A single dose of oritavancin was noninferior to twice-daily vancomycin administered for 7 to 10 days for the treatment of acute bacterial skin and skin-structure infections caused by gram-positive pathogens. (Funded by the Medicines Company; SOLO I ClinicalTrials.gov number, NCT01252719.).
Cell-based therapy continues to be a promising avenue for the treatment of Duchenne muscular dystrophy (DMD), an X-linked skeletal muscle-wasting disease. Recently, we demonstrated that freshly isolated myogenic progenitors contained within the adult skeletal muscle side population (SP) can engraft into dystrophic fibers of nonirradiated mdx(5cv) mice after intravenous transplantation. Engraftment rates, however, have not been therapeutically significant, achieving at most 1% of skeletal muscle myofibers expressing protein from donor-derived nuclei. To enhance the engraftment of transplanted myogenic progenitors, an intraarterial delivery method was adapted from a previously described procedure. Cultured, lentivirus-transduced skeletal muscle SP cells, derived from mdx(5cv) mice, were transplanted into the femoral artery of noninjured mdx(5cv) mice. Based on the expression of microdystrophin or green fluorescent protein (GFP) transgenes in host muscle, sections of the recipient muscles exhibited 5%-8% of skeletal muscle fibers expressing donor-derived transgenes. Further, donor muscle SP cells, which did not express any myogenic markers prior to transplant, expressed the satellite cell transcription factor, Pax7, and the muscle-specific intermediate filament, desmin, after extravasation into host muscle. The expression of these muscle-specific markers indicates that progenitors within the side population can differentiate along the myogenic lineage after intraarterial transplantation and extravasation into host muscle. Given that femoral artery catheterization is a common, safe clinical procedure and that the transplantation of cultured adult muscle progenitor cells has proven to be safe in mice, our data may represent a step toward the improvement of cell-based therapies for DMD and other myogenic disorders.
Aims Endothelin‐1 (ET‐1) is an endogenous vasoconstrictor implicated in pulmonary and systemic hypertension, as well as ventricular dysfunction, through effects on vascular smooth muscle, the kidneys, and cardiomyocytes. We aimed to determine the association between serial ET‐1 levels and acute heart failure patient outcomes. Methods and results We measured plasma ET‐1 at baseline, 48–72 h, and 30 days in a cohort of 872 patients hospitalized with acute heart failure from the ASCEND‐HF trial (randomized to nesiritide vs. placebo), and its association with 30‐day mortality, 180‐day mortality, in‐hospital death or worsening heart failure, and 30‐day mortality or rehospitalization. Median ET‐1 was 7.6 [interquartile range (IQR) 5.9–10] pg/mL at baseline, 6.3 (IQR 4.9–8.1) pg/mL at 48–72 h, and 5.9 (IQR 4.7–7.9) pg/mL at 30 days (P < 0.001). Baseline and 48–72 h ET‐1 were found to be independently associated with 180‐day mortality in a multivariable analysis [hazard ratio (HR) 1.6, 95% confidence interval (CI) 1.3–2.0, P < 0.001 and HR 1.5, 95% CI 1.2–1.9, P = 0.001, respectively, log‐transformed]. ET‐1 that was measured at 48–72 h was also independently associated with death or worsening heart failure prior to discharge [odds ratio (OR) 1.6, 95% CI 1.03–2.4, P = 0.03]. These independent associations remained significant after including NT‐proBNP in the multivariable analysis. Conclusions We observed an independent association between elevated ET‐1 and short‐term in‐hospital clinical outcomes and 180‐day mortality in hospitalized patients with acute heart failure ET‐1 provided additional prognostic information which was incremental to that yielded by NT‐proBNP.
Cell-based therapy is a possible avenue for the treatment of Duchenne muscular dystrophy (DMD), an X-linked skeletal muscle-wasting disease. We have demonstrated that cultured myogenic progenitors derived from the adult skeletal muscle side population can engraft into dystrophic fibers of non-irradiated, non-chemically injured mouse models of DMD (mdx 5cv ) after intravenous and intra-arterial transplantation, with engraftment rates approaching 10%. In an effort to elucidate the cell surface markers that promote progenitor cell extravasation and engraftment after systemic transplantation, we show here that expression of the chemokine receptor CXCR4, whose ligand SDF-1 is overexpressed in dystrophic muscle, enhances the extravasation of these cultured progenitor cells into skeletal muscle after intra-arterial transplantation. One day posttransplantation, mice that received CXCR4-positive eGFP-positive cultured cells derived from the skeletal muscle side population displayed significantly higher amounts of eGFP-positive mononuclear cells in quadriceps and tibialis anterior than mice who received CXCR4-negative eGFP-positive cells derived from the same cultured population. At 30 days post-transplantation, significantly higher engraftment rates of donor cells were observed in mice that received CXCR4-positive cells versus those transplanted with CXCR4-negative fractions. Our data suggest the CXCR4 expression by muscle progenitor cells increases their extravasation into skeletal muscle shortly after transplantation. Furthermore, this enhanced extravasation likely promotes higher donor cell engraftment rates over time.
Background: Before consideration of advanced cardiac therapies, guidelines recommend a comprehensive multidisciplinary examination, including psychosocial assessment. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) has emerged as a highly reproducible tool to assess for psychosocial impairment and is associated with negative medical and psychosocial outcomes after transplantation. We sought to assess the association between SIPAT and outcomes after left ventricular assist device. Methods and Results: We evaluated 128 patients implanted with a first left ventricular assist device at the Cleveland Clinic from 2013 to 2017 who underwent a prospectively collected quantitative psychosocial assessment using SIPAT. Several survival analyses were performed testing the association between SIPAT score and mortality, first adverse event (defined as hospitalization, device exchange, or death), and recurring adverse events after multivariable adjustment. Median SIPAT score was 14 (interquartile range, 9.5–22.5), with higher values (representing more impairment) seen in patients implanted as destination therapy. After a median follow-up of 349 (interquartile range, 178–684) days, there were 319 adverse events (18 deaths, 10 device exchanges, and 291 readmissions) with 2.5±2.4 events per patient. Higher preimplant SIPAT scores were not associated with mortality ( P =0.764) or time to a first adverse event ( P =0.589) but were associated with cumulative adverse events (hazard ratio, 1.31; 95% CI, 1.09–1.58; P =0.005 per Δ10 in score). In addition, SIPAT was associated with days alive outside of the hospital ( P =0.016). Conclusions: A standardized assessment of psychosocial impairment after left ventricular assist device using the SIPAT score was not associated with mortality or time to first adverse event but was associated with cumulative adverse cardiac events. This score may provide insight when structuring mitigation strategies for high-risk patients and should be further tested in a prospective multicenter study.
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