134 research outputs found
Differential Proliferative Characteristics of Alveolar Fibroblasts in Interstitial Lung Diseases: Regulative Role of IL-1 and PGE2
Fibroblasts (Fb) from patients with sarcoidosis (SA) and
hypersensitivity pneumonitis (HP) exhibited a lower proliferative
capacity compared with Fb obtained from control (CO) and diffuse
interstitial fibrosis patients (DIF). Proliferation of Fb from SA or
lip patients was suppressed by autologous LPS-stimulated alveolar
macrophages (AM) supernatants but not by those from CO patients.
Similarly, alveolar macrophages (AM) derived supernatant, obtained
from CO, did not suppress the proliferation of SA and HP Fb. AM from
SA and HP patients secreted higher amounts of IL-1α and β
compared with controls and compared with Fb from SA and HP patients.
Steady levels of IL-1α and βmRNA were expressed in
unstimulated and stimulated cultures. Fb from SA and HP patients
could be stimulated by LPS to secrete significantly higher levels of
PGE2 than those detected in supernatants from LPS
stimulated Fb of DIF patients. Only the proliferation of Fb from SA
and HP patients was sensitive to amounts of IL-1 equivalent to those
detected in the lung of these diseases. As SA and HP are two
diseases where irreversible deterioration occurs in only 20%
of the patients, we hypothesize that mediators in the lung may
modulate Fb proliferation. IL-1 of AM origin and PGE2 of
Fb origin secreted at high levels, may be candidates for this
suppression because it was abrogated by anti IL-1β and indomethacin
Crack-Like Processes Governing the Onset of Frictional Slip
We perform real-time measurements of the net contact area between two blocks
of like material at the onset of frictional slip. We show that the process of
interface detachment, which immediately precedes the inception of frictional
sliding, is governed by three different types of detachment fronts. These
crack-like detachment fronts differ by both their propagation velocities and by
the amount of net contact surface reduction caused by their passage. The most
rapid fronts propagate at intersonic velocities but generate a negligible
reduction in contact area across the interface. Sub-Rayleigh fronts are
crack-like modes which propagate at velocities up to the Rayleigh wave speed,
VR, and give rise to an approximate 10% reduction in net contact area. The most
efficient contact area reduction (~20%) is precipitated by the passage of slow
detachment fronts. These fronts propagate at anomalously slow velocities, which
are over an order of magnitude lower than VR yet orders of magnitude higher
than other characteristic velocity scales such as either slip or loading
velocities. Slow fronts are generated, in conjunction with intersonic fronts,
by the sudden arrest of sub-Rayleigh fronts. No overall sliding of the
interface occurs until either of the slower two fronts traverses the entire
interface, and motion at the leading edge of the interface is initiated. Slip
at the trailing edge of the interface accompanies the motion of both the slow
and sub-Rayleigh fronts. We might expect these modes to be important in both
fault nucleation and earthquake dynamics.Comment: 19 page, 5 figures, to appear in International Journal of Fractur
Mutation Detection with Next-Generation Resequencing through a Mediator Genome
The affordability of next generation sequencing (NGS) is transforming the field of mutation analysis in bacteria. The genetic basis for phenotype alteration can be identified directly by sequencing the entire genome of the mutant and comparing it to the wild-type (WT) genome, thus identifying acquired mutations. A major limitation for this approach is the need for an a-priori sequenced reference genome for the WT organism, as the short reads of most current NGS approaches usually prohibit de-novo genome assembly. To overcome this limitation we propose a general framework that utilizes the genome of relative organisms as mediators for comparing WT and mutant bacteria. Under this framework, both mutant and WT genomes are sequenced with NGS, and the short sequencing reads are mapped to the mediator genome. Variations between the mutant and the mediator that recur in the WT are ignored, thus pinpointing the differences between the mutant and the WT. To validate this approach we sequenced the genome of Bdellovibrio bacteriovorus 109J, an obligatory bacterial predator, and its prey-independent mutant, and compared both to the mediator species Bdellovibrio bacteriovorus HD100. Although the mutant and the mediator sequences differed in more than 28,000 nucleotide positions, our approach enabled pinpointing the single causative mutation. Experimental validation in 53 additional mutants further established the implicated gene. Our approach extends the applicability of NGS-based mutant analyses beyond the domain of available reference genomes
New-Onset Atrial Fibrillation After PCI or CABG for Left Main Disease: The EXCEL Trial
Background: There is limited information on the incidence and prognostic impact of new-onset atrial fibrillation (NOAF) following percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for left main coronary artery disease (LMCAD). Objectives: This study sought to determine the incidence of NOAF following PCI and CABG for LMCAD and its effect on 3-year cardiovascular outcomes. Methods: In the EXCEL (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial, 1,905 patients with LMCAD and low or intermediate SYNTAX scores were randomized to PCI with everolimus-eluting stents versus CABG. Outcomes were analyzed according to the development of NOAF during the initial hospitalization following revascularization. Results: Among 1,812 patients without atrial fibrillation on presentation, NOAF developed at a mean of 2.7 ± 2.5 days after revascularization in 162 patients (8.9%), including 161 of 893 (18.0%) CABG-treated patients and 1 of 919 (0.1%) PCI-treated patients (p < 0.0001). Older age, greater body mass index, and reduced left ventricular ejection fraction were independent predictors of NOAF in patients undergoing CABG. Patients with versus without NOAF had a significantly longer duration of hospitalization, were more likely to be discharged on anticoagulant therapy, and had an increased 30-day rate of Thrombolysis In Myocardial Infarction major or minor bleeding (14.2% vs. 5.5%; p < 0.0001). By multivariable analysis, NOAF after CABG was an independent predictor of 3-year stroke (6.6% vs. 2.4%; adjusted hazard ratio [HR]: 4.19; 95% confidence interval [CI]: 1.74 to 10.11; p = 0.001), death (11.4% vs. 4.3%; adjusted HR: 3.02; 95% CI: 1.60 to 5.70; p = 0.0006), and the primary composite endpoint of death, MI, or stroke (22.6% vs. 12.8%; adjusted HR: 2.13; 95% CI: 1.39 to 3.25; p = 0.0004). Conclusions: In patients with LMCAD undergoing revascularization in the EXCEL trial, NOAF was common after CABG but extremely rare after PCI. The development of NOAF was strongly associated with subsequent death and stroke in CABG-treated patients. Further studies are warranted to determine whether prophylactic strategies to prevent or treat atrial fibrillation may improve prognosis in patients with LMCAD who are undergoing CABG. (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularizatio
Is Specialization Desirable in Committee Decision Making?
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Radical cystectomy with W-shaped orthotopic ileal neobladder constructed with non-absorbable titanium staples-long term follow-up
Differential, Positional-Dependent Transcriptional Response of Antigenic Variation (var) Genes to Biological Stress in Plasmodium falciparum
1% of the genes of the human malaria causing agent Plasmodium falciparum belong to the heterogeneous var gene family which encodes P. falciparum erythrocyte membrane protein 1 (PFEMP1). This protein mediates part of the pathogenesis of the disease by causing adherence of infected erythrocytes (IE) to the host endothelium. At any given time, only one copy of the family is expressed on the IE surface. The cues which regulate the allelic exclusion of these genes are not known. We show the existence of a differential expression pattern of these genes upon exposure to biological stress in relation to their positional placement on the chromosome – expression of centrally located var genes is induced while sub-telomeric copies of the family are repressed - this phenomenon orchestrated by the histone deacetylase pfsir2. Moreover, stress was found to cause a switch in the pattern of the expressed var genes thus acting as a regulatory cue. By using pharmacological compounds which putatively affect pfsir2 activity, distinct changes of var gene expression patterns were achieved which may have therapeutic ramifications. As disease severity is partly associated with expression of particular var gene subtypes, manipulation of the IE environment may serve as a mechanism to direct transcription towards less virulent genes
B-Type Natriuretic Peptide Assessment in Patients Undergoing Revascularization for Left Main Coronary Artery Disease
BACKGROUND: Elevated B-type natriuretic peptide (BNP) is reflective of impaired cardiac function and is associated with worse prognosis among patients with coronary artery disease (CAD). We sought to assess the association between baseline BNP, adverse outcomes, and the relative efficacy of percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG) in patients with left main CAD. METHODS: The EXCEL trial (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) randomized patients with left main CAD and low or intermediate SYNTAX scores (Synergy Between PCI With TAXUS and Cardiac Surgery) to PCI with everolimus-eluting stents versus CABG. The primary end point was the composite of all-cause death, myocardial infarction, or stroke. We used multivariable Cox proportional hazards regression to assess the associations between normal versus elevated BNP (≥100 pg/mL), randomized treatment, and the 3-year risk of adverse events. RESULTS: BNP at baseline was elevated in 410 of 1037 (39.5%) patients enrolled in EXCEL. Patients with elevated BNP levels were older and more frequently had additional cardiovascular risk factors and lower left ventricular ejection fraction than those with normal BNP, but had similar SYNTAX scores. Patients with elevated BNP had significantly higher 3-year rates of the primary end point (18.6% versus 11.7%; adjusted hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.16-2.28; P=0.005) and higher mortality (11.5% versus 3.9%; adjusted HR, 2.49; 95% CI, 1.48-4.19; P=0.0006), both from cardiovascular and noncardiovascular causes. In contrast, there were no significant differences in the risks of myocardial infarction, stroke, ischemia-driven revascularization, stent thrombosis, graft occlusion, or major bleeding. A significant interaction ( Pinteraction=0.03) was present between elevated versus normal BNP and treatment with PCI versus CABG for the adjusted risk of the primary composite end point at 3 years among patients with elevated BNP (adjusted HR for PCI versus CABG, 1.54; 95% CI, 0.96-2.47) versus normal BNP (adjusted HR, 0.74; 95% CI, 0.46-1.20). This interaction was stronger when log(BNP) was modeled as a continuous variable ( Pinteraction=0.002). CONCLUSIONS: In the EXCEL trial, elevated baseline BNP levels in patients with left main CAD undergoing revascularization were independently associated with long-term mortality but not nonfatal adverse ischemic or bleeding events. The relative long-term outcomes after PCI versus CABG for revascularization of left main CAD may be conditioned by the baseline BNP level. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01205776
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