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Forced expiratory volume in 1 second (FEV1) from spirometry is the most commonly used parameter to detect early allograft dysfunction after lung transplantation (LTx). There are concerns regarding its sensitivity. Nitrogen‐multiple breath washout (N2‐MBW) is sensitive at detecting early global (lung clearance index [LCI]) and acinar (Sacin) airway inhomogeneity. We investigated whether N2‐MBWindices indicate small airways pathology after LTx in children with stable spirometry. Thirty‐seven children without bronchiolitis obliterans syndrome [BOS]at a median of 1.6 (0.6‐3.0) years after LTx underwent N2‐MBWand spirometry, 28 of those on 2 occasions (≤6 months apart) during clinically stable periods. Additional longitudinal data (11 and 8 measurements, respectively) are provided from 2 patients with BOS. In patients without BOS,LCIand Sacinwere significantly elevated compared with healthy controls. LCIwas abnormal at the 2 test occasions in 81% and 71% of patients, respectively, compared with 30% and 39% of patients with abnormal FEV1/forced vital capacity (FVC). Correlations of LCIwith FEV1/FVC(r = 0.1, P = .4) and FEV1(r = −0.1, P = .6) were poor. N2‐MBWrepresents a sensitive and reproducible tool for the early detection of airways pathology in stable transplant recipients. Moreover, indices were highly elevated in both patients with BOS. Spirometry and LCIshowed poor correlation, indicating distinct and complementary physiologic measures. The authors advocate a greater role for nitrogen multiple breath washout as a diagnostic tool in monitoring pediatric patients after lung transplantation.

Forced expiratory volume in 1 second (FEV1) from spirometry is the most commonly used parameter to detect early allograft dysfunction after lung transplantation (LTx). There are concerns regarding its sensitivity. Nitrogen-multiple breath washout (N2-MBW) is sensitive at detecting early global (lung clearance index [LCI]) and acinar (Sacin) airway inhomogeneity. We investigated whether N2-MBW indices indicate small airways pathology after LTx in children with stable spirometry. Thirty-seven children without bronchiolitis obliterans syndrome [BOS] at a median of 1.6 (0.6-3.0) years after LTx underwent N2-MBW and spirometry, 28 of those on 2 occasions (≤6 months apart) during clinically stable periods. Additional longitudinal data (11 and 8 measurements, respectively) are provided from 2 patients with BOS. In patients without BOS, LCI and Sacinwere significantly elevated compared with healthy controls. LCI was abnormal at the 2 test occasions in 81% and 71% of patients, respectively, compared with 30% and 39% of patients with abnormal FEV1/forced vital capacity (FVC). Correlations of LCI with FEV1/FVC (r= 0.1, P= .4) and FEV1(r= –0.1, P= .6) were poor. N2-MBW represents a sensitive and reproducible tool for the early detection of airways pathology in stable transplant recipients. Moreover, indices were highly elevated in both patients with BOS. Spirometry and LCI showed poor correlation, indicating distinct and complementary physiologic measures.

Regulatory T cells (Treg) can regulate alloantigens and may counteract chronic lung allograft dysfunction (CLAD) in lung transplantation. We analyzed Treg in peripheral blood prospectively and correlated percentages of subpopulations with the incidence of CLADat 2 years. Among lung‐transplanted patients between January 2009 and July 2011, only patients with sufficient Treg measurements were included into the study. Tregs were measured immediately before lung transplantation, at 3 weeks and 3, 6, 12, and 24 months after transplantation and were defined as CD4+CD25highT cells and further analyzed for CTLA4, CD127, FoxP3, and IL‐2 expressions. Between January 2009 and July 2011, 264 patients were transplanted at our institution. Among the 138 (52%) patients included into the study, 31 (22%) developed CLADwithin 2 years after transplantation. As soon as 3 weeks after lung transplantation, a statistically significant positive association was detected between Treg frequencies and later absence of CLAD. At the multivariate analysis, increasing frequencies of CD4+CD25highCD127low, CD4+CD25highFoxP3+and CD4+CD25highIL‐2+T cells at 3 weeks after lung transplantation emerged as protective factors against development of CLADat 2 years. In conclusion, higher frequencies of specific Treg subpopulations early after lung transplantation are protective against CLADdevelopment. Salman and colleagues explore the relationship between the frequencies of T regulatory cell subpopulations and the development of chronic lung allograft dysfunction after lung transplantation and demonstrate an association between higher CD4+CD25highCD127low, FoxP3+, and IL‐2+T cell frequencies early after lung transplantation and less chronic lung allograft dysfunction at two years.

Regulatory T cells (Treg) can regulate alloantigens and may counteract chronic lung allograft dysfunction (CLAD) in lung transplantation. We analyzed Treg in peripheral blood prospectively and correlated percentages of subpopulations with the incidence of CLAD at 2 years. Among lung-transplanted patients between January 2009 and July 2011, only patients with sufficient Treg measurements were included into the study. Tregs were measured immediately before lung transplantation, at 3 weeks and 3, 6, 12, and 24 months after transplantation and were defined as CD4+CD25highT cells and further analyzed for CTLA4, CD127, FoxP3, and IL-2 expressions. Between January 2009 and July 2011, 264 patients were transplanted at our institution. Among the 138 (52%) patients included into the study, 31 (22%) developed CLAD within 2 years after transplantation. As soon as 3 weeks after lung transplantation, a statistically significant positive association was detected between Treg frequencies and later absence of CLAD. At the multivariate analysis, increasing frequencies of CD4+CD25highCD127low, CD4+CD25highFoxP3+and CD4+CD25highIL-2+T cells at 3 weeks after lung transplantation emerged as protective factors against development of CLAD at 2 years. In conclusion, higher frequencies of specific Treg subpopulations early after lung transplantation are protective against CLAD development.

Experimentally, regulatory T cells inhibit rejection. In clinical transplantations, however, it is not known whether T cell regulation is the cause for, or an epiphenomenon of, long‐term allograft survival. Here, we study naïve and alloantigen‐primed T cell responses of clinical lung transplant recipients in humanized mice. The pericardiophrenic artery procured from human lung grafts was implanted into the aorta of NODrag−/−/IL‐2rγc−/−mice reconstituted with peripheral blood mononuclear cells (PBMCs)from the respective lung recipient. Naïve or primed allogeneic PBMCsprocured 21 days post–lung transplantation with or without enriching for CD4+CD25highT cells were used. Transplant arteriosclerosis was assessed 28 days later by histology. Mice reconstituted with alloantigen‐primed PBMCsshowed significantly more severe transplant arteriosclerosis than did mice with naïve PBMCs(p = 0.005). Transplant arteriosclerosis was equally suppressed by enriching for autologous naïve (p = 0.012) or alloantigen‐primed regulatory T cells (Tregs) (p = 0.009). Alloantigen priming in clinical lung recipients can be adoptively transferred into a humanized mouse model. Transplant arteriosclerosis elicited by naïve or alloantigen‐primed PBMCscan be similarly controlled by potent autologous Tregs. Cellular therapy with expanded autologous Tregs in lung transplantation might be a promising future strategy. Naïve leukocytes from lung transplant recipients carry a strong alloreactive function that further increases following three weeks posttransplant in vivopriming, but this alloreactivity could be fully suppressed by higher autologous regulatory T cell numbers.

The role of mammalian target of rapamycin (mTOR)inhibitors in de novoimmunosuppression after lung transplantation is not well defined. We compared Everolimus versus mycophenolate mofetil in an investigator‐initiated single‐center trial in Hannover, Germany. A total of 190 patients were randomly assigned 1:1 on day 28 posttransplantation to mycophenolate mofetil (MMF)or Everolimus combined with cyclosporine A (CsA) and steroids. Patients were followed up for 2 years. The primary endpoint was freedom from bronchiolitis obliterans syndrome (BOS). The secondary endpoints were incidence of acute rejections, infections, treatment failure and kidney function. BOS‐free survival in intention‐to‐treat (ITT)analysis was similar in both groups (p = 0.174). The study protocol was completed by 51% of enrolled patients. The per‐protocol analysis shows incidence of bronchiolitis obliterans syndrome (BOS): 1/43 in the Everolimus group and 8/54 in the MMFgroup (p = 0.041). Less biopsy‐proven acute rejection (AR)(p = 0.005), cytomegalovirus (CMV)antigenemia (p = 0.005) and lower respiratory tract infection (p = 0.003) and no leucopenia were seen in the Everolimus group. The glomerular filtration rate (GFR)decreased in both groups about 50% within 6 months. Due to a high withdrawal rate, the study was underpowered to prove a difference in BOS‐free survival. The dropout rate was more pronounced in the Everolimus group. Secondary endpoints indicate potential advantages of Everolimus‐based protocols but also a potentially higher rate of drug‐related serious adverse events. Everolimus and mycophenolate mofetil have different adverse event profiles when used in de novolung transplantation.

The role of mammalian target of rapamycin (mTOR) inhibitors in de novoimmunosuppression after lung transplantation is not well defined. We compared Everolimus versus mycophenolate mofetil in an investigator-initiated single-center trial in Hannover, Germany. A total of 190 patients were randomly assigned 1:1 on day 28 posttransplantation to mycophenolate mofetil (MMF) or Everolimus combined with cyclosporine A (CsA) and steroids. Patients were followed up for 2 years. The primary endpoint was freedom from bronchiolitis obliterans syndrome (BOS). The secondary endpoints were incidence of acute rejections, infections, treatment failure and kidney function. BOS-free survival in intention-to-treat (ITT) analysis was similar in both groups (p = 0.174). The study protocol was completed by 51% of enrolled patients. The per-protocol analysis shows incidence of bronchiolitis obliterans syndrome (BOS): 1/43 in the Everolimus group and 8/54 in the MMF group (p = 0.041). Less biopsy-proven acute rejection (AR) (p = 0.005), cytomegalovirus (CMV) antigenemia (p = 0.005) and lower respiratory tract infection (p = 0.003) and no leucopenia were seen in the Everolimus group. The glomerular filtration rate (GFR) decreased in both groups about 50% within 6 months. Due to a high withdrawal rate, the study was underpowered to prove a difference in BOS-free survival. The dropout rate was more pronounced in the Everolimus group. Secondary endpoints indicate potential advantages of Everolimus-based protocols but also a potentially higher rate of drug-related serious adverse events.

Experimentally, regulatory T cells inhibit rejection. In clinical transplantations, however, it is not known whether T cell regulation is the cause for, or an epiphenomenon of, long-term allograft survival. Here, we study naïve and alloantigen-primed T cell responses of clinical lung transplant recipients in humanized mice. The pericardiophrenic artery procured from human lung grafts was implanted into the aorta of NODrag−/−/IL-2rγc−/−mice reconstituted with peripheral blood mononuclear cells (PBMCs) from the respective lung recipient. Naïve or primed allogeneic PBMCs procured 21 days post–lung transplantation with or without enriching for CD4+CD25highT cells were used. Transplant arteriosclerosis was assessed 28 days later by histology. Mice reconstituted with alloantigen-primed PBMCs showed significantly more severe transplant arteriosclerosis than did mice with naïve PBMCs (p = 0.005). Transplant arteriosclerosis was equally suppressed by enriching for autologous naïve (p = 0.012) or alloantigen-primed regulatory T cells (Tregs) (p = 0.009). Alloantigen priming in clinical lung recipients can be adoptively transferred into a humanized mouse model. Transplant arteriosclerosis elicited by naïve or alloantigen-primed PBMCs can be similarly controlled by potent autologous Tregs. Cellular therapy with expanded autologous Tregs in lung transplantation might be a promising future strategy.

Donor alloantigen infusion induces T cell regulation and transplant tolerance in small animals. Here, we study donor splenocyte infusion in a large animal model of pulmonary transplantation. Major histocompatibility complex–mismatched single lung transplantation was performed in 28 minipigs followed by a 28‐day course of methylprednisolone and tacrolimus. Some animals received a perioperative donor or third party splenocyte infusion, with or without low‐dose irradiation (IRR) before surgery. Graft survival was significantly prolonged in animals receiving both donor splenocytes and IRR compared with controls with either donor splenocytes or IRR only. In animals with donor splenocytes and IRR, increased donor cell chimerism and CD4+CD25high+T cell frequencies were detected in peripheral blood associated with decreased interferon‐γ production of leukocytes. Secondary third‐party kidney transplants more than 2 years after pulmonary transplantation were acutely rejected despite maintained tolerance of the lung allografts. As a cellular control, additional animals received third‐party splenocytes or donor splenocyte protein extracts. While animals treated with third‐party splenocytes showed significant graft survival prolongation, the subcellular antigen infusion showed no such effect. In conclusion, minipigs conditioned with preoperative IRR and donor, or third‐party, splenocyte infusions may develop long‐term donor‐specific pulmonary allograft survival in the presence of high levels of circulating regulatory T cells. Early leukocyte chimerism increases with donor spleen cell infusion following low‐dose recipient irradiation in an outbred miniature swine lung transplantation model, resulting in long‐term lung allograft survival but preserved immune competence versus delayed third‐party kidney allografts.

This single‐center study examines the incidence, etiology, and outcomes associated with prolonged mechanical ventilation (PMV), defined as time to definite spontaneous ventilation >21 days after double lung transplantation (LTx). A total of 690 LTx recipients between January 2005 and December 2012 were analyzed. PMVwas necessary in 95 (13.8%) patients with decreasing incidence during the observation period (p < 0.001). Independent predictors of PMVwere renal replacement therapy (odds ratio [OR] 11.13 [95% CI, 5.82–21.29], p < 0.001), anastomotic dehiscence (OR8.74 [95% CI2.42–31.58], p = 0.001), autoimmune comorbidity (OR5.52 [95% CI1.86–16.41], p = 0.002), and postoperative neurologic complications (OR5.03 [95% CI1.98–12.81], p = 0.001), among others. Overall 1‐year survival was 86.0% (90.4% for LTx between 2010 and 2012); it was 60.7% after PMVand 90.0% in controls (p < 0.001). Conditional long‐term outcome among hospital survivors, however, did not differ between the groups (p = 0.78). Multivariate analysis identified renal replacement therapy (hazard ratio [HR] 3.55 [95% CI2.40–5.25], p < 0.001), post‐LTx extracorporeal membrane oxygenation (HR3.47 [95% CI2.06–5.83], p < 0.001), and prolonged inotropic support (HR1.95 [95% CI1.39–2.75], p < 0.001), among others, as independent predictors of mortality. In conclusion, PMVcomplicated 14% of LTx procedures and, although associated with increased in‐hospital mortality, outcomes among patients surviving to hospital discharge were unaffected. This retrospective analysis of double lung transplant recipients shows that postoperative prolonged mechanical ventilation develops in every seventh patient, is associated with increased in‐hospital mortality, but does not affect outcomes among patients surviving to hospital discharge.

Donor alloantigen infusion induces T cell regulation and transplant tolerance in small animals. Here, we study donor splenocyte infusion in a large animal model of pulmonary transplantation. Major histocompatibility complex–mismatched single lung transplantation was performed in 28 minipigs followed by a 28-day course of methylprednisolone and tacrolimus. Some animals received a perioperative donor or third party splenocyte infusion, with or without low-dose irradiation (IRR) before surgery. Graft survival was significantly prolonged in animals receiving both donor splenocytes and IRR compared with controls with either donor splenocytes or IRR only. In animals with donor splenocytes and IRR, increased donor cell chimerism and CD4+CD25high+T cell frequencies were detected in peripheral blood associated with decreased interferon-γ production of leukocytes. Secondary third-party kidney transplants more than 2 years after pulmonary transplantation were acutely rejected despite maintained tolerance of the lung allografts. As a cellular control, additional animals received third-party splenocytes or donor splenocyte protein extracts. While animals treated with third-party splenocytes showed significant graft survival prolongation, the subcellular antigen infusion showed no such effect. In conclusion, minipigs conditioned with preoperative IRR and donor, or third-party, splenocyte infusions may develop long-term donor-specific pulmonary allograft survival in the presence of high levels of circulating regulatory T cells.

This single-center study examines the incidence, etiology, and outcomes associated with prolonged mechanical ventilation (PMV), defined as time to definite spontaneous ventilation >21 days after double lung transplantation (LTx). A total of 690 LTx recipients between January 2005 and December 2012 were analyzed. PMV was necessary in 95 (13.8%) patients with decreasing incidence during the observation period (p < 0.001). Independent predictors of PMV were renal replacement therapy (odds ratio [OR] 11.13 [95% CI, 5.82–21.29], p < 0.001), anastomotic dehiscence (OR 8.74 [95% CI 2.42–31.58], p = 0.001), autoimmune comorbidity (OR 5.52 [95% CI 1.86–16.41], p = 0.002), and postoperative neurologic complications (OR 5.03 [95% CI 1.98–12.81], p = 0.001), among others. Overall 1-year survival was 86.0% (90.4% for LTx between 2010 and 2012); it was 60.7% after PMV and 90.0% in controls (p < 0.001). Conditional long-term outcome among hospital survivors, however, did not differ between the groups (p = 0.78). Multivariate analysis identified renal replacement therapy (hazard ratio [HR] 3.55 [95% CI 2.40–5.25], p < 0.001), post-LTx extracorporeal membrane oxygenation (HR 3.47 [95% CI 2.06–5.83], p < 0.001), and prolonged inotropic support (HR 1.95 [95% CI 1.39–2.75], p < 0.001), among others, as independent predictors of mortality. In conclusion, PMV complicated 14% of LTx procedures and, although associated with increased in-hospital mortality, outcomes among patients surviving to hospital discharge were unaffected.

Scarcity of donors leads transplant surgeons to consider extended-criteria lungs and occasionally to accept the unlikely. Here we report a case of successful single lung transplantation from a donor 8 months after double lung transplantation.

Scarcity of donors leads transplant surgeons to consider extended‐criteria lungs and occasionally to accept the unlikely. Here we report a case of successful single lung transplantation from a donor 8 months after double lung transplantation. A lung transplant recipient is declared brain dead following intracranial bleeding and her right donor lung successfully retransplanted.

Chronic lung allograft dysfunction (CLAD) remains a major problem after lung transplantation with no definitive treatment except redo lung transplantation (re‐LTx) in selected candidates. However, CLAD is not a homogeneous entity and different phenotypes exist. Therefore, we aimed to evaluate the effect of CLAD phenotypes on survival after re‐LTx for CLAD. Patients who underwent re‐LTx for respiratory failure secondary to CLAD in four LTx centers between 2003 and 2013 were included in this retrospective analysis. Bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD) were distinguished using pulmonary function, radiology and explant lung histopathology. Patient variables pre‐ and post‐re‐LTx were collected and analyzed. A total of 143 patients underwent re‐LTx for CLAD resulting in 94 BOS (66%) and 49 rCLAD (34%) patients. Unadjusted and adjusted survival after re‐LTx for rCLAD was worse compared to BOS (HR = 2.60, 1.59–4.24; p < 0.0001 and HR = 2.61, 1.51–4.51; p = 0.0006, respectively). Patients waiting at home prior to re‐LTx experienced better survival compared to hospitalized patients (HR 0.40; 0.23–0.72; p = 0.0022). Patients with rCLAD redeveloped CLAD earlier and were more likely to redevelop rCLAD. Survival after re‐LTx for rCLAD is worse compared to BOS. Consequently, re‐LTx for rCLAD should be critically discussed, particularly when additional peri‐operative risk factors are present. Retransplantation for restrictive chronic lung allograft dysfunction is associated with worse outcome compared to bronchiolitis obliterans syndrome.

Chronic lung allograft dysfunction (CLAD) remains a major problem after lung transplantation with no definitive treatment except redo lung transplantation (re-LTx) in selected candidates. However, CLAD is not a homogeneous entity and different phenotypes exist. Therefore, we aimed to evaluate the effect of CLAD phenotypes on survival after re-LTx for CLAD. Patients who underwent re-LTx for respiratory failure secondary to CLAD in four LTx centers between 2003 and 2013 were included in this retrospective analysis. Bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD) were distinguished using pulmonary function, radiology and explant lung histopathology. Patient variables pre- and post-re-LTx were collected and analyzed. A total of 143 patients underwent re-LTx for CLAD resulting in 94 BOS (66%) and 49 rCLAD (34%) patients. Unadjusted and adjusted survival after re-LTx for rCLAD was worse compared to BOS (HR = 2.60, 1.59–4.24; p < 0.0001 and HR = 2.61, 1.51–4.51; p = 0.0006, respectively). Patients waiting at home prior to re-LTx experienced better survival compared to hospitalized patients (HR 0.40; 0.23–0.72; p = 0.0022). Patients with rCLAD redeveloped CLAD earlier and were more likely to redevelop rCLAD. Survival after re-LTx for rCLAD is worse compared to BOS. Consequently, re-LTx for rCLAD should be critically discussed, particularly when additional peri-operative risk factors are present.

Airway stenosis represents the commonest airway complication following lung transplantation, affecting between 7% and 18% of patients. Existing treatment options offer limited efficacy and can cause additional patient morbidity. Paclitaxel-coated balloons (PCB) have proved effective in managing postinterventional coronary artery re-stenosis. In a first-in-man study, we evaluated similar PCBs in refractory nonanastomotic airway stenosis in 12 patients. Following a single application, luminal patency was maintained in 50% at 270 days. No significant peri-interventional or early postinterventional complications occurred. Given these encouraging initial findings, further studies appear warranted.

Chronic lung allograft dysfunction (CLAD) remains the leading cause of mortality in lung transplant recipients after the first year. Treatment remains limited and unpredictable. Existing data suggests extracorporeal photopheresis (ECP) may be beneficial. This study aimed to identify factors predicting treatment response and the prognostic implications. A single center retrospective analysis of all patients commencing ECP for CLAD between November 1, 2007 and September 1, 2011 was performed. In total 65 patients were included, 64 of whom had deteriorated under azithromycin. Median follow‐up after commencing ECP was 503 days. Upon commencing ECP, all patients were classified using proposed criteria for emerging clinical phenotypes, including “restrictive allograft syndrome (RAS)”, “neutrophilic CLAD (nCLAD)” and “rapid decliners”. At follow‐up, 8 patients demonstrated ≥10% improvement in FEV1, 27 patients had stabilized and 30 patients exhibited ≥10% decline in FEV1. Patients fulfilling criteria for “rapid decliners” (n = 21, p = 0.005), RAS (n = 22, p = 0.002) and those not exhibiting neutrophilia in bronchoalveolar lavage (n = 44, p = 0.01) exhibited poorer outcomes. ECP appears an effective second line treatment in CLAD patients progressing under azithromycin. ECP responders demonstrated improved progression‐free survival (median 401 vs. 133 days). Proposed CLAD phenotypes require refinement, but appear to predict the likelihood of ECP response.

Chronic lung allograft dysfunction (CLAD) remains the leading cause of mortality in lung transplant recipients after the first year. Treatment remains limited and unpredictable. Existing data suggests extracorporeal photopheresis (ECP) may be beneficial. This study aimed to identify factors predicting treatment response and the prognostic implications. A single center retrospective analysis of all patients commencing ECP for CLAD between November 1, 2007 and September 1, 2011 was performed. In total 65 patients were included, 64 of whom had deteriorated under azithromycin. Median follow-up after commencing ECP was 503 days. Upon commencing ECP, all patients were classified using proposed criteria for emerging clinical phenotypes, including “restrictive allograft syndrome (RAS)”, “neutrophilic CLAD (nCLAD)” and “rapid decliners”. At follow-up, 8 patients demonstrated ≥10% improvement in FEV1, 27 patients had stabilized and 30 patients exhibited ≥10% decline in FEV1. Patients fulfilling criteria for “rapid decliners” (n = 21, p = 0.005), RAS (n = 22, p = 0.002) and those not exhibiting neutrophilia in bronchoalveolar lavage (n = 44, p = 0.01) exhibited poorer outcomes. ECP appears an effective second line treatment in CLAD patients progressing under azithromycin. ECP responders demonstrated improved progression-free survival (median 401 vs. 133 days). Proposed CLAD phenotypes require refinement, but appear to predict the likelihood of ECP response.

We report on the use of veno‐arterial extracorporeal membrane oxygenation (ECMO) as a bridging strategy to lung transplantation in awake and spontaneously breathing patients. All five patients described in this series presented with cardiopulmonary failure due to pulmonary hypertension with or without concomitant lung disease. ECMO insertion was performed under local anesthesia without sedation and resulted in immediate stabilization of hemodynamics and gas exchange as well as recovery from secondary organ dysfunction. Two patients later required endotracheal intubation because of bleeding complications and both of them eventually died. The other three patients remained awake on ECMO support for 18–35 days until the time of transplantation. These patients were able to breathe spontaneously, to eat and drink, and they received passive and active physiotherapy as well as psychological support. All of them made a full recovery after transplantation, which demonstrates the feasibility of using ECMO support in nonintubated patients with cardiopulmonary failure as a bridging strategy to lung transplantation.

We report on the use of veno‐arterial extracorporeal membrane oxygenation (ECMO) as a bridging strategy to lung transplantation in awake and spontaneously breathing patients. All five patients described in this series presented with cardiopulmonary failure due to pulmonary hypertension with or without concomitant lung disease. ECMO insertion was performed under local anesthesia without sedation and resulted in immediate stabilization of hemodynamics and gas exchange as well as recovery from secondary organ dysfunction. Two patients later required endotracheal intubation because of bleeding complications and both of them eventually died. The other three patients remained awake on ECMO support for 18–35 days until the time of transplantation. These patients were able to breathe spontaneously, to eat and drink, and they received passive and active physiotherapy as well as psychological support. All of them made a full recovery after transplantation, which demonstrates the feasibility of using ECMO support in nonintubated patients with cardiopulmonary failure as a bridging strategy to lung transplantation.

We study Ca2+release through single and clustered IP3receptor channels on the ER membrane under presence of buffer proteins. Our computational scheme couples reaction-diffusion equations and a Markovian channel model and allows our investigating the effects of buffer proteins on local calcium concentrations and channel gating. We find transient and stationary elevations of calcium concentrations around active channels and show how they determine release amplitude. Transient calcium domains occur after closing of isolated channels and constitute an important part of the channel's feedback. They cause repeated openings (bursts) and mediate increased release due to Ca2+buffering by immobile proteins. Stationary domains occur during prolonged activity of clustered channels, where the spatial proximity of IP3Rs produces a distinct [Ca2+] scale (0.5–10 μM), which is smaller than channel pore concentrations (100 μM) but larger than transient levels. While immobile buffer affects transient levels only, mobile buffers in general reduce both transient and stationary domains, giving rise to Ca2+evacuation and biphasic modulation of release amplitude. Our findings explain recent experiments in oocytes and provide a general framework for the understanding of calcium signals.

Intracellular Ca2+release is a versatile second messenger system. It is modeled here by reaction-diffusion equations for the free Ca2+and Ca2+buffers, with spatially discrete clusters of stochastic IP3receptor channels (IP3Rs) controlling the release of Ca2+from the endoplasmic reticulum. IP3Rs are activated by a small rise of the cytosolic Ca2+concentration and inhibited by large concentrations. Buffering of cytosolic Ca2+shapes global Ca2+transients. Here we use a model to investigate the effect of buffers with slow and fast reaction rates on single release spikes. We find that, depending on their diffusion coefficient, fast buffers can either decouple clusters or delay inhibition. Slow buffers have little effect on Ca2+release, but affect the time course of the signals from the fluorescent Ca2+indicator mainly by competing for Ca2+. At low [IP3], fast buffers suppress fluorescence signals, slow buffers increase the contrast between bulk signals and signals at open clusters, and large concentrations of buffers, either fast or slow, decouple clusters.

We describe a novel technique of pumpless extracorporeal life support in four patients with cardiogenic shock due to end-stage pulmonary hypertension (PH) including patients with veno-occlusive disease (PVOD) using a pumpless lung assist device (LAD). The device was connected via the pulmonary arterial main trunk and the left atrium, thereby creating a septostomy-like shunt with the unique addition of gas exchange abilities in parallel to the lung. Using this approach, all four patients were successfully bridged to bilateral lung transplantation and combined heart-lung transplantation, respectively. Although all patients presented in cardiogenic shock, hemodynamic unloading of the right ventricle using the low-resistance LAD stabilized the hemodynamic situation immediately so that no pump support was subsequently required.

We describe a novel technique of pumpless extracorporeal life support in four patients with cardiogenic shock due to end-stage pulmonary hypertension (PH) including patients with veno-occlusive disease (PVOD) using a pumpless lung assist device (LAD). The device was connected via the pulmonary arterial main trunk and the left atrium, thereby creating a septostomy-like shunt with the unique addition of gas exchange abilities in parallel to the lung. Using this approach, all four patients were successfully bridged to bilateral lung transplantation and combined heart–lung transplantation, respectively. Although all patients presented in cardiogenic shock, hemodynamic unloading of the right ventricle using the low-resistance LAD stabilized the hemodynamic situation immediately so that no pump support was subsequently required.

Intracellular calcium release is a prime example for the role of stochastic effects in cellular systems. Recent models consist of deterministic reaction-diffusion equations coupled to stochastic transitions of calcium channels. The resulting dynamics is of multiple time and spatial scales, which complicates far-reaching computer simulations. In this article, we introduce a novel hybrid scheme that is especially tailored to accurately trace events with essential stochastic variations, while deterministic concentration variables are efficiently and accurately traced at the same time. We use finite elements to efficiently resolve the extreme spatial gradients of concentration variables close to a channel. We describe the algorithmic approach and we demonstrate its efficiency compared to conventional methods. Our single-channel model matches experimental data and results in intriguing dynamics if calcium is used as charge carrier. Random openings of the channel accumulate in bursts of calcium blips that may be central for the understanding of cellular calcium dynamics.

Objectives: Intramyocardial transplantation of bone marrow-derived cells is currently under clinical evaluation as a therapy of heart failure. A major limitation of all clinical studies dealing with myocardial cell engraftment is the inability to track the fate of the transplanted cells. We present a clinically applicable technique using transesophageal echocardiography (TEE) of CliniMACS nanoparticle labeled transplanted CD133^+ cells in ischemic hearts. Methods and Results: CD133^+ cells were isolated from human bone marrow by CliniMACS magnetic bead selection. Positive (5 x 10^6 cells) cells were transplanted into porcine ischemic myocardium (n = 6). Control animals (n = 5) received medium injection. TEE was performed to demonstrate the distribution of the cells during and 8 weeks after the procedure. Accumulations of labeled CD133^+ cells of adjacent injections in the myocardium were discriminatively identified by TEE. Conclusions: TEE is an elegant method for real-time documentation of successful transplantation and cell colony localization of magnetically labeled CD133^+ cells in the ischemic myocardium. Our method should be of special interest for TEE-guided transcatheter injection of cells.

This paper presents the concept of superabrasive electroplated grinding wheels based on defined grain structures. The aim is to improve process stability, minimize heat generation and achieve a high surface quality while preserving a high material removal rate. Based on geometrical models, different patterns of grit settings have been investigated by means of kinematic simulation. Applying the results of the simulation, a prototype grinding wheel with an optimized defined grain structure has been constructed. The performance potential of the prototype has been analyzed through experimental examinations.

The aim of this paper is a derivation of a new multidimensional high-resolution finite volume evolution Galerkin method for system of the Euler equations of gas dynamics. Instead of solving one-dimensional Riemann problems in directions normal to cell interfaces the finite volume evolution Galerkin schemes are based on a genuinely multidimensional approach. The approximate solution at cell interfaces is computed by means of an approximate evolution operator taking all of the infinitely many bicharacteristics explicitly into account. Integrals along the Mach cones are evaluated exactly or by means of numerical quadratures. Second-order resolution is obtained with a conservative piecewise bilinear recovery and the second-order midpoint rule for the time integration. A numerical experiment which illustrates the good multidimensional approximation as well as higher-order resolution is presented. Copyright © 2002 John Wiley & Sons, Ltd.

The aim of this paper is a derivation of a new multidimensional high‐resolution finite volume evolution Galerkin method for system of the Euler equations of gas dynamics. Instead of solving one‐dimensional Riemann problems in directions normal to cell interfaces the finite volume evolution Galerkin schemes are based on a genuinely multidimensional approach. The approximate solution at cell interfaces is computed by means of an approximate evolution operator taking all of the infinitely many bicharacteristics explicitly into account. Integrals along the Mach cones are evaluated exactly or by means of numerical quadratures. Second‐order resolution is obtained with a conservative piecewise bilinear recovery and the second‐order midpoint rule for the time integration. A numerical experiment which illustrates the good multidimensional approximation as well as higher‐order resolution is presented. Copyright © 2002 John Wiley & Sons, Ltd.

A new material model for describing the thermo-viscoplastic flow behavior of workpiece material in metal cutting is presented. In order to express the complex flow behavior which depends on the local strain, strain rate and temperature, a new methodology for sequential formulation is proposed. The material parameters which are achieved by using the flow stress data available at low strain rates are enhanced by matching the results of the experimental investigations and finite element simulations of the orthogonal cutting process. As a result, a material model which has a wide validity range of strain, strain rate and temperature is established.

Myocardial injury from ischemia can be augmented after reperfusion due to proinflammatory events including complement activation, leukocyte adhesion, and release of various chemical mediators. It has been shown that intracoronary administration of a C1 esterase inhibitor (C1 INH) significantly reduces myocardial necrosis in an experimental model of ischemia. Our study addresses the question whether the most susceptible region of the heart for ischemic injury, the right ventricle (RV), can benefit from the protective effects of C1 esterase inhibition after transplantation.

Abstract.: The global error of numerical approximations for symmetric positive systems in the sense of Friedrichs is decomposed into a locally created part and a propagating component. Residual-based two-sided local a posteriori error bounds are derived for the locally created part of the global error. These suggest taking the -norm as well as weaker, dual norms of the computable residual as local error indicators. The dual graph norm of the residual is further bounded from above and below in terms of the norm of where h is the local mesh size. The theoretical results are illustrated by a series of numerical experiments.

Two types of hybrids between cells with erythroid phenotype (Friend cells) and teratocarcinoma cells can be distinguished: cell hybrids with an erythroid phenotype, which release or can be induced to release large amounts of Friend spleen focus-forming virus (F-SFFV) on exposure to bromodeoxyuridine and cell hybrids with a teratocarcinoma phenotype, which do not release Friend virus and are not inducible for F-SFFV release. In this paper, we attempted to relate these differences to the expression of F-SFFV and Friend murine leukemia virus (F-MuLV) functions. Teratocarcinoma phenotype hybrids retained F-SFFV-and F-MuLV-related provirus sequences. They did not express F-SFFV- or F-MuLV-related RNA or proteins. The hybrids differentiated to endoderm-like cells on exposure to retinoic acid or hexamethylene-bis -acetamide. These cells, in contrast to the teratocarcinoma phenotype (uninduced) cells expressing SSEA-1-like antigens, did not express SSEA-1-like antigens; they formed typical, prekeratin-staining cytoskeletal structures and could be induced to release mouse interferon. The differentiating cells, but not the uninduced teratocarcinoma hybrids, were infected productively with F-MuLV or the F-MuLV--F-SFFV complex. They, however, did not express endogenous F-SFFV. Endogenous F-SFFV functions could not be rescued by infection with F-MuLV. Induction of teratocarcinoma hybrids with retinoic acid did not activate endogenous F-MuLV or F-SFFV transcription or protein synthesis. These data demonstrated two control mechanisms of Friend virus repression: one which acted trans during formation of the cell hybrids and was maintained only in teratocarcinoma phenotype cells and the other which acted cis and was still operative during induction of endodermal differentiation.

The operational properties and the performance of components consisting of advanced ceramic materials, for example silicon carbide and silicon nitride, are mainly influenced by processing technology and process conditions. In grinding operations grain engagement and process kinematics determine the resulting surface topography as well as the degree of potential rim defects. The modelling of grain engagement and the computation of uncut chip thickness describe suitable ranges for process parameters resulting in minimized subsurface damages of the ceramic part. By means of single grain diamond scratch tests the limiting uncut chip thickness at the transition between plastic deformation of workpiece material and the occurrence of brittle microchippings during chip removal is evaluated. Based on theoretical models and experimental investigations a contribution to practical applications in grinding of advanced ceramics is explained.

Over the past 20 years the maximum cross-correlation method has been employed both operationally and for research in geophysical sciences. Some weaknesses of the well-understood and established technique have remained, which suggest that a non statistical approach is required to overcome these deficiencies. Presently a new functional analytic approach is adopted from computer vision to derive displacement vector fields from satellite image sequences. Case studies of artificially created images with defined motion patterns as well as displacement vector fields derived from Meteosat water vapour pictures and NOAA-AVHRR sea surface temperature pictures reveal the applicability of the method. Due to the basic constraints, the method is particularly suitable for fuzzy greyvalue structures. Nevertheless, modifications concerning the atmospheric and oceanographic kinematics are still required to allow also strong shear flow to be accounted for.

Stochastic and non-deterministic influences have an effect on cutting processes and lead to an unsteady and dynamic process behaviour. Concepts for the improvement of process reliability and for the control of tolerances have to be developed in order to fulfil the increasing requirements on product quality. A concept for the improvement of manufacturing accuracy through artificial neural networks (ANN) will be presented as an example for the turning process. This ANN model makes it possible to predict the dimensional deviation caused by tool wear. Feeding this back in an open loop within the machine controller the deviation can be compensated by using an adaptive control of the depth of cut.

In grinding of hard and brittle materials such as advanced ceramics or hard metal, process behavior and work result are closely connected with material removal mechanisms. Material removal mechanisms are determined by complex interactions between material properties, geometry of the grits, the kinematics of grit engagements and the mechanical and thermal loads acting on workpiece and tool due to energy transformation in the grinding process. Experimental investigations of surface grinding processes show that material removal mechanisms are also influenced by dynamic conditions in the contact zone. These dynamic conditions, that are not chatter vibrations, can have both a positive and negative influence on surface quality, process forces and wear of the grinding wheel. For a given machine tool and workpiece the dynamic contact zone conditions can be optimized by the dynamic properties of the hub of the grinding wheel. For analyzing the dynamic contact zone conditions based on the behavior of the grinding wheel the finite element method is used. By means of these analyses the dynamic properties of grinding wheels can be adapted to meet the requirements of a determined grinding process with regard to tool wear, surface roughness of the workpiece and process forces.

In grinding technology, the application of superabrasives and increasing demands for higher productivity and higher quality require an appropriate selection of optimum set-up parameters. Therefore, the development of analytical or empirical models for reliable prediction of machining performance and work results is a key issue. This paper presents a comprehensive concept for process modeling which provides a software tool for analyzing and designing high performance grinding processes, using the method of kinematic simulation. On the basis of synthetic 3D-models describing the macro- and micro-geometry of the grinding wheel and the workpiece, together with mathematical models describing the relative motions and kinematic engagement conditions, grinding processes can be reproduced as the cumulation of multiple grit engagements. The proposed simulation tool allows the generation of optional grinding wheel topographies and the analysis and prediction of the machining performance and work result for different grinding techniques, taking into account thermo-mechanical and dynamic effects in the contact area.

Summary.: An adaptive finite element method for the calculation of transonic potential flows was developed. An error indicator based on first order finite differences of gradients is introduced as a local error estimator. It measures second order distributional derivatives. Estimates involving this error estimator, a residual and the error are given. The error estimator can be used as a criterion for mesh refinement. We also give some computational results.