Salmonella phage PSP3, another member of the P2-like phage group

Freshly isolated DNA of phage PSP3, whose morphology closely resembles that of phage P2, contained both circular and linear molecules about 31 kb in length. Linear PSP3 DNA molecules possess single-stranded cohesive termini (cos). Sequencing of the fragment anticipated to contain cos revealed a 19-base sequence identical to cos of phage 186. Of the 107 bp to the right of cos, 94 were identical in 186 DNA (88% similarity), and of the 370 bp to the left, 229 were identical (62% similarity). Cos flanking sequences in both P2 and P4 were also highly conserved in PSP3. A number of restriction sites were at similar locations on the two phage DNAs. The parasitic phage P4 propagated on PSP3 lysogens. PSP3 integrates into the Escherichia coli chromosome at 27 min.     

Prevention of platelet hyperaggregation during coronary angiography

The authors previously reported an increase in platelet aggregration in the days after coronary angiography, accompanied at times by worrying cardiovascular disorders (ventricular fibrillation in one case, death in two others). In the present study, ten patients received a platelet antiaggregating drug (ticlopidin) 5 days before their coronary angiography. No significant changes were detected in the test for circulating platelet aggregates (CPA test) in these patients.     

Auditory-visual multisensory interactions attenuate subsequent visual responses in humans

Effects of multisensory interactions on how subsequent sensory inputs are processed remain poorly understood. We investigated whether multisensory interactions between rudimentary visual and auditory stimuli (flashes and beeps) affect later visual processing. A 2 x 3 design varied the number of flashes (1 or 2) with the number of beeps (0, 1, or 2) presented on each trial, such that '2F1B' refers to the presentation of 2 flashes with 1 beep. Beeps, when present, were synchronous with the first flash, and pairs of stimuli within a trial were separated by 52 ms ISI. Subjects indicated the number of flashes presented. Electrical neuroimaging of 128-channel event-related potentials assessed both the electric field strength and topography. Isolation of responses a visual stimulus that was preceded by a multisensory event was achieved by calculating the difference between the 2F1B and 1F1B conditions, and responses to a visual stimulus preceded by a unisensory event were isolated by calculating the difference between the 2F0B and 1F0B conditions (MUL and VIS, respectively). Comparison of MUL and VIS revealed that the treatment of visual information was significantly attenuated approximately 160 ms after the onset of the second flash when it was preceded by a multisensory event. Source estimations further indicated that this attenuation occurred within low-level visual cortices. Multisensory interactions are ongoing in low-level visual cortices and affect incoming sensory processing. These data provide evidence that multisensory interactions are not restricted in time and can dramatically influence the treatment of subsequent stimuli, opening new lines of multisensory research.     

Systolic BP and Mortality in Older Adults with CKD

Background and objectives

Optimal BP targets for older adults with CKD are unclear. This study sought to determine whether a nonlinear relationship between BP and mortality—as described for the broader CKD population and for older adults in the general population—is present for older adults with CKD.

Design, setting, participants, & measurements

A cohort of 21,015 adults age 65–105 years with a moderate or severe reduction in eGFR (<60 ml/min per 1.73 m²) were identified within the Kaiser Permanente Northwest Health Maintenance Organization population. The relationship between baseline systolic BP (SBP; ≤120, 121–130, 131–140, 141–150, >150 mmHg; referent, 131–140 mmHg) and all-cause mortality across age groups (65–70, 71–80, and >80 years) was examined; patients were followed for up to 11 years after cohort entry.

Results

The median times at risk were 3.15 years, 3.53 years, and 2.76 years for adults age 65–70, 71–80, and >80 years, respectively. Mortality during follow-up was 19.6% for those age 65–70 years, 33.4% for those age 71–80 years, and 55.7% for those age >80 years. The relationship between SBP and mortality varied as a function of age. The risk of death was highest for patients with the lowest SBP in all age groups. Only among adults age 65–70 years was an SBP>140 mmHg associated with a higher risk of death compared with the referent category. Patterns of age modification of the relationship between SBP and mortality were consistent in all sensitivity analyses.

Conclusions

In a cohort of older adults, the relationship between SBP and mortality varied systematically with age. A relationship between higher SBP and mortality was present only for younger members of this cohort and not for those older than 70. These results raise the question of whether the relative benefits and harms of lowering BP to recommended targets for older adults with CKD may vary as a function of age.     

Epstein-Barr virus latent membrane protein 1 activation of NF-kappaB through IRAK1 and TRAF6

Epstein-Barr virus latent membrane protein 1 (LMP1) activation of NF-kappaB is critical for Epstein-Barr virus-infected B lymphocyte survival. LMP1 activates the IkappaB kinase complex and NF-kappaB through two cytoplasmic signaling domains that engage tumor necrosis factor receptor-associated factor (TRAF)1/2/3/5 or TRADD and RIP. We now use cells lacking expression of TRAF2, TRAF5, TRAF6, IKKalpha, IKKbeta, IKKgamma, TAB2, IL-1 receptor-associated kinase (IRAK)1, or IRAK4 to assess their roles in LMP1-mediated NF-kappaB activation. LMP1-induced RelA nuclear translocation was similar in IKKalpha knockout (KO) and WT murine embryo fibroblasts (MEFs) but substantially deficient in IKKbeta KO MEFs. NF-kappaB-dependent promoter responses were also substantially deficient in IKKbeta KO MEFs but were hyperactive in IKKalpha KO MEFs. More surprisingly, NF-kappaB responses were near normal in TRAF2 and TRAF5 double-KO MEFs, IKKgamma KO MEFs, TAB2 KO MEFs, and IRAK4 KO MEFs but were highly deficient in TRAF6 KO MEFs and IRAK1 KO HEK293 cells. Consistent with the importance of TRAF6, LMP1-induced NF-kappaB activation in HEK293 cells was inhibited by expression of dominant-negative TAB2 and Ubc13 alleles. These data extend a role for IKKalpha in IKKbeta regulation, identify an unusual IKKbeta-dependent and IKKgamma-independent NF-kappaB activation, and indicate that IRAK1 and TRAF6 are essential for LMP1-induced NF-kappaB activation.     

Coagulation activation in sickle cell trait: an exploratory study

Recent epidemiologic data suggest that sickle cell trait (HbAS; AS) is a risk factor for venous thromboembolism. We conducted an exploratory study of healthy subjects with AS under baseline conditions to determine whether a chronic basal hyperactivation of coagulation exists, and if so, what mechanism(s) contribute to this state. Eighteen healthy AS individuals were compared to 22 African‐American controls with a normal haemoglobin profile (HbAA; AA) and 17 patients with sickle cell disease (HbSS; SS). Plasma thrombin‐antithrombin complexes and D‐dimer levels were elevated in AS relative to AA patients (P = 0·0385 and P = 0·017, respectively), and as expected, were much higher in SSversusAA (P < 0·0001 for both). Thrombin generation in platelet poor plasma was indistinguishable between AA and AS subjects, whereas a paradoxical decrease in endogenous thrombin potential was observed in SS (P ≤ 0·0001). Whole blood tissue factor was elevated in SS compared to AA (P = 0·005), but did not differ between AA and AS. Plasma microparticle tissue factor activity was non‐significantly elevated in AS (P = 0·051), but was clearly elevated in SS patients (P = 0·004) when compared to AA controls. Further studies in larger cohorts of subjects with sickle cell trait are needed to confirm the results of this preliminary investigation.     

Capsular type K54, clonal group 29 and virulence plasmids: an analysis of K54 and non-K54 closely related isolates of Klebsiella pneumoniae

Capsular type K54 of Klebsiella pneumoniae is associated with hypervirulence and we sought to discover the basis for this among isolates submitted to the UK reference laboratory between 2012 and 2017. Isolates were typed by variable number tandem repeat analysis, and capsular type and virulence elements sought by PCR. The most prevalent type found (15/31 isolates) corresponded to clonal group (CG) 29 and included five representatives carrying rmpA, rmpA2 (regulators of mucoid phenotype), iutA and iroD (from the aerobactin and salmochelin siderophore clusters) associated with virulence plasmids. These included isolate KpvK54, recovered from pus. The remaining isolates did not carry a virulence plasmid. We also noted 11 further related isolates, including NCTC 9159, not of capsular type K54, but nevertheless sometimes associated with sepsis and abscesses. Whole-genome sequencing showed that KpvK54 carried a large virulence plasmid and an ICEKp3-like structure carrying the yersiniabactin cluster, absent in NCTC 9159. Comparative chromosomal analysis with an additional four genomes showed that KpvK54 shared further genes with K1-ST23 hypervirulent isolates, and with LS358, a K54-ST29 isolate from liver abscess puncture fluid. While CG29 isolates displayed varying degrees of virulence, some, especially those with the virulence plasmid (all K54), were clearly associated with hypervirulence.Key words: Klebsiella, typing

The polysaccharide capsule of Klebsiella pneumoniae is regarded as a virulence factor, protecting it against the host immune response. Seventy-nine capsular types have been identified [1–3]. Some of these capsular types have been associated with invasive disease, largely because of particular ‘hypervirulent’ strains belonging to them, most notably clonal groups (CG) 23 (of capsular type K1), 86, 375 and 380 (capsular type K2) all of which have been strongly associated with sepsis and liver abscesses, often in otherwise healthy people [4, 5]. Compared with those belonging to capsular types K1 and K2, isolates belonging to other capsular types have been relatively little studied. Nevertheless, capsular type K54 has also been associated with hypervirulence, particularly representatives of sequence type (ST) 29 [6–10]; the presence of a large virulence plasmid carrying capsule-upregulation genes rmpA/rmpA2 and the aerobactin siderophore cluster is also important. We sought to investigate K. pneumoniae submitted to the UK national reference laboratory and positive for the K54 capsular type for evidence of hypervirulence. In doing so, it quickly became clear that one type (with variants), corresponding to CG29, dominated and that we had both K54 and non-K54 representatives of it, the latter including the reference strain NCTC 9159 [11], the whole-genome sequence of which had been determined in the NCTC 3000 project [12]. In addition, whole-genome sequences were available of two isolates of capsular type K54 and of ST29; one from liver abscess puncture fluid from China (LS358, {"type":"entrez-nucleotide","attrs":{"text":"CP025629","term_id":"1325141028"}}CP025629) and the other from the environment in Australia (KP-1, {"type":"entrez-nucleotide","attrs":{"text":"CP012883","term_id":"940656576"}}CP012883). This provided a rare opportunity to be able to compare these isolate sets, with the aim of providing potential insights into the hypervirulent phenotype and the importance or otherwise of CG and capsular type.     

Clostridium difficile infection, Colorado and the northwestern United States, 2007

To determine the incidence of Clostridium difficile infection during 2007, we examined infection in adult inpatient and outpatient members of a managed-care organization. Incidence was 14.9 C. difficile infections per 10,000 patient-years. Extrapolating this rate to US adults, we estimate that 284,875 C. difficile infections occurred during 2007.     

THE ACRASIN ACTIVITY OF 3′,5′-CYCLIC NUCLEOTIDES

3',5'-Cyclic nucleotides are acrasins for the cellular slime mold, Dictyostelium discoideum; they have chemotactic activity on the myxamoebae at very low concentrations. However, not all cyclic nucleotides can evoke the adhesiveness necessary for aggregate formation. 2',3'-Cyclic nucleotides and dibutyrylcyclic adenosine monophosphate are not acrasins, though they enhance the rate of differentiation and morphogenesis. The addition of 3',5'-cyclic nucleotides to agar test plates stimulates the rate of morphogenesis. While the stimulatory effect of cyclic nucleotides is concentration-dependent, it is fairly uniform between pH 5 and 7, with an optimum at pH 6. The acrasins may be metabolized by extracellular phosphodiesterase to 5'-nucelotides which may then stimulate differentiation and morphogenesis.