Intrahepatic CD206+ macrophages contribute to inflammation in advanced viral-related liver disease.

BACKGROUND & AIMS: Liver inflammation is key in the progression of chronic viral hepatitis to cirrhosis and hepatocellular carcinoma. The magnitude of viral replication and the specific anti-viral immune responses should govern the degree of inflammation, but a direct correlation is not consistently found in chronic viral hepatitis patients. We aim to better define the mechanisms that contribute to chronic liver inflammation. METHODS: Intrahepatic CD14+ myeloid cells from healthy donors (n=19) and patients with viral-related liver cirrhosis (HBV, HBV/HDV or HCV; n=15) were subjected to detailed phenotypic, molecular and functional characterisation. RESULTS: Unsupervised analysis of multi-parametric data showed that liver disease was associated with the intrahepatic expansion of activated myeloid cells mainly composed of pro-inflammatory CD14+HLA-DRhiCD206+ cells, which spontaneously produced TNFα and GM-CSF. These cells only showed heightened pro-inflammatory responses to bacterial TLR agonists and were more refractory to endotoxin-induced tolerance. A liver-specific enrichment of CD14+HLA-DRhiCD206+ cells was also detected in a humanised mouse model of liver inflammation. This accumulation was abrogated following oral antibiotic treatment, suggesting a direct involvement of translocated gut-derived microbial products in liver injury. CONCLUSIONS: Viral-related chronic liver inflammation is driven by the interplay between non-endotoxin-tolerant pro-inflammatory CD14+HLA-DRhiCD206+ myeloid cells and translocated bacterial products. Deciphering this mechanism paves the way for the development of therapeutic strategies specifically targeting CD206+ myeloid cells in viral-related liver disease patients. Lay summary: Viral-related chronic liver disease is driven by intrahepatic pro-inflammatory myeloid cells accumulating in a gut-derived bacterial product-dependent manner. Our findings support the use of oral antibiotics to ameliorate liver inflammation in these patients.

Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver.

The ability of innate immune cells to sense and respond to impending danger varies by anatomical location. The liver is considered tolerogenic but is still capable of mounting a successful immune response to clear various infections. To understand whether hepatic immune cells tune their response to different infectious challenges, we probed mononuclear cells purified from human healthy and diseased livers with distinct pathogen-associated molecules. We discovered that only the TLR8 agonist ssRNA40 selectively activated liver-resident innate immune cells to produce substantial quantities of IFN-γ. We identified CD161(Bright) mucosal-associated invariant T (MAIT) and CD56(Bright) NK cells as the responding liver-resident innate immune cells. Their activation was not directly induced by the TLR8 agonist but was dependent on IL-12 and IL-18 production by ssRNA40-activated intrahepatic monocytes. Importantly, the ssRNA40-induced cytokine-dependent activation of MAIT cells mirrored responses induced by bacteria, i.e., generating a selective production of high levels of IFN-γ, without the concomitant production of TNF-α or IL-17A. The intrahepatic IFN-γ production could be detected not only in healthy livers, but also in HBV- or HCV-infected livers. In conclusion, the human liver harbors a network of immune cells able to modulate their immunological responses to different pathogen-associated molecules. Their ability to generate a strong production of IFN-γ upon stimulation with TLR8 agonist opens new therapeutic opportunities for the treatment of diverse liver pathologies.

IL-7 licenses activation of human liver intrasinusoidal mucosal-associated invariant T cells.

Human mucosal-associated invariant T (MAIT) cells are a T cell population characterized by the expression of a semi-invariant TCR capable of recognizing bacterial products in the context of MR1. MAIT cells are enriched in the human liver, which is constantly exposed to bacterial products from the intestine. Whether this specific parenchymal localization influences their function remains unknown. We analyzed MAIT cells resident in the vascular bed of livers and showed that they represented the majority of T cells expressing NK markers and the dominant IL-17A(+) T cell subset in the human liver sinusoids. In comparison with MAIT cells purified from peripheral blood, intrasinusoidal MAIT cells expressed markers of T cell activation; however, TCR-mediated cytokine production was equally suppressed in both circulating and intrasinusoidal MAIT cells. MAIT cells also expressed high levels of IL-7R, and we showed that IL-7, a cytokine produced by hepatocytes during inflammation, regulated TCR-mediated activation of MAIT cells, licensing them to dramatically increase Th1 cytokines and IL-17A production. Our quantitative and functional data indicate that MAIT cells are a specialized cell population highly adapted to exert their immune functions in the vascular network of the liver.

Computer clinical decision support that automates personalized clinical care: a challenging but needed healthcare delivery strategy.

How to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems.

Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is an aggressive malignancy with few treatment options. As the status of the tumour immune microenvironment can affect progression of established tumours, we evaluated potential immune mechanisms associated with survival in HCC. METHODS: Immune gene expression profiles were analyzed in tumour and non-tumour liver tissues from resected HCC patients using quantitative PCR and immunohistochemistry. Tumour-infiltrating leukocytes (TILs) were isolated to verify the expression of immune genes and to identify proliferating TILs. These parameters were analyzed statistically in relation with patient survival and tumour phenotype (apoptosis and proliferation). RESULTS: The immune microenvironment within tumours was found to be heterogeneous, although globally more inert compared to the adjacent non-tumour liver tissue. Univariate analysis in 61 patients identified a group of innate immune genes whose expression within tumours is positively associated with patient survival. TNF, IL6 and CCL2 are the most significant genes, with TNF being an independent predictor of survival in multivariate analysis. The gene set includes macrophage and NK-associated molecules such as TLR4, TLR3, CCR2, NCR3. Most of these molecules are expressed by TILs. Importantly, proliferating immune cells, predominantly NK and T cells, are present in tumours of patients with longer survival, and exclusively in areas devoid of proliferating tumour cells. NK and CD8(+) T cell densities are correlated positively with tumour apoptosis, and negatively with tumour proliferation. CONCLUSIONS: Hence, an inflammatory immune microenvironment within HCC tumours could be an important means to control tumour progression via TIL activation and proliferation.

Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND & AIMS: Tumor and viral antigens are expressed by hepatocellular carcinoma (HCC) in patients with chronic hepatitis B, but little is known about the immunodominance and function of tumor- and virus-specific CD8+ T cells in these patients. METHODS: HLA-A2-restricted T-cell responses to 16 tumor antigens and hepatitis B virus (HBV) proteins were tested using 49 previously described epitopes. Cells from 30 HLA-A2+, HBV-infected patients (10 with HCC, 10 with HBV cirrhosis, and 10 HBV but no cirrhosis) were analyzed, after expansion, by enzyme-linked immunosorbent spot (ELISPOT). Interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2 production, as well as expression of the degranulation marker CD107a on tumor-specific CD8+ T cells, were evaluated. RESULTS: Cells from all groups had tumor-specific responses. The tumor antigens NY-ESO-1 and SSX-2 were most frequently targeted and were immunogenic in the HLA-A2 subtypes that are characteristic of Asian ethnicity. Tumor-specific T cells had low affinities; T cells from non-HCC patients were polyfunctional (IFN-gamma+, TNF-alpha+, CD107a+) and those from HCC patients displayed an exhausted phenotype (IFN-gamma+, CD107a+). Programmed Death 1 (PD-1) was expressed at higher levels on T cells from tumor and liver than peripheral blood from HCC patients and might contribute to T-cell exhaustion. Blocking PD-1/PD-L1 increased the frequency of tumor-specific T cells in HCC patients but did not restore T cell function. CONCLUSIONS: Patients with or without HCC have a quantitative and functional hierarchy of tumor-specific T cells. HLA-A2-restricted T cells from HCC patients target NY-ESO-1, but exist in an exhausted state that might require additional activation to restore function.

Lactate, procalcitonin, and amino-terminal pro-B-type natriuretic peptide versus cytokine measurements and clinical severity scores for prognostication in septic shock.

The biomarkers lactate, procalcitonin, and amino-terminal pro-B-type natriuretic peptide (NT-proBNP) are often promoted as being useful for prognostication in septic shock. This study aimed to compare the prognostic utility of these biomarkers with each other and with cytokine measurements and clinical severity scores, and to assess how these biomarkers may be combined to improve their prognostic utility. Seventy-two patients with septic shock were studied. The biomarkers were measured on the first 3 days of stay in the intensive care unit together with serum IL-1beta, IL-6, IL-10, and TNF-alpha levels. Although elevated baseline lactate levels predicted 28-day mortality, elevated procalcitonin and NT-proBNP levels were only predictive from days 2 and 3, respectively. The prognostic utility of baseline lactate levels was poorer than that of baseline cytokine levels, the Acute Physiology and Chronic Health Evaluation II score, and the Sequential Organ Failure Assessment score. However, a rising trend in lactate and procalcitonin levels between days 1 and 2 had superior prognostic utility compared with absolute levels. Indeed, using multivariate analysis, the presence of a concurrent increase in both lactate and procalcitonin levels between days 1 and 2 superseded all cytokine measurements and clinical severity scores as the sole independent predictor of 28-day mortality. In conclusion, elevated baseline lactate levels offer superior prognostic accuracy to baseline procalcitonin levels, which in turn are superior to NT-proBNP levels. To improve their prognostic utility beyond those of cytokine measurements and clinical severity scores, serial lactate and procalcitonin measurements may be combined.

Living donor liver transplantation for hepatocellular carcinoma: a single centre experience.

BACKGROUND: The indications of liver transplantation in hepatocellular carcinoma (HCC) are evolving. With the advent of living donor liver transplantation (LDLT), there is a renewed interest in this procedure for tumors beyond the standard Milan criteria. METHODS: We retrospectively analyzed the outcome of 28 patients who underwent LDLT for HCC in one institution. Survival analysis was done using the Kaplan-Meier method. RESULTS: Of the 28 patients, 9, 12 and 7 had Child's A, B and C cirrhosis respectively; 26 (93%) had underlying hepatitis B or C. Nineteen patients (68%) had tumors exceeding the Milan criteria. Postoperative (within 90 days) mortality and morbidity rates were 2/28 (7%) and 7/28 (25%) respectively. The actuarial overall 1-year, 2-year and 3-year survival rates were 76%, 76% and 51%, respectively. The actuarial 1-year, 2-year and 3-year recurrence free survival rates (computed by censoring the data of patients who died of causes other than HCC recurrence) were 88%, 82% and 70%, respectively. Although the survival rates were better for tumors within the Milan criteria than those exceeding them, the difference was not significant. CONCLUSIONS: LDLT is an effective modality in the treatment of HCC in patients with liver cirrhosis. It may also provide an opportunity for potential cure to patients with tumors beyond Milan criteria.

The role of liver transplantation for hilar cholangiocarcinoma.

BACKGROUND: Hilar cholangiocarcinoma is a devastating disease. Surgery is the only potentially curative modality. However, the results of surgical resection for hilar cholangiocarcinomas are disappointing. The introduction of liver transplantation for this condition has brought new hope for the management of this disease. The aim of this review is to discuss the role of liver transplantation in this disease. DATA SOURCES: A MEDLINE search was conducted for the articles on liver transplantation for hilar cholangiocarcinoma. Their results have been compiled and compared with the existing literature on resection for this disease. RESULTS: The earlier series on liver transplantation for hilar cholangiocarcinoma were not encouraging because of poor patient selection. The Mayo Clinic protocol of neoadjuvant chemoradiation followed by liver transplantation has shown remarkable success (survival at 1-, 3-, and 5-year post-transplantation being 92%, 82%, and 82%, respectively). With better patient selection and integration of neoadjuvant chemoradiation, the long-term survival is superior to that of the patients who undergo resection, as shown by the published literature on resection. The limitations of organ availability can be overcome by the living donor liver transplantation programme. This review article discusses the rationale, pros and cons of liver transplantation vis-á-vis resection for hilar cholangiocarcinoma. CONCLUSIONS: Liver transplantation, especially living donor liver transplantation, is a new and exciting alternative to resection for hilar cholangiocarcinoma. Integration of neoadjuvant chemoradiation has the potential to further improve the curative potential of liver transplantation. The strategy of combining neoadjuvant chemoradiation and liver transplantation brings new hope for the treatment of this difficult disease.

Pre-transplant optimization by Molecular Adsorbent Recirculating System in patients with severely decompensated chronic liver disease.

BACKGROUND: The outcome of liver transplantation (LT) is influenced by the recipient's clinical condition. In a retrospective observational study, we evaluated the role of pre-LT Molecular Adsorbent Recirculating System (MARS) treatment in improving the clinical status and thereby the outcome of patients with chronic liver disease and severe hepatic decompensation. METHODS: Between March 2002 and September 2006, 70 patients with end-stage chronic liver disease underwent living-donor LT (LDLT). Of these, 9 (13%) patients with severely decompensated liver function (serum bilirubin> 350 micromol/L [20 mg/dL] and/or hepatic encephalopathy > or = grade 2) received pre-LT MARS treatment. RESULTS: The median MELD score was 33 (range, 26-47). A median of 2 (range, 1-6) sessions (8 hour/session) of MARS dialysis was performed per patient. MARS treatment was associated with reduction in serum bilirubin, creatinine and ammonia levels and no procedure-related complications. CONCLUSION: Pre-LT MARS is well tolerated and results in reduction of jaundice and improvement in renal function and may be useful in the management of patients with severe hepatic decompensation.

Adult living donor liver transplantation in Singapore: the Asian centre for liver diseases and transplantation experience.

INTRODUCTION: Living donor liver transplantation (LDLT) has progressed dramatically in Asia due to the scarcity of cadaver donors and is increasingly performed in Singapore. The authors present their experience with adult LDLT. MATERIALS AND METHODS: Adult LDLTs performed at the Asian Centre for Liver Diseases and Transplantation, Singapore from 20 April 2002 until 20 March 2006 were reviewed. All patients received right lobe grafts and were managed by the same team throughout this period. Data were obtained by chart review. This study presents both recipient and donor outcomes in a single centre. RESULTS: A total of 65 patients underwent LDLT. Forty-three were genetically related while 22 were from emotionally-related donors. The majority were chronic liver failure while 14% were acute. The most common indication for LDLT was end-stage liver disease due to hepatitis B virus. A total of 22 patients with hepatoma were transplanted and overall 1-year disease specific survival was 94.4%. The mean model for end-stage liver disease (MELD) score was 17.4 +/- 9.4 (range, 6 to 40). Six patients had preoperative molecular adsorbent recycling system (MARS) dialysis with 83% transplant success rate. The mean follow-up was 479.2 days with a median of 356 days. One-year overall survival was 80.5%. There was 1 donor mortality and morbidity rate was 17%. Our series is in its early stage with good perioperative survival outcome with 1-month and 3-month actuarial survival rates of 95.4% and 87.3% respectively. CONCLUSION: The study demonstrates that LDLT can be done safely with good results for a variety of liver diseases. However, with dynamically evolving criteria and management strategies, further studies are needed to maximise treatment outcome.

Population pharmacokinetics of tacrolimus in whole blood and plasma in asian liver transplant patients.

OBJECTIVES: The objectives of this study were to develop population pharmacokinetic models of tacrolimus in an Asian population with whole blood and plasma drug concentration data, to compare the variability of the pharmacokinetic parameters in these two matrices and to search for the main patient characteristics that explain the variability in pharmacokinetic parameters. STUDY DESIGN: Prospective pharmacokinetic assessment followed by model fitting. PATIENTS: Whole blood samples from 31 liver transplant patients in a local hospital receiving oral tacrolimus as part of their immunosuppressive therapy were assessed. Plasma samples from 29 of the 31 patients were also evaluated. Concentrations of tacrolimus in whole blood and plasma were determined by an electrospray high-performance liquid chromatography with tandem mass spectrometry. Two hundred and thirteen whole blood and 157 plasma tacrolimus concentrations were used for building two nonlinear mixed-effects population models to describe the disposition of tacrolimus in whole blood and plasma, respectively. Covariates that were investigated included demographic characteristics, biological markers of liver and renal functions, corticosteroid dose and haematological parameter. RESULTS: A one-compartment model was used to describe the whole blood and plasma concentration-time data of tacrolimus after oral administration. For the whole blood population model, the population estimates of the first-order absorption rate constant (k(a)), apparent clearance based on whole blood concentration after oral administration (CL(B)/F) and apparent volume of distribution based on whole blood concentrations after oral administration (V(d,B)/F) were 2.08h(-1), 14.1 L/h and 217L, respectively. The coefficient of variations (CVs) of interpatient variabilities in CL(B)/F and V(d,B)/F were 65.7% and 63.8%, respectively. Bodyweight, liver and renal function influenced CL(B)/F, while height and haematocrit influenced V(d,B)/F. The residual (unexplained) variability was 34.8%. For the plasma population model, the population estimates of the k(a), apparent clearance based on plasma concentrations after oral administration (CL(P)/F) and apparent volume of distribution based on plasma concentrations after oral administration (V(d,P)/F) were 5.21h(-1), 537 L/h and 563L, respectively. The CVs of interpatient variabilities in CL(P)/F and V(d,P)/F were 96.0% and 105.4%, respectively. Bodyweight was found to influence CL(P)/F, while the erythrocyte-to-plasma concentration ratio influenced V(d,P)/F. The residual (unexplained) variability was 49.8% at the mean plasma concentration of 1.1 ng/mL. CONCLUSIONS: Whole blood and plasma population pharmacokinetic models of tacrolimus in Asian adult and paediatric liver transplant patients were developed using prospective data in a clinical setting. This has identified and quantified sources of interindividual variability in CL(B)/F, V(d,B)/F, CL(P)/F and V(d,P)/F of tacrolimus in Asian liver transplant patients. Information derived from the whole blood population model may subsequently be used by clinicians for dosage individualisation through Bayesian forecasting.

Evaluating the pharmacoeconomic effect of adding tiotropium bromide to the management of chronic obstructive pulmonary disease patients in Singapore.

OBJECTIVE: To perform a pharmacoeconomic analysis on the treatment of chronic obstructive pulmonary disease (COPD) with the addition of tiotropium bromide. METHODS: Pharmacoeconomic modeling was performed utilizing the efficacy of tiotropium bromide from the literature on different settings and severity of COPD. Reductions in exacerbations, hospitalizations, and number of exacerbation days per year were derived from these studies. Cost of drug treatment, exacerbations, hospitalization, and loss of income were derived from local data in Singapore and reported in Singapore dollars (US$1=S$1.71). A model was constructed to calculate the impact of one-year treatment with tiotropium bromide, and the results were reported for the total incremental cost per year, cost per year needed to reduce one hospitalization in one year, and cost-savings from hospitalizations in one year. Sensitivity analysis were performed for different number of patients treated per year, differing cost of hospitalization, different cost for tiotropium bromide, different impact of tiotropium bromide on clinical outcomes, and the different amount of substitution drug utilized in the comparator group. RESULTS: Using the different clinical effects and looking at the impact on treating 1000, 2000, and 10,000 patients per year, most of the results showed a high level of decrease in overall cost per year that ranged from S$145.40 to S$840.37 per patient treated. Cost per year needed to reduce one hospitalization in one year ranged from S$3217.31 to S$18,148.92. Cost-savings from hospitalizations in one year per patient treated ranged from $57.16 to $322.49. This may contribute as high as 83% of the overall cost saving. Sensitivity analysis supports the cost savings finding. CONCLUSION: Adding tiotropium bromide for severe COPD patients would lead to a significant cost savings for the economy.

Nitric oxide synthase and heme oxygenase expressions in human liver cirrhosis.

AIM: Portal hypertension is a common complication of liver cirrhosis. Intrahepatic pressure can be elevated in several ways. Abnormal architecture affecting the vasculature, an increase in vasoconstrictors and increased circulation from the splanchnic viscera into the portal system may all contribute. It follows that endogenous vasodilators may be able to alleviate the hypertension. We therefore aimed to investigate the levels of endogenous vasodilators, nitric oxide (NO) and carbon monoxide (CO) through the expression of nitric oxide synthase (NOS) and heme oxygenase (HO). METHOD: Cirrhotic (n=20) and non-cirrhotic (n=20) livers were obtained from patients who had undergone surgery. The mRNA and protein expressions of the various isoforms of NOS and HO were examined using competitive PCR, Western Blot and immunohistochemistry. RESULTS: There was no significant change in either inducible NOS (iNOS) or neuronal NOS (nNOS) expressions while endothelial NOS (eNOS) was up-regulated in cirrhotic livers. Concomitantly, caveolin-1, an established down-regulator of eNOS, was up-regulated. Inducible HO-1 and constitutive HO-2 were found to show increased expression in cirrhotic livers albeit in different localizations. CONCLUSION: The differences of NOS expression might be due to their differing roles in maintaining liver homeostasis and/or involvement in the pathology of cirrhosis. Sheer stress within the hypertensive liver may induce increased expression of eNOS. In turn, caveolin-1 is also increased. Whether this serves as a defense mechanism against further cirrhosis or is a consequence of cirrhosis, is yet unknown. The elevated expression of HO-1 and HO-2 suggest that CO may compensate in its role as a vasodilator albeit weakly. It is possible that CO and NO have parallel or coordinated functions within the liver and may work antagonistically in the pathophysiology of portal hypertension.

Expression of the FAT10 gene is highly upregulated in hepatocellular carcinoma and other gastrointestinal and gynecological cancers.

The ubiquitin-like modifier (UBL) family has recently generated much interest in the scientific community, as it is implicated to play important regulatory roles via novel protein-protein modification. FAT10 (diubiquitin) belongs to this family of proteins, comprising two ubiquitin-like moieties fused in tandem, and has been implicated to be involved in the maintenance of spindle integrity during mitosis. As FAT10 may play a role in the regulation of genomic stability, we examined if there is an association between FAT10 expression and hepatocellular carcinoma (HCC) or other cancers. Northern blot analyses revealed upregulation of FAT10 expression in the tumors of 90% of HCC patients. In situ hybridization as well as immunohistochemistry utilizing anti-FAT10 antibodies localized highest FAT10 expression in the nucleus of HCC hepatocytes rather than the surrounding immune and non-HCC cells. FAT10 expression was also found to be highly upregulated in other cancers of the gastrointestinal tract and female reproductive system. In conclusion, we demonstrated upregulation of FAT10 expression in various gastrointestinal and gynecological cancers. Its overexpression is unrelated to the general increase in protein synthesis or a general immune/inflammatory response to cancer. Rather, FAT10 may modulate tumorigenesis through its reported interaction with the MAD2 spindle-assembly checkpoint protein.

In-hospital and 5-year mortality of patients treated in the ICU for acute exacerbation of COPD: a retrospective study.

STUDY OBJECTIVES: The prognosis of patients with COPD requiring admission to the ICU is generally believed to be poor. There is a paucity of long-term survival data. We undertook a study to examine both the in-hospital and 5-year mortality rates and to identify the clinical predictors of these outcomes. DESIGN: We conducted a retrospective cohort study of 57 patients admitted to the ICU between January 1999 and December 2000 for acute respiratory failure attributable to COPD. RESULTS: The mean (+/-SD) age of the study population was 70 +/- 8 years. More than 90% of patients required intubation, and the mean duration of mechanical ventilation (MV) was 2.3 +/- 2.2 days. The in-hospital mortality rate for the entire cohort was 24.5%. The mortality rates at 6 months and 1, 3, and 5 years were 39.0%, 42.7%, 61.2%, and 75.9%, respectively, following admission to the ICU. The median survival time for all patients was 26 months. The mortality rate at 5 years was 69.6% for patients who were discharged alive from the hospital. Using multivariate analysis, hospital mortality correlated positively with age, previous history of MV, long-term use of oral corticosteroids, ICU admission albumin level, APACHE (acute physiology and chronic health evaluation) II score, and duration of hospitalization. No factors predictive of mortality at 5 years were identified. CONCLUSIONS: We support previous findings of good early survival and significant but acceptable long-term mortality rates in patients who have been admitted to the ICU for acute exacerbation of COPD. Increased age, previous history of MV, poor nutritional status, and higher APACHE II score on ICU admission could be identified as risk factors associated with increased mortality rates. Long-term survival of patients with COPD who required MV for an acute exacerbation of their disease cannot be predicted simply from data available at the time of intubation. Physicians should incorporate these factors in their decision-making process.

Inhalational nickel carbonyl poisoning in waste processing workers.

BACKGROUND: Nickel carbonyl is formed when carbon monoxide comes into contact with active nickel. The inhaled nickel carbonyl is rapidly absorbed and distributed mainly to the lungs, brain, adrenal glands, and kidneys. In severe cases, acute nickel carbonyl exposure has been reported to cause death. DESIGN: Descriptive study. PATIENTS: Seven young men presented with fever, chills, substernal pleuritic chest pain, and exertional dyspnea. Extensive microbiological and toxicological investigations (including blood, urine, and bronchial specimens) for known pathogens and occupational toxins were performed. The clinical course and radiologic findings of each patient, including autopsy findings of three patients who died, were described. RESULTS: Four patients received treatment in the ICU. Elevated urinary nickel concentration was detected in all patients. Results of extensive microbiological investigations were unremarkable. No patients received chelating agents. Pulmonary consolidation, edema, hemorrhage, and fibrosis were observed at autopsy in patients who died. An out-of-date chemical used during neutralization of nickel waste was implicated as the source of nickel carbonyl poisoning. CONCLUSIONS: High mortality was reported in patients who presented subacutely following nickel carbonyl exposure. Further studies should be performed to clarify the role of chelation therapy in the subacute phases following nickel carbonyl exposure.

Noninvasive ventilation in hypercapnic acute respiratory failure due to chronic obstructive pulmonary disease vs. other conditions: effectiveness and predictors of failure.

OBJECTIVE: This study compared the effectiveness of noninvasive ventilation (NIV) and the risk factors for NIV failure in hypercapnic acute respiratory failure (ARF) due to chronic obstructive pulmonary disease (COPD) vs. non-COPD conditions. DESIGN AND SETTING: Prospective cohort study in the medical intensive care unit of a university hospital. PATIENTS AND PARTICIPANTS: 111 patients with hypercapnic ARF, 43 of whom had COPD exacerbations and 68 other conditions. Baseline characteristics of the two groups were similar. MEASUREMENTS AND RESULTS: The risk of NIV failure, defined as the need for endotracheal intubation, was significantly lower in COPD than in other conditions (19% vs. 47%). High APACHE II score was an independent predictor of NIV failure in COPD (OR 5.38 per 5 points). The presence of pneumonia (OR 5.63), high APACHE II score (OR 2.59 per 5 points), rapid heart rate (OR 1.22 per 5 beats/min), and high PaCO(2) 1 h after NIV (OR 1.22 per 5 mmHg) were independent predictors of NIV failure in the non-COPD group. Failure of NIV independently predicted mortality (OR 10.53). CONCLUSIONS: Noninvasive ventilation was more effective in preventing endotracheal intubation in hypercapnic ARF due to COPD than non-COPD conditions. High APACHE II score predicted NIV failure in both groups. Noninvasive ventilation was least effective in patients with hypercapnic ARF due to pneumonia.

Feasibility of using low-volume tissue samples for gene expression profiling of advanced non-small cell lung cancers.

PURPOSE: The majority of patients with non-small cell lung cancer (NSCLC) present at an advanced clinical stage, when surgery is not a recommended therapeutic option. In such cases, tissues for molecular research are usually limited to the low-volume samples obtained at the time of diagnosis, usually via fine-needle aspiration (FNA). We tested the feasibility of performing gene expression profiling of advanced NSCLCs using amplified RNA from lung FNAs. EXPERIMENTAL DESIGN AND RESULTS: A total of 46 FNAs was tested, of which 18 yielded RNA of sufficient quality for microarray analysis. Expression profiles of these 18 samples were compared with profiles of 17 pairs of tumor and normal lung tissues that had been surgically obtained. Using a variety of unsupervised and supervised analytical approaches, we found that the FNA profiles were highly distinct from the normal samples and similar to the tumor profiles. CONCLUSIONS: We conclude that when RNA amplification is successful, gene expression profiles from NSCLC FNAs can determine malignancy and suggest that with additional refinement and standardization of sample collection and RNA amplification protocols, it will be possible to conduct additional and more detailed molecular analysis of advanced NSCLC using lung FNAs.

Temporal expression of hepatic inducible nitric oxide synthase in liver cirrhosis.

AIM: Nitric oxide (NO) has been implicated in the pathogenesis of liver cirrhosis. We have found inducible nitric oxide synthase (iNOS) can be induced in hepatocytes of cirrhotic liver. This study further investigated the temporal expression and activity of hepatic iNOS in cirrhosis development. METHODS: Cirrhosis was induced in rats by chronic bile duct ligation (BDL). At different time points after the operation, samples were collected to examine NO concentration, liver function, and morphological changes. Hepatocytes were isolated for determination of iNOS mRNA, protein and enzymatic activity. RESULTS: Histological examination showed early cirrhosis 1-2 wk after BDL, with advanced cirrhosis at 3-4 wk. Bilirubin increased dramatically 3 d after BDL, but decreased by 47% on d 14. Three weeks after BDL, it elevated again. Systemic NO concentration did not increase significantly until 4 wk after BDL, when ascites developed. Hepatocyte iNOS mRNA expression was identified 3 d after BDL, and enhanced with time to 3 wk, but reduced thereafter. iNOS protein showed a similar pattern to mRNA expression. iNOS activity decreased from d 3 to d 7, but increased again thereafter till d 21. CONCLUSION: Hepatic iNOS can be induced in the early stage, which increases with time as cirrhosis develops. Its enzymatic activity is significantly correlated with protein expression and histological alterations of the liver, but not with systemic NO levels, nor with absolute values of liver function markers.