中田 孝明

Purpose: Cytokines play pivotal roles in the pathophysiology of severe sepsis/septic shock, and continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter (PMMA-CHDF) removes cytokines efficiently and continuously, mainly through adsorption to a hemofilter membrane. The aim of this study was to investigate the clinical efficacy of enhanced intensity PMMA-CHDF in treating refractory septic shock. Methods: Seventy-two septic shock patients admitted to the intensive care unit (ICU) underwent critical care including PMMA-CHDF We employed enhanced intensity PMMA-CHDF to improve the cytokine removal rate by increasing the hemofilter membrane area in 10 refractory septic shock patients (enhanced intensity group, El group; 2 extracorporeal CHDF circuits using the hemofilter with a larger membrane area of 2.1 m(2)). Other patients undergoing conventional PMMA-CHDF and matched for severity with the El group, comprised a matched conventional group (MC group; using a PMMA membrane hemofilter with a membrane area of 1.0 m(2); n=15). The case-control comparison was performed between the 2 groups. Results: Enhanced intensity PMMA-CHDF significantly increased mean arterial pressure by 23.8% in 1 hour (p=0.037), decreased the blood lactate level by 28.6% in 12 hours (p=0.006), and reduced blood IL-6 level in 24 hours (p=0.005). The ICU survival rate in the El group was significantly better than that in the MC group (60% vs. 13.3%, p=0.028). Conclusion: Enhanced intensity PMMA-CHDF may improve hemodynamics and survival rate in patients with refractory septic shock.

Objective: Angiotensin II and its postreceptor signaling are crucial in regulating vasomotor tone. The objective of this study was to test the hypothesis that single nucleotide polymorphisms in angiotensin II pathway genes alter outcome of septic shock. Design: Genetic association study and in vitro experiment. Setting: Intensive care units at academic teaching centers. Patients: Derivation and validation septic shock cohorts (n = 589 and n = 616, respectively) and a coronary artery bypass surgery cohort (n = 551). Interventions: Patients with septic shock in the derivation cohort were genotyped for tag single nucleotide polymorphisms: angiotensin-converting enzyme (six single nucleotide polymorphisms), angiotensin II receptor type 1 (five single nucleotide polymorphisms), and angiotensin II type 1 receptor-associated protein (three single nucleotide polymorphisms), which is a negative regulator of angiotensin II receptor type 1. Patients in the septic shock replication cohort and the coronary artery bypass graft cohort were genotyped for the angiotensin II type 1 receptor-associated protein rs11121816. Measurements and Main Results: The primary outcome variable was 28-day mortality. Secondary outcome variables were blood pressure and heart rate. Angiotensin II type 1 receptor-associated protein messenger RNA expression was measured in genotyped lymphoblastoid cells in vitro. Patients with septic shock patients the GG genotype of angiotensin II type 1 receptor-associated protein rs11121816 had increased 28-day mortality in the derivation cohort (54.8% vs. 41.4%; adjusted hazard ratio, 1.46; 95% confidence interval, 1.09-1.93; p =.010 [all ethnicities]; p =.050 [white]) and in the replication cohort (43.8% vs. 32.3%; hazard ratio, 1.42; 95% confidence interval, 1.03-1.98; p =.035 [all ethnicities]; p =.037 [white]). Patients having the GG genotype had decreased mean arterial pressure (98.3% of other genotype, p =.058 [derivation cohort]; 97.7%, p =.00060 [replication cohort]) and increased heart rate (104.1%, p = .023 [derivation cohort], 102.9%, p = nonsignificant [replication cohort]). GG genotype patients undergoing coronary artery bypass grafting had decreased postoperative mean arterial pressure and increased postoperative heart rate (p < .05). GG genotype lymphoblastoid cells had 2.0-fold higher angiotensin II type 1 receptor-associated protein messenger RNA expression (p < .05). Conclusions: For angiotensin II type 1 receptor-associated protein, the negative regulator of angiotensin II receptor type 1, the GG genotype of rs11121816 was associated with increased angiotensin II type 1 receptor-associated protein expression, decreased blood pressure, and increased heart rate as well as increased 28-day mortality in septic shock. (Crit Care Med 2011; 39: 1641-1648)

Background: Vasopressin is an essential peptide hormone regulating cardiovascular homeostasis and an adjunctive vasopressor therapy for septic shock. Methods: We tested for association between single nucleotide polymorphisms (SNPs) in vasopressin pathway genes and altered outcome in derivation (n = 589) and replication (n = 616) cohorts of patients with septic shock. The primary outcome was 28-day mortality and the secondary outcome was vasopressin clearance. In a third cardiac surgical cohort (n = 977), we tested for locus-specific heritability of scrum sodium concentrations. Results: Of 17 tested tag SNPs in five vasopressin pathway genes (arginine vasopressin [AVP], arginine vasopressin receptor 1A and 1B [AVPR1A, AVPR1B], leucyl/cystinyl aminopeptidase [LNPEP], and oxytocin receptor [OXTR]), rs18059 in LNPEP (also known as vasopressinase) was associated with 28-day mortality in the derivation cohort (P = .037). Therefore, we resequenced the 160-kb haplotype block encompassing the LNPEP gene, including rs18059, and genotyped the 230 identified SNPs in the derivation cohort. The strongest signal was found for LNPEP rs4869317 (adjusted P = .044). The rs4869317 TT genotype was associated with increased 28-day mortality in the derivation cohort (51.0% [TT] vs 34.5% [AA/AT]; adjusted hazard ratio [HR], 1.58; 95% CI, 1.21-2.06; P = .00073) and the replication cohort (38.6% vs 29.6%; HR, 1.36; 95% CI, 1.03-1.80; P = .030). We found that the TT genotype was associated with increased plasma vasopressin clearance (P = .028), and the rs4869317 genotype accounted for 80% of the variance of serum sodium concentrations (locus-specific heritability) in cardiac surgical patients. Conclusions: The genetic variation in LNPEP (vasopressinase) is associated with 28-day mortality in septic shock and is associated with biologic effects on vasopressin clearance and serum sodium regulation. Further confirmation in additional cohorts is required. CHEST 2011; 139(5):1042-1049

Genetic polymorphisms have recently been found to be related to clinical outcome in septic patients. The present study investigated to evaluate the influence of genetic polymorphisms in Japanese septic patients on clinical outcome and whether use of genetic polymorphisms as predictors would enable more accurate prediction of outcome. Effects of 16 genetic polymorphisms related to pro-inflammatory mediators and conventional demographic/clinical parameters (age, sex, past medical history, and APACHE II score) on ICU mortality as well as disease severity during ICU stay were examined in the septic patients (n = 123) admitted to the ICU between October 2001 and November 2007 by multivariable logistic regression analysis. ICU mortality was significantly associated with TNF -308GA, IL1 beta -31CT/TT, and APACHE II score. Receiver-operating characteristics (ROC) analysis demonstrated that, compared with APACHE II score alone (ROC-AUC = 0.68), use of APACHE II score and two genetic parameters (TNF -308 and IL1 beta -31) enabled more accurate prediction of ICU mortality (ROC-AUC = 0.80). Significant association of two genetic polymorphisms, TNF -308 and IL1 beta -31, with ICU mortality was observed in septic patients. In addition, combined use of these genetic parameters with APACHE II score may enable more accurate prediction of outcome in septic patients. (C) 2010 Elsevier Ltd All rights reserved.

Objective: To determine whether central venous pressure and fluid balance after resuscitation for septic shock are associated with mortality. Design: We conducted a retrospective review of the use of intravenous fluids during the first 4 days of care. Setting: Multicenter randomized controlled trial. Patients: The Vasopressin in Septic Shock Trial (VASST) study enrolled 778 patients who had septic shock and who were receiving a minimum of 5 mu g of norepinephrine per minute. Interventions: None. Measurements and Main Results: Based on net fluid balance, we determined whether one's fluid balance quartile was correlated with 28-day mortality. We also analyzed whether fluid balance was predictive of central venous pressure and furthermore whether a guideline-recommended central venous pressure of 8-12 mm Hg yielded a mortality advantage. At enrollment, which occurred on average 12 hrs after presentation, the average fluid balance was +4.2 L. By day 4, the cumulative average fluid balance was +11 L. After correcting for age and Acute Physiology and Chronic Health Evaluation II score, a more positive fluid balance at both at 12 hrs and day 4 correlated significantly with increased mortality. Central venous pressure was correlated with fluid balance at 12 hrs, whereas on days 1-4, there was no significant correlation. At 12 hrs, patients with central venous pressure <8 mm Hg had the lowest mortality rate followed by those with central venous pressure 8-12 mm Hg. The highest mortality rate was observed in those with central venous pressure >12 mm Hg. Contrary to the overall effect, patients whose central venous pressure was <8 mm Hg had improved survival with a more positive fluid balance. Conclusions: A more positive fluid balance both early in resuscitation and cumulatively over 4 days is associated with an increased risk of mortality in septic shock. Central venous pressure may be used to gauge fluid balance <= 12 hrs into septic shock but becomes an unreliable marker of fluid balance thereafter. Optimal survival in the VASST study occurred with a positive fluid balance of approximately 3 L at 12 hrs. (Crit Care Med 2011; 39: 259-265)

Introduction: Interleukin 17A (IL17A) plays a key role in host defense against microbial infection including Gram-positive bacteria. Genetic factors contribute to the host defense, but the role of IL17A single nucleotide polymorphisms (SNPs) has not yet been investigated in severe sepsis. Therefore, we hypothesized that SNPs in the IL17A gene alter susceptibility to infection and clinical outcome of severe sepsis. Methods: We tested for the association of IL17A SNPs with susceptibility to infection and clinical outcome of severe sepsis using two cohorts of European ancestry (derivation cohort, St Paul's Hospital (SPH), n = 679; validation cohort, Vasopressin and Septic Shock Trial (VASST), n = 517). The primary outcome variable was susceptibility to Gram-positive bacterial infection. The secondary outcome variable was 28-day mortality. Results: Of four tested IL17A tag SNPs (rs4711998, rs8193036, rs2275913, rs1974226), rs1974226 SNP was associated with altered susceptibility to Gram-positive infection in the derivation SPH cohort (corrected P = 0.014). Patients having the rs1974226 GG genotype were more susceptible to Gram-positive infection, compared to AG/AA genotype in the two cohorts of severe sepsis (SPH, P = 0.0036, odds ratio (OR) 2.19, 95% confidence interval (CI) 1.28-3.72; VASST, P = 0.011, OR 1.95, 95% CI 1.16-3.27) and in the subgroup having lung infection (P = 0.017, OR 1.90, 95% CI 1.12-3.21). Furthermore, the IL17A rs1974226 G allele was associated with increased 28-day mortality in two cohorts (SPH, adjusted OR 1.44, 95% CI 1.04-2.02, P = 0.029; VASST, adjusted OR 1.67, 95% CI 1.17-2.40, P = 0.0052). Conclusions: IL17A genetic variation is associated with altered susceptibility to Gram-positive infection and 28-day mortality of severe sepsis.

Mutations in IRAK4 have been associated with recurrent Gram-positive infections in children. Given the central role of IRAK4 in innate immunity signaling, we hypothesized that common genetic variants of IRAK4 may be associated with prevalence of Gram-positive infection in critically ill adults. Haplotype clade tag single nucleotide polymorphisms (SNPs) of the IRAK4 gene were selected and genotyped in a cohort of 1,029 critically ill patients with systemic inflammatory response syndrome (SIRS). We found that a haplotype clade tagged by the A allele of the htSNP G29429A (Ala428Thr) was associated with increased relative risk of Gram-positive infection at admission to ICU (RR = 1.2, p < 0.05). Furthermore, the 29429A allele was associated with decreased lymphoblastoid cell response to CpG (as measured by IL-6 production) (raw values +/- 95% CI 40.3 +/- 32.3 vs. 85.8 +/- 29.4 pg/ml; log-transformed values +/- 95% CI 1.13 +/- 0.37 vs. 1.55 +/- 0.18, p < 0.04). We also found that IRAK4-deficient fibroblasts transfected with an IRAK4 expression plasmid containing the 29429A allele produced less IL-6 in response to lipopolysaccharide (p = 0.07). Our data suggest that the IRAK4 haplotype clade marked by 29429A (428Thr) alters susceptibility to Gram-positive bacteria, by decreasing cellular response to TLR ligands. Copyright (C) 2011 S. Karger AG, Basel

Rationale: The CysGlyGln haplotype of the beta(2)-adrenergic receptor gene (ADRB2) is functional and associated with altered responses to adrenergic agonists in patients with asthma. Whether this functional haplotype alters outcome in patients receiving adrenergic agonists in septic shock is unknown. Objectives: To determine whether genetic variation of ADRB2 influences outcome in septic shock. Methods: Two cohorts of patients with septic shock were studied: a single center (St. Paul's Hospital [SPH]) cohort (n = 589) and the Vasopressin and Septic Shock Trial (VASST) cohort (n = 616). The A allele of the rs1042717 G/A polymorphism is in complete linkage disequilibrium with the CysGlyGln haplotype of ADRB2; therefore, rs1042717 was genotyped. Modulation by norepinephrine and salbutamol of IL-6 production by stimulated in vitro lymphoblastoid cells was measured by genotype. Measurements and Main Results: Patients who had the AA genotype of rs1042717 displayed increased 28-day mortality in SPH (adjusted hazard ratio, 2.23; 95% confidence interval, 1.33-3.72; P = 0.0022), and this result was replicated in VASST (adjusted hazard ratio 2.82; 95% confidence interval, 1.56-5.09; P = 0.0006). This genotypic effect was eliminated in patients treated with acute low-dose corticosteroids. In all patients, the AA genotype was associated with more organ dysfunction. Patients with the AA genotype had a higher heart rate (SPH; P < 0.05; VASST; P < 0.05) and required a higher norepinephrine dose over Days I through 3 (VASST, P < 0.05). The AA genotype was associated with decreased norepinephrine and salbutamol inhibition of IL-6 production by stimulated lymphoblastoid cells in vitro (P < 0.05). Conclusions: The AA genotype of ADRB2 rs1042717, identifying homozygotes for the CysGlyGln haplotype, was associated with increased mortality and more organ dysfunction in septic shock.

It has been reported that various types of blood purification intended for the removal of humoral mediators, such as cytokines, were performed in patients with severe sepsis/septic shock. While high-volume hemofiltration, hemofiltration using high cut-off membrane filters, and direct hemoperfusion with a polymyxin-B immobilized column are widely used in the treatment of severe sepsis/septic shock, we perform continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter (PMMA-CHDF), which shows an excellent cytokine-adsorbing capacity, for the treatment of severe sepsis/septic shock. In our previous study, it was found that PMMA-CHDF could efficiently remove various pro-inflammatory cytokines such as INF alpha, IL-6 and IL-8 from the bloodstream, resulting in early recovery from septic shock. Furthermore, PMMA-CHDF could remove anti-inflammatory cytokines such as IL-10 from bloodstream, suggesting that it might improve immunoparalysis as well. These findings suggest that PMMA-CHDF is useful for the treatment of patients with severe sepsis/septic shock as a cytokine modulator. Copyright (C) 2010 S. Karger AG, Basel

まれな外傷性腎梗塞を経験したので報告する。症例は61歳，男性。工場内で作業中に約8mの高さから転落し受傷。軽度の肺挫傷，肝損傷および右肋骨骨折，右橈骨骨折，骨盤骨折，右大腿骨骨折があり，造影CT検査にて右腎臓の造影不良を認めた。血管造影検査を行ったところ右腎動脈が起始部で途絶しており，血行再建を目的に開腹術を施行した。しかし右腎臓の鬱血は高度であったため右腎を摘出した。術後，肺炎による人工呼吸管理が長期化し退院まで100日を要した。外傷性梗塞腎に対する血行再建の成績は悪く，本症例のような血行動態が安定している片側腎梗塞の場合は治療方針として保存的療法を第1選択にすべきと思われた。

Objectives: To investigate the usefulness of analysis of single nucleotide polymorphism (SNP) using a newly developed DNA chip assay involving single base extension(SBE) and subsequent hybridization in cytokine-related genes in critical care patients. Design and methods: Genotyping was performed in 76 ICU patients admitted to the ICU. First, the DNA samples from 58 patients were subjected to PCR and SBE conditioning for DNA. Second, another 18 patients were subjected to genotyping for SNPs in IL-6 -596G/A, -572C/G, -174G/C, TNF-alpha -308G/A, -238G/A, IL-1 beta -511C/T and -31T/C by both TaqMan and DNA chip method, and by DNA direct sequencing prospectively. Results: First, PCR and SBE condition were established with initial sample sets, which were consistent with results by TaqMan method. Second, no difference was observed between two assay methods in prospective validation set. Conclusions: The genotyping assay using the new chip was developed and its usefulness was confirmed. (C) 2009 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Introduction: Most patients with cardiac arrest (CA) admitted to hospitals after successful cardiopulmonary resuscitation (CPR) are discharged with various degree of neurological deficits. To determine predictor of neurological outcome early and accurately, and to determine cutoff values, serum levels of protein S-100B and neuron-specific enolase (NSE) within 24 h after CA were assessed. Methods and results: A multicenter prospective observational study was conducted between May 2007 and April 2008 at three medical institutions in Japan on 107 consecutive non-traumatic CA patients with return of spontaneous circulation after CPR. Based on "best-ever achieved" Glasgow-Pittsburgh cerebral performance categories (CPC) score within 6 months after CA, patients were classified into a "poor neurological outcome" group (CPC3 to CPC5) (n = 67) and "favorable neurological outcome" group (CPC1 and CPC2) (n = 13). Blood was sampled on admission, at 6 and 24 h after CA. Serum S-100B and NSE in "poor outcome" group were higher than those in "favorable outcome" group (P < 0.01). On ROC analysis, area under the curve of S-100B was 0.85, 0.94 and 1.0, respectively. These were greater than those of NSE at all sampling points. The "100%-specific" cutoff values of S-100B predictive of poor neurological outcome were 1.41, 0.21, and 0.05 ng/mL, respectively. These values corresponded to sensitivities of 20.9%, 62.8%, and 100%, respectively, each of which was higher than those of NSE. Conclusions: S-100B is more reliable as an early predictor of poor neurological outcome within 24 h after CA than NSE and can be applied clinically. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Background. None of the parameters can predict the deterioration of sepsis early enough. A new predictor allowing earlier detection of changes in septic patients' condition is indispensable. Methods. We examined whether cytokine-related mRNA expression in peripheral leukocytes, cytokine blood level, and monocyte human leukocyte antigen (HLA)-DR expression rate could be useful predictors of deterioration of sepsis. Twenty septic patients were enrolled. mRNA expression levels were quantified using real-time reverse transcriptase-polymerase chain reaction and assessed by percent changes during the first 24 h. Cytokine blood levels on admission and day 3 and monocyte HLA-DR expression rate on day 3 were also measured. Correlations between each of these parameters, and between these parameters and outcome were analyzed. Results. Among seven kinds of cytokines studied, only IL-10 mRNA level showed significant difference between survivors and non-survivors (P < 0.05). Mortality rate of interleukin (IL)-10 mRNA level upregulated group was significantly higher than that of IL-10 mRNA level down-regulated group (P < 0.05). HLA-DR expression rate in non-survivors were significantly lower than that in survivors (P < 0.05). Although IL-10 blood level on day 3 significantly correlated with HLA-DR expression on day 3(r = 0.54, P < 0.05), IL-10 blood level on admission did not correlate with it. Contrarily, the degree of up-regulation of IL-10 mRNA expression during the first 24 h significantly correlated with the degree of diminished HIA-DR expression on day 3 (r = 0.78, P < 0.001). Conclusions. Up-regulated IL-10 mRNA expression and diminished HLA-DR expression could be indicators of poor outcome. Furthermore, IL-10 mRNA expression measurement could predict the onset of immunoparalysis indicated by diminished HLA-DR expression earlier than IL-10 blood level measurement, leading to earlier commencement of the treatment. (C) 2008 Elsevier Inc. All rights reserved.

Septic shock is the most severe form of sepsis. It is widely accepted that cytokines play pivotal roles in the pathophysiology of septic shock. We reported previously that continuous hemodiafiltration (CHDF) using a polymethylmethacrylate (PMMA) membrane hemofilter removed various cytokines from blood continuously and efficiently, mainly by adsorption to membrane matrix of the hemofilter. Furthermore, in April 2000, we introduced to clinical practice a rapid assay system that determines blood levels of IL (interleukin)-6 in approximately 30 min. This enabled us to routinely measure blood IL-6 as an index of cytokine cascade activation in critically ill patients for real-time clinical monitoring of hypercytokinemia. The aim of the present cohort study was to evaluate the clinical efficacy of PMMA-CHDF in septic shock, a typical condition associated with hypercytokinemia. Forty-three patients with septic shock were assessed by monitoring of blood IL-6 level with a rapid assay system and immediate initiation of critical care including PMMA-CHDF for cytokine removal. Following initiation of PMMA-CHDF, early improvement of hemodynamics was noted, as well as an increase in urine output. PMMA-CHDF treatment improved both hypercytokinemia (assessed by measurement of blood IL-6 level) and dysoxia (assessed by measurement of blood lactate level). The present findings suggest that cytokine-oriented critical care using PMMA-CHDF might be an effective strategy for the treatment of septic shock.

56歳、男性。胆石膵炎に対し加療受けるも改善せず当院紹介となった。厚生労働省の急性膵炎重症度スコアは転院時13点、CT gradeはVであった。胆石は自然排石していた。PMMA-CHDFやSDDを含む集中治療を開始したが、経過中septic shockに陥り、steroidの使用を余儀なくされた。さらに感染性膵壊死を合併し、第40病日にnecrosectomy+open peritoneal drainageを施行した。当初腹腔内は細菌感染が主であったが、その後真菌が検出されmicafungin sodiumの投与を開始した。しかしその後も感染が制御できず炎症反応高値が遷延し、血液培養からTrichosporon asahiiが検出された。抗真菌薬をfluconazoleへ変更し血液培養は陰性化したが、他の感染を制御できず第138病日に永眠された。近年新しい抗真菌薬の開発・使用に伴い、真菌のbreakthroughが問題となっている。本症例のように著しい免疫不全の状態にある重症患者では特に注意が必要である。(著者抄録)

近年、敗血症性ショックに対する循環管理法は凄まじい勢いで進歩しており、その治療成績も向上していると考えられる。しかしながら、敗血症性ショック症例の中には、通常の循環管理に反応せず、急激な経過をとり死亡する場合も存在する。このように激烈な経過をとる敗血症性ショックでは経皮的心肺補助(PCPS)による循環のサポートが必要と考えられるが、敗血症性ショックに対するPCPS治療は侵襲が大きく、一般的ではない。われわれはIABPやCHDFを併用することで、PCPS施行に伴う侵襲を最小限度とするよう配慮し、敗血症性ショックに対しても、適応があればPCPSを施行することにしている。幾つかの工夫を施せば敗血症性ショックにおいてもPCPS治療は、安全にかつ効果的に施行できるものと考えられる。(著者抄録)

クリティカルケア領域における肝不全の診断や肝機能の評価は、まず肝細胞機能を評価し、その上で肝機能を代謝合成能、排泄能、細網内皮系機能に分け、これらを総合的に判断して行う。肝細胞機能としては動脈血中ケトン体比(AKBR)やosmolality gap(OG)、血中乳酸値の測定がある。劇症肝不全患者においては、生存例でAKBRの有意な上昇が認められ肝機能評価法として有用と考えられた。OGは治療経過中に正常値域に収斂する傾向にあったが、OGの算出法や有用性に依然として議論があり、肝機能評価法として極めて有用とは言い難い。また、代謝合成能としてはprothrombin timeやhepaplastin test等の凝固因子活性測定が一般的である。排泄能としてはbilirubinやD/T比測定、ICG試験が一般的に行われている。細網内皮機能としては99m-Tc-phytate colloid scintigraphによりKupffer cell機能を評価できる。これらの指標を組み合わせることで、重症患者の肝機能評価を正しく行うことが可能である。(著者抄録)

Objective: To evaluate the effect of genotypic differences and the blood interleukin-1 receptor antagonist (IL-1ra) / interleukin-1β (IL-1β) levels ratio within IL-1 gene cluster polymorphisms on the outcome. Methods: One hundred and ninety consecutive critically ill patients recruited on admission to the ICU, regardless of diagnosis, were studied. Interleukin-6 (IL-6) blood levels were measured daily with chemiluminescent enzyme immunoassay. IL-1β and IL-1ra blood levels at corresponding time when routinely measured IL-6 showed maximal values were measured retrospectively with enzyme amplified sensitivity immunoassay. Single nucleotide polymorphisms at position -511 and +3953 sites of the IL-1β (IL-1β-511^*C/T and IL1β+3953^*C/T) were identified with restriction fragment length polymorphism method. IL-1ra intron 2nd various number of tandem repeat polymorphism (IL-1RN^*1-5) was identified after polymerase chain reaction with gel electrophoresis. Results: IL-1RN^*1.1 homozygotes had significantly higher survival (P = 0.04) and higher blood IL-1ra/IL-1β ratio (P = 0.01) than the other genotypes in IL-1RN^*1-5. However, all those three polymorphisms (IL-1β-511^*C/T, IL-1β+3953^*C/T, and IL-1RN^*1-5) solely affect neither IL-1β nor IL-1ra blood levels in each. Conclusions: Non-IL-1RN^*1 alleles are associated with poor outcome and decrease in IL-1ra/IL-1β ratio causing overproduction of IL-6. Therefore, IL-1ra/IL-1β imbalance is considered to have induced the cytokine network collapse in those genetically high risk patients for hypercytokinemia.

Blood purification has been steadily improved in the field of critical care, supported by advances in related biomedical technologies as well as efforts to develop better operating procedures. As it has become clear that hypercytokinemia plays a key role in the pathophysiology of critical pathological conditions, use of various blood purification techniques to control hypercytokinemia has been investigated. Answers to questions concerning the optimal cytokine-removing device (dialyzer/hemofilter/adsorber) as well as operating procedures and conditions of such devices in particular clinical conditions have been obtained in the course Of Such investigations. The recent success in real-time monitoring of cytokine levels in clinical practice to assess the extent of cytokine network activation may improve the precision and efficacy of blood purification in the treatment of hypercytokinemia. In addition, the recently documented effects of genetic factors oil hypercytokinemia suggest that the introduction of tailor-made medicine considering the differences in genetic background among individual patients may improve the efficacy of blood purification as a countermeasure to hypercytokinemia. (c) 2006 Elsevier Ltd. All rights reserved.

The innate recognition of microbial components and subsequent activation of cytokine network are important in the pathophysiology of sepsis. Recently, functional gene polymorphisms in molecules associated with these responses were demonstrated. On the other hand, it has been claimed that there are ethnic differences in genetic polymorphisms. This study investigated toll-like receptor (TLR) 4, CD14, tumor necrosis factor (TNF)-alpha and -beta, and interleukin (IL)-10 gene polymorphisms in 197 Japanese critically ill patients and 214 healthy control subjects to evaluate the influence of these polymorphisms on clinical outcome. No Japanese participant carrying TLR4Asp299Gly or Thr399Ile was detected. No association of CD14-159C/T polymorphisms with genotype frequency or sepsis mortality was observed. Frequency of TNF-alpha-308 GA genotype was significantly higher in the sepsis group than in the control group and TNF-alpha-308GA and IL-10-592CC genotypes were related to poor outcome of sepsis. Ethnic differences in genetic variations are very important issues and the frequencies in this study differ from those previously reported in Caucasians. In conclusion, this study may indicate that TNF-alpha-308G/A and IL-10-592C/A polymorphisms involved in subsequent activation of cytokine network had a larger effect on clinical outcome in patients with sepsis than TLR4Asp299Gly, Thr399Ile, and CD14-159C/T polymorphisms associated with the initial host-microbial interaction. (c) 2005 Elsevier Inc. All rights reserved.

Background: The aim of the present study was to investigate whether tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6-related genotypic differences affect IL-6 blood levels m patients with systemic inflammatory response syndrome (SIRS) in an intensive care unit (ICU). Methods: Seven polymorphisms of TNF, IL-1, and IL-6-related polymorphisms were studied with an allele-specific polymerase chain reaction. One hundred and thirteen patients diagnosed with SIRS whose sequential organ failure assessment scores were ≥5 at the time when their daily measured IL-6 blood level peaked during the ICU stay (IL-6 max) were examined. IL-6 max, survival, and septic complications were compared between carriers and non-carriers of less frequent alleles, indicated as allele*2, in each polymorphism. Results: In single nucleotide polymorphism (SNP) at position -238 site of TNF-α (TNF-α- 238*G/A), IL-6-596*G/A, and IL-6-174*C/T, allele*2 frequencies were much lower in the Japanese than in the Caucasian population. IL-6 max was significantly higher in allele*2 carriers of IL-1β-511*C/T. Associations were found between susceptibility to septic shock and allele*2 carriage for both IL-1β-511*C/T and TNF-α-308*G/A, and also between poor prognosis and allele*2 carriage in both IL-1 receptor antagonist second intron various number of tandem repeats polymorphism (IL-1raRN*1-5) and TNF-α-308*G/A. IL-1β-511*C/T and IL-1raRN*1-5 were in linkage disequilibrium in this study population. Conclusions: Carriers of less frequent alleles in IL-1-related polymorphisms appear to have significant vulnerability to production of excessive IL-6 blood levels and to deterioration in septic shock. Copyright © 2005 by Lippincott Williams &amp Wilkins, Inc.

CHDF施行808例を対象に,血液浄化器膜素材の種類や膜面積,操作条件と小・中・大分子量物質のclearance(CL),filter life(FL)との関係について検討した.その結果,中・大分子量物質においては血流量や透析液流量,濾液流量を増加させてもCLはそれほど増大しないが膜面積を大きくすると増大することが明らかになった.小分子量物質ついては以下のことが判明した.濾液流量+透析液流量を増加させればCLは増大する.血流量や膜面積を大きくしてもCLはそれほど増大しない.膜素材によるCL差はほとんどない.濾液流量を大きくするとFLは短縮する.膜面積を大きくするとFLは延びる.膜素材によってFLは異なる