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Nocardia transvalensis is a rarely reported cause of clinically significant disease, and, to our knowledge, has not been reported previously as a cause of infection in the cardiac transplant population. We report a case of N transvalensis new taxon-2 pulmonary infection that disseminated to the brain and skin in a cardiac transplant recipient despite adequate sulfonamide serum levels. Subsequent isolates were resistant to sulfonamides, and molecular ribotyping of the primary and subsequent isolates confirmed that these were the same N transvalensis new taxon-2 strain. The taxonomic and diagnostic considerations, as well as the clinical significance of anti-microbial-resistant nocardia, are reviewed and discussed herein.

The earliest form of vascular remodeling occurs during embryonic development, during vascular formation. In this process endothelial cells arise and form a dense plexus throughout the mesoderm. This plexus then remodels to form a recognizable branching vascular pattern. This remodeling has been considered to be primarily an endothelial cell event. It is now increasingly clear that this earliest form of remodeling actually represents a complex coordinated development process involving endothelial cells and smooth muscle cells. Recent gene-targeting experiments have begun to dissect the signaling pathways that mediate various aspects of this complex process, which appears to be regulated by secreted factors and physical forces. Subsequently, there is extensive remodeling as the primitive vascular pattern reorganizes to reflect the definitive circulation found in higher vertebrates. And finally, there is continuous remodeling in embryogenesis and during postnatal development as the organism increases in size.

Hematopoietic stem cells (HSCs) reside predominantly in bone marrow, but low numbers of HSCs are also found in peripheral blood. We examined the fate of blood-borne HSCs using genetically marked parabiotic mice, which are surgically conjoined and share a common circulation. Parabionts rapidly established stable, functional cross engraftment of partner-derived HSCs and maintained partner-derived hematopoiesis after surgical separation. Determination of the residence time of injected blood-borne progenitor cells suggests that circulating HSCs/progenitors are cleared quickly from the blood. These data demonstrate that HSCs rapidly and constitutively migrate through the blood and play a physiological role in, at least, the functional reengraftment of unconditioned bone marrow.

Endothelium critically regulates systemic and pulmonary vascular function, playing a central role in hemostasis, inflammation, vasoregulation, angiogenesis, and vascular growth. Indeed, the endothelium integrates signals originating in the circulation with those in the vessel wall to coordinate vascular function. This highly metabolic role differs significantly from the historic view of endothelium, in which it was considered to be merely an inert barrier. New lines of evidence may further change our understanding of endothelium, in regard to both its origin and function. Embryological studies suggest that the endothelium arises from different sites, including angiogenesis of endothelium from macrovascular segments and vasculogenesis of endothelium from microcirculatory segments. These findings suggest an inherent phenotypic distinction between endothelial populations based on their developmental origin. Similarly, diverse environmental cues influence endothelial cell phenotype, critical to not only normal function but also the function of a diseased vessel. Consequently, an improved understanding of site-specific endothelial cell function is essential, particularly with consideration to environmental stimuli present both in the healthy vessel and in development of vasculopathic disease states. The need to examine endothelial cell phenotypes in the context of vascular function served as the basis for a recent workshop sponsored by the National Heart, Lung, and Blood Institute (NHLBI). This report is a synopsis of pertinent topics that were discussed, and future goals and research opportunities identified by the participants of the workshop are presented.

We provide anatomic and functional evidence that nicotine induces angiogenesis. We also show that nicotine accelerates the growth of tumor and atheroma in association with increased neovascularization. Nicotine increased endothelial-cell growth and tube formation in vitro, and accelerated fibrovascular growth in vivo. In a mouse model of hind-limb ischemia, nicotine increased capillary and collateral growth, and enhanced tissue perfusion. In mouse models of lung cancer and atherosclerosis, we found that nicotine enhanced lesion growth in association with an increase in lesion vascularity. These effects of nicotine were mediated through nicotinic acetylcholine receptors at nicotine concentrations that are pathophysiologically relevant. The endothelial production of nitric oxide, prostacyclin and vascular endothelial growth factor might have a role in these effects.

Purpose INTERMACS profiles provide important prognostic information for patients with advanced heart failure (HF) receiving mechanical support. The role for INTERMACS profiling of advanced HF patients undergoing an initial strategy of medical management is not yet known. Methods and Materials The MedaMACS Screening Pilot enrolled 167 pts with chronic NYHA Class III-IV HF, EF≤30%, and ≥1 HF hospitalization in the prior year. Pts were excluded if listed for transplant or on inotropes. Comprehensive data were collected from usual care, with INTERMACS profiles assigned at enrollment using standard definitions. Subjects were followed for 12mos, or until death, VAD or transplant. Event rates were calculated by the Kaplan-Meier method and risk of death or VAD was analyzed using Cox modeling. Results Mean age was 57yrs, EF 17%, 47% had an ischemic etiology, and 57% had HF >5yrs. At enrollment 23% of subjects were INTERMACS profile 4, 32% profile 5, and 45% profile 6/7. Cumulative follow-up was 117 patient-yrs. Patients in lower INTERMACS profiles had been hospitalized more often in the prior 6 mos, were less often on a beta-blocker, and had higher Seattle HF model scores. Lower INTERMACS profile was associated with increased risk of death or VAD by 12 months. [ figure 1 ] Successively lower INTERMACS profile remained strongly associated with failure of medical therapy (HR 1.61, 95%CI 1.12-2.39) after adjustment for renal function, right ventricular function, and Seattle HF score quartile. Conclusions INTERMACS profiles are a useful short-hand for risk stratification in advanced HF. Lower profiles identify patients who may benefit from current mechanical support devices under existing indications.

Introduction Hypersensitivity myocarditis (HM) is a potentially fatal disease that can lead to refractory heart failure if left untreated. Numerous drugs have been implicated in causing HM. We present a case of HM in a heart transplant recipient treated with Rituximab for post-transplant lymphoproliferative disorder (PTLD). Case Report A 59 yo man was diagnosed with PTLD 8 months after undergoing heart transplantation. He had an early 2R acute cellular rejection that resolved with increasing baseline immunosuppression that consisted of tacrolimus, Cellcept and prednisone. An upper endoscopy done for dysphagia, anorexia and weight loss revealed a gastric ulcer and pathology consistent with high grade B cell lymphoma. PET/CT showed cervical, mediastinal, abdominal and pelvic lymphadenopathy as well as hypermetabolic liver and spine lesions consistent with stage IV metastatic disease. Bone marrow biopsy did not show any lymphoma. He was treated with 4 doses of weekly Rituximab and decreased baseline immunosuppression. He was maintained on tacrolimus with a target level around 6 ng/ml and low dose prednisone. He presented one month later with severe heart failure and allograft dysfunction. Heart biopsy showed pericellular and perivascular mixed inflammatory cell infiltrate rich in eosinophils with many degranulating forms suggestive of hypersensitivity myocarditis. There was no evidence of fungal or parasitic infection or heart involvement of the recently diagnosed B cell lymphoma. No eosinophils were seen during the prior cellular rejection. Patient was treated with high dose IV Solu-Medrol and a follow up biopsy one week later showed marked clearing of the eosinophilic infiltrate. Summary This patient presented with allograft dysfunction after receiving Rituximab, an agent putatively associated with hypersensitivity pneumonitis. Although a complete histologic distinction between HM and acute cellular rejection is not feasible, the features of this infiltrate were more consistent with HM, which was attributed to Rituximab.

enrolled NYHA class III/IV HF patients who were not listed for transplant, were not requiring inotropes, had an LVEF 30% and either had 2 HF hospitalizations in 12 mos or 1 HF hospitalization and 1 high-risk clinical feature. Results: Mean age was 57 yrs and LVEF was 17%. The distribution of IM profiles 4, 5, 6 and 7 was 23%, 31%, 34% and 12%, respectively. A majority described limitations with 4 of 5 health state dimensions: mobility (75%), usual activities (80%), pain/discomfort (62%), and anxiety/depression (64%). The mean visual analogue scale (VAS) score was 52 21, which was in-line with previously reported trends (Figure). The mean EQ-5D index score was 0.67 0.19. The EQ-5D index score significantly increased across increasing IM profiles (p 0.01). Diabetes, lower IM profiles, and unemployment status were independently associated with a lower EQ-5D index score (p 0.01) after adjusting for traditional covariates (age 60, male, white, ischemic, and creatinine 1.6) and other covariates that were significant on univariate analysis. Conclusions: Patients with INTERMACS profile 4-7 heart failure have significantly reduced QOL. Lower INTERMACS profiles, diabetes, and unemployment status were independently associated with a worse health state as determined by the EQ-5D index score. This data may be helpful when determining whether LVADs can be beneficial earlier in the spectrum of advanced heart failure.

Introduction: Recent findings report the potential for bone marrow(BM) or cardiac-derived stem and progenitor cell mobilization and differentiation to repair the infarcted myocardium. Following myocardial infarction (MI), there is an influx of inflammatory cells and secretion of cytokines, leading to cardiomyocyte death and ventricular remodeling. Mobilized c-Kitþ progenitor cells, either from the BM or cardiac niches, play a key role in maintenance of the number of myocytes in aging or postMI. We focused on determining the role of the c-Kit receptor in long term remodeling post-MI. Methods and Results: Functional repair in c-kit mutant (W/W) and littermate wild type (WT) mice post-MI was compared by evaluating in vivo left ventricular (LV) pressure-volume performance and pathology at 5 and 24 weeks post-MI. Evaluation of LV end-systolic and diastolic volume (ESV and EDV) showed a significant worsening of heart function and greater left ventricular dilatation at 5 and 24 weeks post-MI in W/W mice compared to WT (Figure 1). Similarly, the W/W sham and MI operated groups developed greater LV dilatation at 24 weeks when compared to W/W sham and MI mice at 5 weeks. Interestingly, WT sham and MI mice did not demonstrate any significant worsening of heart function at 24 weeks when compared to 5 weeks post-MI. Conclusion: This demonstrates the importance of c-Kit receptors in maintaining heart function post-MI and in aging. These findings provide further evidence indicating the presence of BMor cardiac residentderived stem progenitor cells in maintenance of myocardial health with age and post-injury. 133