Recovery Of Organ Function Research Articles

Self-reported Depressive Symptoms and Memory Complaints in Survivors Five Years After ARDS

Survivors of ARDS report depressive symptoms and memory complaints, the prevalence of which after 5 years is unknown. We administered instruments assessing symptoms of depression (Beck Depression Inventory II [BDI-II]) and memory complaints (Memory Assessment Clinics Self-Rating Scale [MAC-S]) to 64 survivors of ARDS from four university-affiliated ICUs 5 years after ICU discharge. We compared BDI-II scores to quality of life (Medical Outcomes Study 36-Item Short Form [SF-36]) mental health domains (role emotional, mental health, mental component summary), compared BDI-II and MAC-S scores to earlier scores (median, 22 months postdischarge), and examined return to work. Forty-three (67.2%), 46 (71.9%), and 38 (59.4%) patients fully completed the BDI-II, MAC-S ability subscale, and MAC-S frequency of occurrence subscale, respectively. Responders were young (median, 48 years; first-third quartile [Q1-Q3], 39-61 years) with high illness severity. The median BDI-II score was 10 (Q1-Q3, 3-18); eight of 43 (18.6%) had moderate to severe depressive symptoms compared with 14 of 43 (32.6%) earlier (P = .15, n = 38 with paired data). Median MAC-S ability and MAC-S frequency scores were 81 (Q1-Q3, 57-92) and 91.5 (Q1-Q3, 76-105), respectively, similar to earlier scores (P = .67 and P = .64, respectively); 0% to 4.3% scored > 2 SDs below population norms. Higher BDI-II score was predicted by higher earlier BDI-II score, slower recovery of organ function, and longer duration of mechanical ventilation and ICU stay. Higher MAC-S score was predicted by higher earlier MAC-S score. SF-36 mental health domain scores were very stable (P = .57-.83). BDI-II and SF-36 mental health domains were negatively correlated (Spearman coefficient, -0.50 to -0.82). Most patients returned to work regardless of depressive symptoms (minimal to mild, 31 of 35 [88.6%]; moderate to severe, five of eight [62.5%]; P = .12). Compared with ∼ 2 years postdischarge from the ICU, depressive symptoms and memory complaints were similar at 5 years. Mental health domains of the SF-36 may not be sensitive to small changes in mood symptoms.

Rehabilitation nursing research of hepatolenticular degeneration patients with dysarthria

Objective To explore the efficacy and the clinical practice value of rehabilitation nursing to hepatolenticular degeneration patients with dysarthria. Methods 136 hepatolenticular degeneration patients with dysarthria in hospital were enrolled in this study, and they were randomly assigned to rehabilitation nursing group and usual nursing group. Both groups were treated formally by sodium dimercaptosulphonate, the 68 patients of usual nursing group were given general nursing, the 68 patients of rehabilitation nursing group were given general nursing and rehabilitation nursing of dysarthria. Frenchay dysarthria measurement, Phonolaryngeal graph,Microspiro, Activity of Daily Living Scale and WHOQOL-BREF were used to evaluate and compare the therapeutic effect after 8 weeks. Results The total effect rate of rehabilitation nursing group was 95.6％, and usual nursing group was 72. 1％, and the difference was significant (X2 = 13.88, P ＜ 0. 01). MPT in rehabilitation nursing group was different before and after treatment [(6. 12 ± 5.36) s vs (8.94 ± 6.43) s, t =2. 78, P ＜0. 01] and FVC was also different (t =2.46, P ＜0.05). The MPT and FVC in the two group were different (P ＜ 0. 01). WHOQOL-BREF results have reach the statistically significance in the two group after treatment (P ＜ 0. 01 or P ＜0. 05). Conclusions Dysarthria is a common language barrier of hepatolenticular degeneration; it seriously affects the physical and mental health of patients. Early speech rehabilitation training,with the treatment of hepatolenticular degeneration patients by sodium dimercaptosulphonate, can greatly promote sound organ function recovery, can obviously improve the speech function of patients and can improve daily life ability and the life quality of them, it has high value of clinical applications. Key words: Hepatolenticular degeneration; Rehabilitation nursing; Dysarthria

SRT1720 Induces Mitochondrial Biogenesis and Rescues Mitochondrial Function after Oxidant Injury in Renal Proximal Tubule Cells

Mitochondrial biogenesis occurs under basal conditions and is an adaptive response initiated by cells to maintain energetic demands and metabolic homeostasis after injuries targeting mitochondrial function. Identifying pharmacological agents that stimulate mitochondrial biogenesis is a critical step in the development of new therapeutics for the treatment of these injuries and to test the hypothesis that these agents will expedite recovery of cell and organ function after acute organ injuries. In this study, we examined the effects of N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b][1,3]thiazol-6-yl]phenyl]quinoxaline-2-carboxamide (SRT1720) on mitochondrial biogenesis and function in primary cultures of renal proximal tubule cells (RPTCs). We also tested the ability of this compound to restore mitochondrial functions after oxidant-induced RPTC injury. SRT1720 (3-10 microM) induced mitochondrial biogenesis in RPTCs within 24 h as determined by elevations in mitochondrial DNA copy number, increased expression of the mitochondrial proteins NADH dehydrogenase 1beta subcomplex subunit 8 (NDUFB8) and ATP synthase beta, and elevated mitochondrial respiration rates and ATP levels. Induction of mitochondrial biogenesis depended on mammalian sirtuin 1 (SIRT1) deacetylase activity, correlated with deacetylated nuclear peroxisome proliferator-activated receptor coactivator (PGC)-1alpha, and occurred in the absence of AMP-dependent kinase (AMPK) activation. Finally, SRT1720 treatment accelerated recovery of mitochondrial functions after acute oxidant injury. This study demonstrates that SRT1720 can induce mitochondrial biogenesis through SIRT1 activity and deacetylated PGC-1alpha, but not AMPK, in RPTCs within 24 h after oxidant injury. The results support further study of mitochondrial biogenesis as a repair process and a pharmacological target in acute organ injuries and disorders plagued by mitochondrial impairment.

Temporal increase of platelet mitochondrial respiration is negatively associated with clinical outcome in patients with sepsis

IntroductionMitochondrial dysfunction has been suggested as a contributing factor to the pathogenesis of sepsis-induced multiple organ failure. Also, restoration of mitochondrial function, known as mitochondrial biogenesis, has been implicated as a key factor for the recovery of organ function in patients with sepsis. Here we investigated temporal changes in platelet mitochondrial respiratory function in patients with sepsis during the first week after disease onset.MethodsPlatelets were isolated from blood samples taken from 18 patients with severe sepsis or septic shock within 48 hours of their admission to the intensive care unit. Subsequent samples were taken on Day 3 to 4 and Day 6 to 7. Eighteen healthy blood donors served as controls. Platelet mitochondrial function was analyzed by high-resolution respirometry. Endogenous respiration of viable, intact platelets suspended in their own plasma or phosphate-buffered saline (PBS) glucose was determined. Further, in order to investigate the role of different dehydrogenases and respiratory complexes as well as to evaluate maximal respiratory activity of the mitochondria, platelets were permeabilized and stimulated with complex-specific substrates and inhibitors.ResultsPlatelets suspended in their own septic plasma exhibited increased basal non-phosphorylating respiration (state 4) compared to controls and to platelets suspended in PBS glucose. In parallel, there was a substantial increase in respiratory capacity of the electron transfer system from Day 1 to 2 to Day 6 to 7 as well as compared to controls in both intact and permeabilized platelets oxidizing Complex I and/or II-linked substrates. No inhibition of respiratory complexes was detected in septic patients compared to controls. Non-survivors, at 90 days, had a more elevated respiratory capacity at Day 6 to 7 as compared to survivors. Cytochrome c increased over the time interval studied but no change in mitochondrial DNA was detected.ConclusionsThe results indicate the presence of a soluble plasma factor in the initial stage of sepsis inducing uncoupling of platelet mitochondria without inhibition of the electron transfer system. The mitochondrial uncoupling was paralleled by a gradual and substantial increase in respiratory capacity. This may reflect a compensatory response to severe sepsis or septic shock, that was most pronounced in non-survivors, likely correlating to the severity of the septic insult.

Sepsis induces platelet mitochondrial uncoupling and a gradual increase in respiratory capacity that is negatively associated with clinical outcome

Mitochondrial dysfunction has been suggested as a contributing factor in the pathogenesis of multiple organ dysfunction syndrome (MODS) and sepsis is the leading cause of MODS. Also, restoration of mitochondrial function, known as mitochondrial biogenesis, has been implicated as a key factor for the recovery of organ function in patients with sepsis. Here we investigated platelet mitochondrial respiratory function in patients with sepsis during the first week after disease onset.

Case report: paradoxical ventricular septal motion in the setting of primary right ventricular myocardial failure

In this report, a case of right ventricular (RV) failure, hemodynamic instability, and systemic organ failure is described to highlight how paradoxical ventricular systolic septal motion (PVSM), or a rightward systolic displacement of the interventricular septum, may contribute to RV ejection. Multiple inotropic medications and vasopressors were administered to treat right heart failure and systemic hypotension in a patient following combined aortic and mitral valve replacement. In the early postoperative period, echocardiographic evaluation revealed adequate left ventricular systolic function, akinesis of the RV myocardial tissues, and PVSM. In the presence of PVSM, RV fractional area of contraction was > or =35% despite akinesis of the primary RV myocardial walls. The PVSM appeared to contribute toward RV ejection. As a result, the need for multiple inotropes was re-evaluated, in considering that end-organ dysfunction was the result of systemic hypotension and prolonged vasopressor administration. After discontinuation of phosphodiesterase inhibitors, native vascular tone returned and the need for vasopressors declined. This was followed by recovery of systemic organ function. Echocardiographic re-evaluation two years later, revealed persistent akinesis of the RV myocardial tissues and PVSM, the latter appearing to contribute toward RV ejection. This case highlights the importance of left to RV interactions, and how PVSM may mediate these hemodynamic interactions.

Effect of continuous blood purification and thymosin alpha1 on the cellular immunity in patients with severe sepsis: a prospective, randomized, controlled clinical trial

To discuss the effect of continuous blood purification (CBP), thymosin alpha1 and combined therapy on cellular immunity in patients with severe sepsis. Ninety-one patients, age over 18 years, suffering from severe sepsis with Marshall score over 5, admitted to the intensive care unit (ICU) from June, 2004 to October, 2007, were randomly divided into four groups. The patients in control group (24 cases) were treated with classical Surviving Sepsis Campaign (SSC) therapy, those in CBP group (22 cases) were treated with continuous renal replacement therapy (CRRT) or molecular adsorbent recirculating system (MARS) in the first 3 days. The group of thymosin alpha1 (23 cases) were treated with thymosin alpha1, in a dose of 1.6 mg subcutaneous injection per day for 7 days. The patients in the group of combined therapy (22 cases) were treated with CBP and thymosin alpha1. All three treatment groups were treated with classical SSC therapy at the same time. Acute physiology and chronic health evaluation II (APACHE II) score and Marshall score were evaluated. CD14(+) monocyte human leucocyte antigen DR (HLA-DR) levels and the count of T lymphocyte were measured before treatment and 3 days and 7 days after the treatment. All 91 patients were included in the study. Compared with the control group, the 28-day mechanical ventilation (MV) time, length of ICU stay, 28-day mortality of three treatment groups were decreased. There was statistically significant difference in the length of ICU stay of the CBP group, and also the 28-day MV time, length of ICU stay of the group of combined therapy group (all P<0.05). Compared with the variables before treatment, Marshall scores were decreased significantly and levels of HLA-DR, CD3(+), CD4(+), CD8(+)T lymphocytes were increased significantly after 7-day treatment with thymosin alpha1 group (all P<0.05) . The above indexes and APACHE II scores were changed significantly as early as 3 days after treatment in CBP group and combined therapy group (P<0.05 or P<0.01). Compared with the variables at the same period in the control group, only CD3(+) T lymphocytes were increased significantly after 7-day treatment in thymosin alpha1 group (P<0.05), APACHE II scores and Marshall scores were decreased significantly , levels of HLA-DR and CD3(+), CD4(+), CD8(+) T lymphocytes were increased significantly after 7-day treatment in CBP group (all P<0.05). The above indexes were already changed significantly after 3-day treatment in the combined therapy group (P<0.05 or P<0.01). Compared with thymosin alpha1 group, all the indexes were improved but only level of CD3(+) T lymphocytes after 3-day treatment in the combined therapy group increased significantly (P<0.05). CBP and thymosin alpha1 could increase cellular immunity in patients with severe sepsis, promote recovery of organ function and improve prognosis. The effect of CBP appears earlier and more pronounced. Combined treatment can be more effective.

Updated Results of a Phase I/II Trial of Autologous Peripheral Blood Progenitor Cell Transplantation with Velcade™ Maintenance as Treatment for Intermediate- and Advanced-Stage Multiple Myeloma

Pts (median age 59 yrs, range 38–73 yrs) with intermediate- and advanced-stage multiple myeloma were assigned to maintenance therapy with bortezomib beginning a minimum of three and a maximum of four mos after the day of autologous PBPC transplantation following a standard preparative regimen of high-dose melphalan (200 mg/m2). Eligibility for the initiation of maintenance required nl organ function, post-transplant neutrophil and plt recovery (defined as ANC ≥1000 mm−3 and untransfused plt ≥30,000 mm−3). Cohorts of 3 pts each were entered at 1 of 3 dose levels of bortezomib (1.0, 1.3, and 1.6 mg/m2) given IV q wk for 3 wks followed by a 1-wk rest period constituting 1 treatment cycle for a total of 8 cycles. To-date, 30 pts were eligible for study treatment and 24 pts received at least 1 dose of maintenance. Reasons for not proceeding to maintenance included 1 pt with an ANC < 1000 mm−3, 1 pt with a serum creatinine > 2 mg/dl, and 4 additional pts unable to travel to the center. The median t from diagnosis to transplant was 11.7 mos (range, 4.9 to 59.7 mos), and the median t from autologous transplant to the initiation of bortezomib maintenance was 3.1 mos. Protocol adherence was excellent with only 1 pt missing the final dose of treatment and 1 other pt discontinuing therapy due to personal reasons. After completion of the Phase I portion of the study, the DLT was determined to be 1.6 mg/m2 based on grade 3 diarrhea in 2 pts after 2 and 3 cycles of treatment, respectively. All subsequent pts entered were treated at the MTD of 1.3 mg/m2. Other, non-dose-limiting toxicities included fatigue (19 pts), musculoskeletal pain (17pts), neuropathy (10 pts), thrombocytopenia (9 pts), nausea (9 pts), diarrhea (7 pts), Herpes zoster reactivation (6 pts), neutropenia (6 pts), cough (3 pts), as well as upper respiratory infection, chills, fever, dyspepsia, rash and anorexia (1 pt each). Disease assessment consisted of serum and urine PEP monthly for all pts, and bone marrow aspiration quarterly for those pts with nonsecretory myeloma. Repeat bone surveys were required for pts 3, 9, 15, and 21 mos post-transplant. 2 pts required termination of the study drug, 1 at the end of treatment cycle 8 and the other during cycle 3, due to unacceptable side effects. 2 separate pts terminated the study due to disease progression, 1 during cycle 5 and the other during cycle 6, respectively. One additional pt discontinued further study treatments due to personal reasons during cycle 2. All 24 pts are eligible for response assessment. 11 pts continue to be followed every 3 mos for evidence of disease recurrence in the post-treatment period while 1 pt continues on active treatment. After a median follow-up from transplantation of 22.7 mos (range 8.7 to 39.5 mo), 10 pts have relapsed while 2 have died of recurrent myeloma. The current median relapse-free survival is 20.2 mos. This phase I/II trial demonstrates that bortezomib can be safely administered as a maintenance after conventional autologous PBPC transplantation with a MTD of 1.3mg/m2 given 3 times per month for 8 mos; treatment consolidated remission achieved by autologous transplant as will be presented. However, preliminary results with bortezomib maintenance suggest that progression free survival is not appreciably prolonged by this maintenance strategy.

A new approach in organ preservation: potential role of new polymers

The storage conditions of the donor kidney may influence the deleterious consequences of ischemia/reperfusion (IR), which remains a major source of complications in clinical practice. Delayed graft function (DGF), seen in 20% to 50% of transplanted cadaver kidneys, is a major risk factor affecting early and long-term graft survival, patient management, and costs of transplantation. Cold preservation plays a key role in this process and is based on hypothermia and high potassium solutions. In this review, the authors focused on the major molecular mechanisms of cold storage (CS) injury at the cellular level, which have been recently evidenced with modern biochemical and cell biologic methods. These newly uncovered aspects of cold preservation injury are often not fully addressed by preservation solutions in current clinical practice. The role of new molecules such as polyethylene glycol (PEG) is presented and their properties are analyzed in the organ preservation context. PEG improves organ function recovery and reduces inflammation and fibrosis development in several models. Because organs shortage is also a real public health problem, organs from non-heart beating donors or marginal donors are now used to expand pool of organs. As a consequence, the development of better organ preservation methods remains a major target and deserves scientific consideration.

Comment on: Early Enteral Supplementation With Key Pharmaconutrients Improves Sequential Organ Failure Assessment Score in Critically Ill Patients With Sepsis: Outcome of a Randomized, Controlled, Double‐Blind Trial

Objective: To assess the safety and efficacy of an early enteral pharmaconutrition supplement containing glutamine dipeptides, antioxidative vitamins and trace elements, and butyrate in critically ill, septic patients. Design: A prospective, randomized, controlled, double‐blind clinical trial. Setting: Adult intensive care unit in a university hospital. Patients: Fifty‐five critically ill, septic patients requiring enteral feeding. Interventions: Patients received either an enteral supplement (500 ml of Intestamin, Fresenius Kabi) containing conditionally essential nutrients or a control solution via the nasogastric route for up to 10 days. Inclusion occurred within 24 hours of intensive care unit admission. Additionally, patients received enteral feeding with an immunonutrition formula (experimental group) or standard formula (control group) initiated within 48 hours after enrollment. Measurements and main results: Organ dysfunction was assessed by daily total Sequential Organ Failure Assessment (SOFA) score over the 10‐day study period in both patient groups. Patients receiving the experimental supplement showed a significantly faster decline in the regression slopes of delta daily total SOFA score over time compared with control. The difference between the regression coefficients of the 2 slopes was significant irrespective of the level of analysis: intent to treat –0.32 vs –0.14, P &lt; .0001; per protocol– 0.34 vs –0.14, P &lt; .0001; and completers (patients receiving ≥80% of the calculated caloric target over a period of 6 days)– 0.26 vs –0.16, P = .0005. Vitamin C, as a marker of supplement absorption, increased from 10.6 (1.9‐159.4) μmol/L (normal range 20‐50 μmol/L) on day 1 to 58.7 (5.4‐189.9) μmol/L by day 3 (P = .002) in the intervention group but remained below the normal range in the control group 17.0 (2.8‐78.5) on day 1 and 14.3 (2.4‐179.6) on day 3. Serum levels of glycine, serine, arginine, ornithine, vitamin E, and β‐carotene all increased significantly with treatment in the supplementation group. Conclusions: In medical patients with sepsis, early enteral pharmaconutrition with glutamine dipeptides, vitamin C and E, β‐carotene, selenium, zinc, and butyrate in combination with an immunonutrition formula results in significantly faster recovery of organ function compared with control.

Continuous Hemofiltration for Anasarca: Recovery of Renal Function after 71 Liters of net Ultrafiltration

We report on a 64-year-old female presenting with anasarca secondary to volume loading in the setting of chronic liver disease, acute on chronic renal failure, circulatory failure and sepsis. Over 37 days, a net negative fluid balance of 71 L was achieved using continuous hemofiltration, with spontaneous recovery of urine output, vasopressor independence and resolution of coagulopathy. This case report underlines the pathophysiological role of tissue edema in the downward spiral of hepato-renal and cardio-renal dysfunction and illustrates that very large volumes of tissue fluid can be safely and effectively removed with continuous renal replacement therapy, thereby permitting recovery of organ function. To our knowledge, there have been no previous reports of such large volume net fluid removal by progressive ultrafiltration in the intensive care unit.

Early enteral supplementation with key pharmaconutrients improves Sequential Organ Failure Assessment score in critically ill patients with sepsis: Outcome of a randomized, controlled, double-blind trial*

To assess the safety and efficacy of an early enteral pharmaconutrition supplement containing glutamine dipeptides, antioxidative vitamins and trace elements, and butyrate in critically ill, septic patients. A prospective, randomized, controlled, double-blind clinical trial. Adult intensive care unit in a university hospital. Fifty-five critically ill, septic patients requiring enteral feeding. Patients received either an enteral supplement (500 mL of Intestamin, Fresenius Kabi) containing conditionally essential nutrients or a control solution via the nasogastric route for up to 10 days. Inclusion occurred within 24 hrs of intensive care unit admission. Additionally, patients received enteral feeding with an immunonutrition formula (experimental group) or standard formula (control group) initiated within 48 hrs after enrollment. Organ dysfunction was assessed by daily total Sequential Organ Failure Assessment (SOFA) score over the 10-day study period in both patient groups. Patients receiving the experimental supplement showed a significantly faster decline in the regression slopes of delta daily total SOFA score over time compared with control. The difference between the regression coefficients of the two slopes was significant irrespective of the level of analysis: intent to treat -0.32 vs. -0.14, p < .0001; per protocol -0.34 vs. -0.14, p < .0001; and completers (patients receiving > or = 80% of the calculated caloric target over a period of 6 days), -0.26 vs. -0.16, p = .0005. Vitamin C, as a marker of supplement absorption, increased from 10.6 (1.9-159.4) micromol/L (normal range 20-50 micromol/L) on day 1 to 58.7 (5.4-189.9) micromol/L by day 3 (p = .002) in the intervention group but remained below the normal range in the control group 17.0 (2.8-78.5) on day 1 and 14.3 (2.4-179.6) on day 3. Serum levels of glycine, serine, arginine, ornithine, vitamin E, and beta-carotene all increased significantly with treatment in the supplementation group. In medical patients with sepsis, early enteral pharmaconutrition with glutamine dipeptides, vitamin C and E, beta-carotene, selenium, zinc, and butyrate in combination with an immunonutrition formula results in significantly faster recovery of organ function compared with control.

Phase I/II Trial of Bortezomib Maintenance in Order To Prolong Remission-Duration Following Autologous Peripheral Blood Progenitor Cell Transplantation as Treatment for Intermediate- and Advanced-Stage Multiple Myeloma.

Pts (median age 60 yrs, range 37 – 73 yrs) with intermediate- and advanced-stage multiple myeloma were assigned to maintenance therapy with bortezomib beginning a minimum of three and a maximum of four mos after the day of autologous PBPC transplantation following a standard preparative regimen of high-dose melphalan (200 mg/m2). Eligibility for the initiation of maintenance required nl organ function, post-transplant neutrophil and plt recovery (defined as ANC ≥ 1000 mm−3 and untransfused plt ≥30,000 mm−3). Cohorts of 3 pts each were entered at 1 of 3 dose levels of bortezomib (1.0, 1.3, and 1.6 mg/m2) given IV q wk for 3 wks followed by a 1-wk rest period constituting 1 treatment cycle for a total of 8 cycles. To-date, 29 pts were eligible for study treatment and 23 pts received at least 1 dose of maintenance. Reasons for not proceeding to maintenance included 1 pt with an ANC < 1000 mm−3, 1 pt with a serum creatinine > 2 mg/dl, and 4 additional pts unable to travel to the center. The median t from diagnosis to transplant was 11.4 mos (range, 4.9 to 59.7 mos), and the median t from autologous transplant to the initiation of bortezomib maintenance was 3.7 mos. Protocol adherence was excellent with one pt missing the final dose of treatment and one other pt discontinuing therapy due to personal reasons. After completion of the Phase I portion of the study, the DLT was determined to be 1.6 mg/m2 based on grade 3 diarrhea in 2 pts after 2 and 3 cycles of treatment, respectively. All subsequent pts entered were treated at the MTD of 1.3 mg/m2. Other, non-dose-limiting toxicities included thrombocytopenia (14 pts), neuropathy (12 pts), anemia (12 pts), fatigue (11 pts), neutropenia (8 pts), musculoskeletal pain (7pts), nausea (5 pts), Herpes zoster reactivation (4 pts), diarrhea (3 pts), edema (3 pts), cough (2 pts), as well as upper respiratory infection, chills, fever, dyspepsia, and anorexia (1 pt each). Disease assessment consisted of serum and urine PEP monthly for all pts, and bone marrow aspiration quarterly for those pts with nonsecretory myeloma. Repeat bone surveys were required for pts 3, 9, 15, and 21 mos post-transplant. 2 pts required termination of the study drug, 1 at the end of treatment cycle 8 and the other during cycle 3, due to unacceptable side effects. 2 separate pts terminated the study due to disease progression, 1 during cycle 5 and the other during cycle 6, respectively. One additional pt discontinued further study treatments due to personal reasons during cycle 2. All 23 pts are eligible for response assessment. 13 pts continue to be followed every 3 mos for evidence of disease recurrence in the post-treatment period while 4 others continue on treatment. After a median follow-up from transplantation of 17.1 mos (range 4.1 to 30.3 mo), 6 pts have relapsed while none have died of recurrent myeloma. The current median relapse-free survival is 15.8 mos. This phase I/II trial demonstrates that bortezomib can be safely administered as a maintenance after conventional autologous PBPCl transplantation with an MTD of 1.3mg/m2 given 3 times per month for 8 mos; treatment consolidated remission achieved by autologous transplant as will be presented. These preliminary results, when compared to published results of autologous transplantation for myeloma, suggest that with further follow-up, bortezomib maintenance may favorably impact t- to-recurrence.

Glycine Does Not Add to the Beneficial Effects of Perioperative Oral Immune‐Enhancing Nutrition Supplements in High‐Risk Cardiac Surgery Patients

Elderly patients and patients with a poor cardiac function have increased morbidity rates when undergoing cardiac surgery. The aim of this study was to determine whether addition of glycine to a standard preoperative oral immune-enhancing nutrition supplement (OIENS) improves outcome. Glycine-enriched OIENS was compared with 2 formulas: standard OIENS and control. In this double-blind, 3-armed study, patients scheduled to undergo cardiac surgery with the use of extracorporeal circulation received either the glycine-enriched OIENS (OIENS + glyc, n = 24), standard OIENS (OIENS, n = 25), or control formula (Control, n = 25) for minimally 5 preoperative days. Patients were included if they were aged 70 years or older, had a compromised left ventricular function, or were planned for mitral valve surgery. Main outcome measures were postoperative infectious morbidity, organ function, and postoperative recovery. Infectious morbidity was significantly lower in both treatment groups compared with the control group (p = .02). An infection was diagnosed in 5 and 4 patients in the OIENS + glyc and OIENS groups, respectively, and in 12 control patients. Less supportive therapy was necessary to stabilize circulation in both treatment groups compared with the control group. Median length of hospital stay was 7.0, 6.5, and 8.0 days in the OIENS + glyc, OIENS, and control groups, respectively. Inflammatory responses, as measured by systemic levels of proinflammatory cytokines and surface markers on polymorphonuclear cells, were comparable for all groups. Preoperative OIENS reduces postoperative infectious morbidity and results in a more stable circulation; the addition of glycine does not result in any beneficial effect over standard OIENS.

THE PROTECTIVE EFFECTS OF PUGNAC ON CARDIAC FUNCTION AFTER TRAUMA-HEMORRHAGE ARE MEDIATED VIA INCREASED PROTEIN O-GlcNAc LEVELS

We have previously shown that administration of glucosamine after trauma-hemorrhage (TH) improved cardiac output and organ perfusion, and this was associated with increased levels of O-linked N-acetylglucosamine (O-GlcNAc) on proteins in the heart and brain. An alternative means of increasing O-GlcNAc levels is by inhibition of O-linked N-acetylglucosaminidase, which catalyzes the removal of N-acetylglucosamine from proteins, with O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate (PUGNAc). The goal of this study, therefore, was to determine whether PUGNAc administration after TH also improves recovery of organ perfusion and function. Fasted male rats were bled to and maintained at a mean arterial blood pressure of 40 mmHg for 90 min, followed by fluid resuscitation. Intravenous administration of PUGNAc (200 micromol/kg body weight) 30 min after the onset of resuscitation significantly improved cardiac output compared with the vehicle controls (12.3 +/- 1.3 mL/min per 100 g body weight vs. 25.5 +/- 2.0 mL/min per 100 g body weight; P < 0.05), decreased total peripheral resistance (6.6 +/- 0.8 mmHg/mL per minute per 100 g body weight vs. 3.7 +/- 0.3 mmHg/mL per minute per 100 g body weight; P < 0.05), and increased perfusion of critical organ systems, including the kidney and liver, determined at 2 h after the end of resuscitation. Treatment with PUGNAc also attenuated the TH-induced increase in plasma IL-6 levels (864 +/- 112 pg/mL vs. 392 +/- 188 pg/mL; P < 0.05) and TNF-alpha levels (216 +/- 21 pg/mL vs. 94 +/- 11 pg/mL; P < 0.05) and significantly increased O-GlcNAc levels in the heart, liver, and kidney. Thus, PUGNAc, like glucosamine, improves cardiac function and organ perfusion and reduced the level of circulating IL-6 and TNF-alpha after TH. The similar effects of glucosamine and PUGNAc support the notion that the protection associated with both interventions is mediated via increased protein O-GlcNAc levels.

Increased intra-abdominal pressure: is it of any consequence in severe acute pancreatitis?

Background. Increased intra-abdominal pressure (IAP) is detrimental for the recovery of organ function in trauma and emergency patients. The aim of this study was to assess the correlation between the dynamics of IAP and organ dysfunction in severe acute pancreatitis (SAP). Materials and methods. Management of SAP between 2000 and 2004 was analysed. SAP was classified according to Atlanta 1992. Organ dysfunction, systemic inflammatory response syndrome (SIRS) and outcomes in relation to the IAP were assessed. IAP was measured indirectly. Results. A total of 65 patients, with an average APACHE II score of 6.44, complied with the Atlanta criteria. In all, 34 patients received conservative treatment and 31 were operated. SIRS was observed in 59 cases and multiple organ dysfunction syndrome (MODS) in 61 cases. IAP was significantly higher in the 25 most complicated patients requiring renal replacement therapy (RRT), compared with 40 patients without RRT, 31.72 vs 21.4 cm/H2O (p=0.037). IAP interrelated positively with SOFA score (r =+ 0.371, p<0.01) and organs involved (r =+ 0.356, p<0.01), and negatively with platelet count and enterally provided volume (r =− 0.284, p<0.01; r =− 0.5, p<0.01, respectively). Overall mortality (9.2%) was associated with surgery and sustained increase of the IAP over 25 cm/H2O. Our data support the pathophysiological interrelation of elevated IAP and development of organ dysfunction. Conclusion. Development of organ dysfunction in SAP could be associated with increased IAP. Grade III increase of IAP should be considered as an indicator for revision of treatment modalities.

Scheduling of Radiation and Chemotherapy for Limited-Stage Small-Cell Lung Cancer: Repopulation As a Cause of Treatment Failure?

Themeta-analystcancastabroadnettogainstatisticalpower, possibly obtaining results clouded by the combining of heterogeneous trials, or can focus on more homogeneous data, thereby sacrificingpower.Inthisissue,DeRuysscheretal 1 havechosenthe latter approach to test the plausible hypothesis that initial chemotherapy or protracted radiotherapy can trigger repopulation of surviving cells in limited-stage small-cell lung cancer (LSCLC), thus decreasing the effectiveness of treatment. Repopulation of cells in critical normal tissues between individual dose fractions of either radiotherapy or chemotherapy is important for recovery or retention of normal organ function, thereby improving tolerance to treatment. Thus, a schedule of radiotherapy administered over 6 to 7 weeks leads to less normal tissuereactionthanasimilartotaldoseadministeredoverashorter time, and the kinetics of repopulation in the bone marrow allow repetitive scheduling of cycle-active chemotherapy at approximately 3-week intervals. However, repopulation of surviving tumor cells also occurs between dose fractions of either radiation or chemotherapy and effectively decreases tumor-cell kill (Fig 1). 2,3 There is evidence in several tumor types for an increase in the rate of repopulation during the latter part of a course of radiation treatment, which is an effect long recognized as a mechanism of clinicallysignificantresistancetotreatment. 4 Therearefewdataon the role of repopulation in the longer intervals between cycles of chemotherapy, but accelerating repopulation probably occurs and can lead to clinical resistance, even if there is no change in the inherent sensitivity of the cancer cells. 2

SLPI LIMITS POSTISCHEMIC INFLAMMATION AND PREVENTS SEVERE MYOCYTE NECROSIS IN RESPONSE TO COLD ISCHEMIA AND HEART TRANSPLANTATION

P74 Aims: SLPI is a 12 kD protein with an inhibitory effect on protease activity, crucially involved in wound healing and inflammatory cell activation. We previously demonstrated SLPI upregulation in response to cold ischemia and cardiac transplantation, in this study we analysed the effect of SLPI on graft function and morphology. Methods: Hearts from SLPI knockout mice (SLPI−/−) were heterotopically transplanted to SLPI−/− recipients. Grafts underwent 10 hours of cold ischemia prior to transplantation or were transplanted immediately. C57Bl/6 wild type isografts (WT) undergoing the same procedure served as controls. In selected groups, recombinant SLPI (rSLPI) was given at 200μg i.v. after reperfusion. Hearts were removed at 15min, 12h, 24h and 10 days, graft function was assessed using a 4 point scoring system and morphology was investigated by HE histology. SLPI gene expression was analysed using real-time PCR (Taqman technology). SLPI protein expression was studied by immunohistochemistry using a monoclonal antibody (SLPI mAb Novocastra Lab.). Results: At 15min recovery of graft function was normal in WT and SLPI −/− mice transplanted without cold ischemia (4,0±0,0). In contrast, SLPI −/− hearts showed no or marginal recovery of organ function (0,36±0,51). At 24h cardiac function in SLPI −/− (2,8±0,89) was less when compared with WT (3,36±0,55), at 10 days, however, no difference was observed. Histology demonstrated a mild mononuclear cell infiltrate and small focal necrosis in all groups at 24h. At 10 days, postischemic inflammation as well as myocyte necrosis was significantly higher in the SLPI −/− group (2,5±0,5 vs 1,8±0,4 and 1,6±0,5 vs 0,2±0,4). In addition, myocyte vacuolisation as a sign of sublethal ischemic injury was present at high level in SLPI −/− mice undergoing prolonged cold ischemia only. Single administration of rSLPI did not alter graft function or morphology. Upregulation of SLPI gene expression was detected in WT groups at 12 and 24 hours after reperfusion. Gene transcription at 12h was significantly higher after prolonged cold ischemia (7,99 vs 1,57 orders of magnitude). SLPI protein as demonstrated by immunohistology was found 24 hours after reperfusion in WT groups. High levels of SLPI protein were observed 10 days after transplantation, SLPI-positive cells were mainly identified as macrophages. Conclusions: Herein we demonstrate, that SLPI has a substantial effect in prevention of inflammation and myocyte damage in response to ischemia and reperfusion of the heart. In addition, SLPI seems to be crucial for recovery of organ function early after heart transplantation and represents a promising target for modulating the destructive processes of postischemic inflammation while preserving its restorative nature.

Relationships between hemodynamic parameters and myocardial energy and antioxidant status in heart transplantation

The relationships between high-energy phosphate levels, oxidative insult and mechanical function represent a key point in heart transplantation and related post-ischemic functional recovery. We evaluated myocardial purine compounds and glutathione antioxidant defence mechanism during 19 heart transplant operations. Heart biopsies were taken before harvesting on beating heart (t1), at the end of cold static preservation (t2) and 30 min after implantation and reperfusion (t3); perchloric extracts of the tissue were analyzed by capillary electrophoresis (CE). Correlation analyses were performed with hemodynamic parameters evaluated 90 min after aortic declamping (T90), 6 h following admission in intensive care unit (T6A) and 1 d post-operation (D1). We evidenced that AMP levels measured at T1 negatively correlate with both cardiac index (CI) and oxygen delivery index (DO2I) evaluated at T6A, respectively. The same behavior was evident plotting IMP levels measured at T3 with CI and DO2I evaluated at D1. After t2 the nucleotide/(nucleoside + base) ratio was in positive correlation with hemodynamic parameters at T6A. Energy charge and GSH/GSSG ratio measured before harvesting were in positive correlation with DO2I evaluated at T90. The present research shows that despite the complexity of the high-energy phosphate metabolism and that of the events associated to a clinical heart transplantation, there are some parameters that, besides reflecting the degree of myocardial preservation, also represents predictive parameters for the following organ functional recovery. It also suggests that heart preservation strategies should carefully take into account the sub-optimal nature of the donor heart at the time of procurement, through a broad spectrum of purine compound and glutathione antioxidant system measurements.

Extracorporeal support of the failing liver.

Successes in machine-based extracorporeal support for different organ functions stimulated research in the field of liver support approximately 50 years ago. Initial failure to improve outcome using detoxification methods like dialysis, blood and plasma exchange, or plasmapheresis over sorbents fueled interest in biologic liver support concepts using bioreactors or combined methods. New device configurations, technical improvement of existing detoxification methods, and the refinement in cell culture techniques led to a boost in research on biologic and nonbiologic approaches. Currently, many systems are in the preclinical phase or have entered clinical studies. A number of completed clinical trials have reported a favorable therapeutic impact of the most advanced solutions on the course and outcome of liver failure. Often, findings must be reconfirmed. However, current knowledge suggests that extracorporeal liver support can successfully stabilize liver function, improve the clinical condition of patients, and considerably improve survival in certain subgroups of patients with fulminant hepatic failure and acute decompensation of chronic hepatic failure. Although the initial focus of liver support methods was bridging to liver transplantation, bridging to recovery of organ function and treatment of intractable pruritus are now valuable indications.