remission (CR) rate, shorter CR duration, and shorter survival. The outcome was particularly poor in patients whose leukemic cells had proliferative responses to all four or any of the growth factors, compared to patients whose leukemic cells had no response. This increased response may be a marker of poor prognosis in patients with AML.

Weekly administration of EPO 36 000 IU significantly increased hemoglobin level and ameliorated the decline of QOL in CIA patients over the 8-week administration period.