A Mechano-Activated Cell Reporter System as a Proxy for Flow-Dependent Endothelial Atheroprotection.

The vascular endothelium plays a critical role in the health and disease of the cardiovascular system. Importantly, biomechanical stimuli generated by blood flow and sensed by the endothelium constitute important local inputs that are translated into transcriptional programs and functional endothelial phenotypes. Pulsatile, laminar flow, characteristic of regions in the vasculature that are resistant to atherosclerosis, evokes an atheroprotective endothelial phenotype. This atheroprotective phenotype is integrated by the transcription factor Kruppel-like factor-2 (KLF2), and therefore the expression of KLF2 can be used as a proxy for endothelial atheroprotection. Here, we report the generation and characterization of a cellular KLF2 reporter system, based on green fluorescence protein (GFP) expression driven by the human KLF2 promoter. This reporter is induced selectively by an atheroprotective shear stress waveform in human endothelial cells, is regulated by endogenous signaling events, and is activated by the pharmacological inducer of KLF2, simvastatin, in a dose-dependent manner. This reporter system can now be used to probe KLF2 signaling and for the discovery of a novel chemical-biological space capable of acting as the "pharmacomimetics of atheroprotective flow" on the vascular endothelium.

Hemodynamic Control of Endothelial Cell Fates in Development.

Biomechanical forces are emerging as critical regulators of embryogenesis, particularly in the developing cardiovascular system. From the onset of blood flow, the embryonic vasculature is continuously exposed to a variety of hemodynamic forces. These biomechanical stimuli are key determinants of vascular cell specification and remodeling and the establishment of vascular homeostasis. In recent years, major advances have been made in our understanding of mechano-activated signaling networks that control both spatiotemporal and structural aspects of vascular development. It has become apparent that a major site for mechanotransduction is situated at the interface of blood and the vessel wall and that this process is controlled by the vascular endothelium. In this review, we discuss the hemodynamic control of endothelial cell fates, focusing on arterial-venous specification, lymphatic development, and the endothelial-to-hematopoietic transition, and present some recent insights into the mechano-activated pathways driving these cell fate decisions in the developing embryo.

Frailty and Transplantation.

Consequences of aging are gaining clinical relevance. In transplantation, aging and immunosenescence impact treatment and outcomes. The impact of aging, however, will critically depend on distinguishing healthy, chronological aging from biological aging that may result into frailty. Approximately 15% of individuals older than 65 years are frail, and it is expected that this condition will gain more clinical relevance with an expected increase to greater than 20% over the next 5 years. Clearly, frailty impacts various general aspects of health care and organ transplantation in particular including patient selection, waitlist management and treatment after transplantation. In general, frailty has been characterized by a compromised physiological reserve and an augmented vulnerability. In comparison to healthy aging, inflammatory markers and cytokines are increased in frail older adults. Thus, modifications of the immune response, in addition to physical limitations and changes of metabolism, are likely to impact outcomes after transplantation. Here, we provide a risk assessment of frailty at the time of transplant evaluation and review effects on outcomes and recovery after transplantation. Moreover, we summarize our current understanding of the pathophysiology of frailty and consequences on immune responses and metabolism.

Immunosenescence in renal transplantation: a changing balance of innate and adaptive immunity.

PURPOSE OF REVIEW: With global demographic changes and an overall improved healthcare, more older end-stage renal disease (ESRD) patients receive kidney transplants. At the same time, organs from older donors are utilized more frequently. Those developments have and will continue to impact allocation, immunosuppression and efforts improving organ quality. RECENT FINDINGS: Findings mainly outside the field of transplantation have provided insights into mechanisms that drive immunosenescence and immunogenicity, thus providing a rationale for an age-adapted immunosuppression and relevant clinical trials in the elderly. With fewer rejections in the elderly, alloimmune responses appear to be characterized by a decline in effectiveness and an augmented unspecific immune response. SUMMARY: Immunosenescence displays broad and ambivalent effects in elderly transplant recipients. Those changes appear to compensate a decline in allospecific effectiveness by a shift towards an augmented unspecific immune response. Immunosuppression needs to target those age-specific changes to optimize outcomes in elderly transplant recipients.

Ischemia/reperfusion Injury and its Consequences on Immunity and Inflammation.

Ischemia/reperfusion injury (IRI), an inherent component of transplantation, affects organ quality and transplant outcomes. Although the complexity of the pathophysiology is recognized, detailed mechanisms remain unclear, and strategies preventing the consequences of IRI have been challenging. Of critical significance appears the link between IRI, the initiation of innate immune responses, and the (potential) augmentation of adaptive immunity. An improved understanding of those complex mechanisms and interactions may pave the way for more effective treatment strategies.

Mechanisms and consequences of injury and repair in older organ transplants.

Donor organ scarcity remains a significant clinical challenge in transplantation. Older organs, increasingly utilized to meet the growing demand for donor organs, have been linked to inferior transplant outcomes. Susceptibility to organ injury, reduced repair capacity, and increased immunogenicity are interrelated and impacted by physiological and pathological aging processes. Insights into the underlying mechanisms are needed to develop age-specific interventional strategies with regards to organ preservation, immunosuppression, and allocation. In this overview, we summarize current knowledge of injury and repair mechanisms and the effects of aging relevant to transplantation.

Effect of primary versus revisional Roux-en-Y gastric bypass: inferior weight loss of revisional surgery after gastric banding.

BACKGROUND: Laparoscopic adjustable gastric banding is a popular and effective restrictive bariatric procedure. However, with longer follow-up, it has become clear that a considerable number of patients require revisional surgery, of which Roux-en-Y gastric bypass (RYGB) is the most commonly performed procedure. Studies that compared the outcomes of primary RYGB and revisional RYGB have not been conclusive. Our objective was to determine whether significant differences exist in the 1-year outcomes between primary RYGB (prim-RYGB) and revisional RYGB after laparoscopic adjustable gastric banding (rev-RYGB) at a major training hospital in The Netherlands. METHODS: All prim-RYGB and rev-RYGB procedures performed from 2007 to 2009 were analyzed. Data were collected regarding weight loss, hospitalization, operative time, postoperative complications, and co-morbidities. RESULTS: A total of 292 RYGB procedures were performed: 66 rev-RYGB and 226 prim-RYGB procedures. The operative time was significantly shorter in the prim-RYGB group (136.6±37.5 versus 167.5±40.6 min; P<.0001). No significant differences were found in hospitalization time (4.4±1.7 versus 4.9±2.4 d; P= .063) or complication rate (14.7% versus 15.2%; P=.962). No deaths occurred in either group. The number of patients with resolved diabetes and hypertension did not differ between the 2 groups (50.1% versus 23.1%; P=.116; and 40.7% versus 25.0%; P=.384, respectively). Weight loss was significantly greater in the prim-RYGB group in terms of excess weight loss (71.6%±20.8% versus 48.4%±26.8%; P<.0001), body mass index reduction (13.0±3.8 versus 10.2±5.6 kg/m(2); P<.0001), absolute weight loss (37.4±11.5 versus 29.3±17.2 kg; P=.001), and percentage of weight loss (29.7%±8% versus 21.7%±11.5%; P<.0001). CONCLUSION: rev-RYGB is a safe procedure with outcomes similar to those of prim-RYGB in terms of complication rate, hospitalization time, and effect on co-morbidity. Weight loss, however, was significantly less after rev-RYGB than after prim-RYGB.