The calcium-activated phosphatase calcineurin is regulated by a binding cofactor known as modulatory calcineurin-interacting protein (MCIP) in yeast up through mammals. The physiologic function of MCIP remains an area of ongoing investigation, because both positive and negative calcineurin regulatory effects have been reported. Here we disrupted the mcip1 and mcip2 genes in the mouse and provide multiple lines of evidence that endogenous MCIP functions as a calcineurin facilitator in vivo. Mouse embryonic fibroblasts deficient in both mcip1͞2 showed impaired activation of nuclear factor of activated T cells (NFAT), suggesting that MCIP is required for efficient calcineurin-NFAT coupling. Mice deficient in mcip1͞2 showed a dramatic impairment in cardiac hypertrophy induced by pressure overload, neuroendocrine stimulation, or exercise, similar to mice lacking calcineurin A␤. Moreover, simultaneous deletion of calcineurin A␤ in the mcip1͞2-null background did not rescue impaired hypertrophic growth after pressure overload. Slow͞oxidative fiber-type switching in skeletal muscle after exercise stimulation was also impaired in mcip1͞2 mice, similar to calcineurin A␤-null mice. Moreover, CD4 ؉ T cells from mcip1͞2-null mice showed enhanced apoptosis that was further increased by loss of calcineurin A␤. Finally, mcip1͞2-null mice displayed a neurologic phenotype that was similar to calcineurin A␤-null mice, such as increased locomotor activity and impaired working memory. Thus, a loss-of-function analysis suggests that MCIPs serve either a permissive or facilitative function for calcineurin-NFAT signaling in vivo.heart ͉ PP2B ͉ signal transduction

Adult and pediatric patients with ESRD have impaired maximum oxygen consumption (VO 2 max), a reflection of the cardiopulmonary system's ability to meet increased metabolic demands. We sought to determine factors associated with decreased VO 2 max in pediatric patients with different stages of CKD. VO 2 max was measured using a standardized exercise testing protocol in patients with stage 2 to 4 chronic kidney disease (CKD) (n ϭ 46), in renal transplant recipients (n ϭ 22), in patients treated with maintenance hemodialysis (n ϭ 12), and in age-matched healthy controls (n ϭ 33). VO 2 max was similar between children with stage 2 CKD and controls, whereas lower VO 2 max was observed among children with stage 3 to 4 CKD, those treated with hemodialysis, and transplant recipients. In univariate analysis, VO 2 max was significantly associated with body mass index, resting heart rate, C-reactive protein, serum triglycerides, serum creatinine, and measures of diastolic function; no significant associations with left ventricular structure or systolic function were identified. In multivariate regression analysis, patient category versus control and the presence of diastolic dysfunction were independent predictors of lower VO 2 max. These results suggest that aerobic capacity is decreased in the early stages of CKD in children and that lower VO 2 max can be predicted by the presence of diastolic dysfunction, even if systolic function is normal. Maximal aerobic capacity (VO 2 max) represents the cardiovascularsystem'sabilitytotakeup,distribute,andutilize oxygen to perform work during maximal exercise. Healthy individuals can sustain a three-fold increase in heart rate (HR) and a two-fold increase in stroke volume to generate maximal aerobic capacity. 1 Therefore, VO 2 max has been used to assess the capacity of the cardiovascular system to respond to metabolic challenge in numerous disease states including ESRD. 2,3 Impaired maximal aerobic capacity was observed in adult and adolescent patients with ESRD as well as after renal transplantation. [4][5][6][7] The significance of these findings was underscored by studies suggesting lower survival rates in adults with ESRD and decreased VO 2 max. 8 The impairedVO 2 maxinthesepatientswasassociatedwithseveralfactors,includinglowerserumalbumin,anemia,and chronic heart failure. 9 Symptomatic heart disease is a rare event in pediatric patients with CKD. However abnormal cardiac structure and function in children with CKD is well recognized. These patients have left ventricular (LV) diastolic dysfunction and increased LV mass even before the onset of ESRD. 10,11 LV systolic function is generally preserved at rest, but altered contractile reserve was observed during exercise in di-

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We are developing an artificial lung (AL) as an eventual bridge to lung transplant or recovery. The device is rigidly housed, noncompliant, and has a very low resistance to blood flow. In eight sheep, arterial cannulae were anastomosed end-to-side to the proximal and distal main pulmonary artery, and attached to the AL. A pulmonary artery snare between anastomoses diverted full pulmonary blood flow through the AL. Eight of eight sheep survived the preparation. Mean pressure gradient across the AL was 8 mm Hg (3 Wood units; 8 mm Hg/2.8 L/min). Four of eight sheep tolerated immediate full diversion of blood flow and died at 24 and 40 hours (exsanguination) or 168 and 168 hours (elective sacrifice). Four of eight sheep were intolerant of full flow: two died of right heart failure at <8 hours with full flow through the device (full snare); the other two survived with partial device flow (partial snare), but the device clotted. These two then underwent successful closed-chest cannula thrombectomy and device change-out at 53 and 75 hours, and subsequently tolerated full flow. Long-term (up to 7 day) survival with complete diversion of pulmonary blood flow through a non-compliant, low-resistance AL is possible. Initial right heart failure in this model was 50% (4 of 8).

Percutaneous arteriovenous CO2 removal (AVCO2R) uses a simple arteriovenous (A-V) shunt for near-total CO2 removal that allows significant reductions in minute ventilation. We critically reviewed our algorithm-directed perioperative anesthesia management in our LD40 ovine smoke-burn injury model of acute respiratory distress syndrome (ARDS) treated with AVCO2R. General anesthesia is required for: (1) Vascular access followed by ARDS model development by smoke insufflation (36 breaths) plus 40% TBSA III degrees burn with mechanical ventilation. Induction: 12.5 mg/kg im ketamine and 4% halothane by mask, then intubation. Maintenance: 1.0-2.5% halothane in 100% O2; (2) When PaO2/FiO2 < 200 (48-52 h), sheep randomized to the AVCO2R (n = 8) or SHAM (n = 8) procedure. Induction: 66% N2O and 5% isoflurane in balance O2. Maintenance: 1.5-2.5% isoflurane in 100% O2 for AVCO2R, cannulation (10F carotid artery, 14F jugular vein); (3) Postop, both groups had algorithm-directed ventilator management, identical heparin (ACT > 300 s), fluid, and analgesia management. All sheep met criteria for ARDS, survived anesthesia, and were standing by 0.5-5 h. There were no complications attributable to anesthesia. The absence of anesthesia-related complications allows model development for outcomes studies for ARDS in general and AVCO2R specifically.

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An artificial lung may offer a bridge to recovery or transplant. Utilizing our recently developed paracorporeal artificial lung (PAL) in survival studies in sheep, we critically review our perioperative/anesthetic protocol. Adult Suffolk ewes (n = 15) underwent general anesthesia induced by ketamine (7-15 mg/kg, im) and isoflurane by mask, then intubated and maintained by 4.0-5.0% isoflurane titrated to mean arterial pressure (MAP) 70-110 mm Hg. After a latissimus-sparing thoracotomy and systemic heparinization (200 IU/kg), arterial grafts were anastomosed to the proximal and distal main pulmonary artery in an end-of-graft to side-of-artery fashion. A snare was passed around the pulmonary artery between anastomoses. When the snare was tightened, full pulmonary blood flow was diverted through the cannulae and immediately through the PAL. Perioperative crystalloids included a 500-mL prime, lactated Ringer's (LR) titrated to CVP 5-7 mm Hg, and a heparin infusion (activated clotting time [ACT] 250-300 s). Buprenorphine (0.3 mg im tid) controlled postoperative pain. Hemodynamic parameters, arterial blood gases (ABGs), and ACTs were measured every 6 h. Thirteen of 15 sheep survived the operation and were extubated in less than 20 min. Two groups were studied for up to 7-day survival. Both groups underwent immediate connection to the PAL diverting full pulmonary blood flow. Group 1 (n = 8) underwent immediate connection to a rigidly housed PAL, and 4 of 8 demonstrated immediate right heart failure. In Group 2 a compliance chamber was added to the PAL inflow, and 6 of 7 had stable hemodynamic function for the duration of the study. Incremental improvements in the PAL and our anesthetic and perioperative care have resulted in reliable survival in adult sheep allowing for artificial lung development.

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