Stratified Whole Genome Linkage Analysis of Chiari Type I Malformation Implicates Known Klippel-Feil Syndrome Genes as Putative Disease Candidates

Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of “CTD-negative” families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3–5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI.     

Occurrence of early and late asthmatic reaction after provocation with antigen and the status of pulmonary ventilation in patients with hay fever after the pollination season]

Pulmonary ventilation and asthmatic reaction under laboratory conditions have been investigated in 23 patients with allergic rhinitis hypersensitive to grass pollen. Pulmonary ventilation has been assessed with the aid of VCin, FVC, FEV1, FEV1/VCin, PEF, MEF50, and MTT. Asthmatic reaction has been produced by an inhalation of allergens mixture with dose-response technique. An early reaction has been diagnosed, when FEV1 decreased by at least 20% or MEF50 by 30% within 10 minutes, and late reaction when the same parameters decreased after 6 or 24 hours. An early asthmatic reaction has been noted in 2 patients (8.7%), late--in 4 patients (17.4%), and double (both early and late) reaction in 2 patients (8.7%). Pulmonary ventilation has been normal in all examined patients, except two of them with peripheral airways obstruction (MEF50 less than 70% of the normal value). Results suggest, that asthmatic reaction may be provoked in the laboratory in patients with pollinosis and normal pulmonary ventilation after pollen season. Such a reaction may also be expected during a natural exposition to pollens.     

Frequency of common colds and serum levels of sICAM-1 (CD54), sLFA-3 (CD58) and sIL-2R (CD25).

Epidemiologic case-control studies have suggested an inverse relationship between past medical history of frequency of common colds and subsequent cancer risk for various sites. One hypothetical explanation for this finding may be that there are unknown differences in immune responsiveness between patients developing cancer and healthy individuals. The present study examines the relationship between the frequency of common colds and a) plasma levels of sICAM-1/CD54, sLFA-3/CD58 and sIL-2R/CD25 which are believed to modulate activation of immune responses, and b) cell-mediated immunity in vivo as determined by Multitest Mérieux. The investigation was conducted as a correlation study amongst a healthy group of individuals from the general population in Germany. We found a statistically significant inverse relationship between frequency of common colds and levels of sCD58 and, partially, sCD54. No association was found between levels of sCD25 and results of Multitest Mérieux.     

Inbreeding depresses immune response in song sparrows (Melospiza melodia): direct and inter-generational effects

A thorough knowledge of relationships between host genotype and immunity to parasitic infection is required to understand parasite-mediated mechanisms of genetic and population change. It has been suggested that immunity may decline with inbreeding. However, the relationship between inbreeding level and a host's response to a novel immune challenge has not been investigated in a natural population. We used the pedigreed population of song sparrows (Melospiza melodia) inhabiting Mandarte Island, Canada, to test the hypothesis that a sparrow's cell-mediated immune response (CMI) to an experimental challenge would decline with individual or parental inbreeding. CMI in 6-day-old chicks declined significantly with their mother's coefficient of inbreeding, demonstrating an inter-generational effect of maternal inbreeding on offspring immunity. In fledged juveniles and adult sparrows, CMI declined markedly with an individual's own coefficient of inbreeding, but not its mother's. This relationship was consistent across seasons, and was not attributable solely to heterosis in offspring of immigrant breeders. CMI also declined with age and increased with body condition in adult sparrows, but inbreeding explained 37% of the total variation. We emphasize the implications of this dramatic inbreeding depression in cell-mediated immunity for theories of parasite-mediated evolution and the susceptibility of small, inbred populations.     

Hydrodynamic and Longitudinal Impedance Analysis of Cerebrospinal Fluid Dynamics at the Craniovertebral Junction in Type I Chiari Malformation

Elevated or reduced velocity of cerebrospinal fluid (CSF) at the craniovertebral junction (CVJ) has been associated with type I Chiari malformation (CMI). Thus, quantification of hydrodynamic parameters that describe the CSF dynamics could help assess disease severity and surgical outcome. In this study, we describe the methodology to quantify CSF hydrodynamic parameters near the CVJ and upper cervical spine utilizing subject-specific computational fluid dynamics (CFD) simulations based on in vivo MRI measurements of flow and geometry. Hydrodynamic parameters were computed for a healthy subject and two CMI patients both pre- and post-decompression surgery to determine the differences between cases. For the first time, we present the methods to quantify longitudinal impedance (LI) to CSF motion, a subject-specific hydrodynamic parameter that may have value to help quantify the CSF flow blockage severity in CMI. In addition, the following hydrodynamic parameters were quantified for each case: maximum velocity in systole and diastole, Reynolds and Womersley number, and peak pressure drop during the CSF cardiac flow cycle. The following geometric parameters were quantified: cross-sectional area and hydraulic diameter of the spinal subarachnoid space (SAS). The mean values of the geometric parameters increased post-surgically for the CMI models, but remained smaller than the healthy volunteer. All hydrodynamic parameters, except pressure drop, decreased post-surgically for the CMI patients, but remained greater than in the healthy case. Peak pressure drop alterations were mixed. To our knowledge this study represents the first subject-specific CFD simulation of CMI decompression surgery and quantification of LI in the CSF space. Further study in a larger patient and control group is needed to determine if the presented geometric and/or hydrodynamic parameters are helpful for surgical planning.     

Evaluation of influenza vaccine‐induced cell‐mediated immunity: Comparison between methods using peripheral blood mononuclear cells and whole blood

Assessment of cell‐mediated immunity (CMI) may be critical to evaluating the ability of individuals to protect themselves against influenza virus infection. However, it has been difficult to evaluate CMI because no simple means of measuring it is currently available. The aim of this study was to compare the performance of a CMI measurement method developed by us, which involves reacting whole blood with antigen, with the conventional method, which is based on isolating peripheral blood mononuclear cells (PBMCs). Correlations between these methods before and after vaccination of 26 healthy adults (aged 28–58 years; 12 men and 14 women) were assessed and changes in CMI after influenza vaccination in PBMCs cultured with antigen for 48 and 96 hr and whole blood cultured with antigen for 48 hr were studied. Results of CMI measurement using whole blood on Day 2 and PBMCs on Day 4 were found to be correlated. Spearman's correlation coefficients with four antigens (A [H1N1], A [H3N2], B [Yamagata lineage], and B [Victoria lineage]) before vaccination were 0.55, 0.61, 0.58, and 0.70, respectively and 0.40, 0.45, 0.62, and 0.52, respectively, after vaccination. CMI was detected sooner when whole blood was reacted with antigen than when PBMCs were reacted with antigen. The rate of positive reaction of influenza A (H1N1 and H3N2) in whole blood on Day 2 was higher than that in PBMCs on Day 2. Our method is simple and may be useful for vaccine development because it can measure CMI in a small amount of blood without separating off PBMCs.     

Assessing labile organic carbon in soils undergoing land use change in Brazil: A comparison of approaches

The labile organic C (LC) and C management index (CMI) may be useful indicators of alterations of soil organic matter (SOM) in areas undergoing land use change (LUC) for biofuels production. However, there is no consensus on which methodology is best suited for quantifying LC and CMI. The main goal of this study was to assess alterations on LC contents and CMI values in sites undergoing the LUC native vegetation (NV)-pasture (PA)-sugarcane (SC) in south-central Brazil, and evaluated the sensitivity of different methods commonly used to assess LC and CMI, in order to select a best-suited method to quantify these indicators in tropical regions. The conversion NV-PA decreased the LC and CMI, whilst the conversion of PA-SC tended to increase the CMI. Accordingly, cropping sugarcane in areas previously used as pastures, as currently has been observed in Brazil, enhance SOM quality. The methodology used to quantify the LC and the CMI is critical to infer about LUC effects. Both methods proposed by Blair et al. (1995) and Diekow et al. (2005) were highly sensitive to the conversions evaluated in this research. However, Diekow et al. (2005) is the most suitable method to estimate the LC and CMI in sites undergoing LUC in Brazil, since the approach of Blair et al. (1995) notably overestimates these SOM quality indicators. We reiterate that the SOM changes are well expressed by the total soil organic C in areas undergoing LUC and, integrated approaches, such as the CMI, are quite suitable to evaluate the effects of LUC on SOM.     

2型糖尿病患者心脏代谢指数与白蛋白尿的关系研究

摘要 目的：探讨2型糖尿病（T2DM）患者心脏代谢指数（CMI）与白蛋白尿的关系。方法：选取2012年2月~2020年7月期间在江苏大学附属医院内分泌代谢科就诊且被诊断为T2DM的患者555例,收集患者的临床资料。根据CMI不同数值将患者分为低CMI（L-CMI）组（n=185）、中CMI（M-CMI）组（n=185）和高CMI（H-CMI）组（n=185）,按照尿白蛋白/肌酐比值（UACR）将研究对象分为正常白蛋白尿组（n=294）、微量白蛋白尿组（n=209）和大量白蛋白尿组（n=52）,然后对CMI与T2DM患者发生异常白蛋白尿的关系进行分析,通过受试者工作特征（ROC）曲线评估CMI对T2DM患者发生异常白蛋白尿的预测价值。结果：不同UACR组的收缩压（SBP）、舒张压（DBP）、体质量指数（BMI）、CMI、甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、糖化血红蛋白（HbA1c）、空腹血糖（FPG）、空腹胰岛素（FINS）、空腹C肽（FC-P）、稳态模型评估胰岛素抵抗指数（HOMA-IR）、尿素氮（BUN）、血尿酸（SUA）、血肌酐（Scr）及肾小球滤过率（eGFR）比较均有统计学差异（P＜0.05）。L-CMI组、M-CMI组、H-CMI组异常白蛋白尿发生比例分别为21.08%、42.70%、77.30%,异常白蛋白尿发生比例呈显著递增趋势（P＜0.05）。Spearman秩相关分析结果显示,T2DM患者UACR与FINS、BUN、 CMI、Scr、SUA、SBP、DBP、BMI、TG、TC、HbA1c、FPG、FC-P、HOMA-IR呈正相关（P<0.05）,与eGFR、HDL-C呈负相关（P<0.05）。多元线性回归分析显示,CMI对UACR的影响强度最大（P＜0.05）。Logistic回归分析结果显示,年龄、SBP、CMI、TC、LDL-C及HbA1c是T2DM患者发生异常白蛋白尿的独立危险因素（P＜0.05）。CMI预测异常白蛋白尿发生的曲线下面积为0.801,预测异常白蛋白尿的敏感性、特异性分别为68.60%、76.90%。结论：T2DM患者异常白蛋白尿发生风险与CMI密切相关,提示CMI有望成为临床上糖尿病肾病（DKD）的预测指标。     

Detection of antibody-dependent complement-mediated inactivation of both autologous and heterologous virus in primary human immunodeficiency virus type 1 infection

Specific CD8 T-cell responses to human immunodeficiency virus type 1 (HIV-1) are induced in primary infection and make an important contribution to the control of early viral replication. The importance of neutralizing antibodies in containing primary viremia is questioned because they usually arise much later. Nevertheless antienvelope antibodies develop simultaneously with, or even before, peak viremia. We determined whether such antibodies might control viremia by complement-mediated inactivation (CMI). In each of seven patients studied, antibodies capable of CMI appeared at or shortly after the peak in viremia, concomitantly with detection of virus-specific T-cell responses. The CMI was effective on both autologous and heterologous HIV-1 isolates. Activation of the classical pathway and direct viral lysis were at least partly responsible. Since immunoglobulin G (IgG)-antibodies triggered the CMI, specific memory B cells could also be induced by vaccination. Thus, consideration should be given to vaccination strategies that induce IgG antibodies capable of CMI.     

Conditional mutual inclusive information enables accurate quantification of associations in gene regulatory networks

Mutual information (MI), a quantity describing the nonlinear dependence between two random variables, has been widely used to construct gene regulatory networks (GRNs). Despite its good performance, MI cannot separate the direct regulations from indirect ones among genes. Although the conditional mutual information (CMI) is able to identify the direct regulations, it generally underestimates the regulation strength, i.e. it may result in false negatives when inferring gene regulations. In this work, to overcome the problems, we propose a novel concept, namely conditional mutual inclusive information (CMI2), to describe the regulations between genes. Furthermore, with CMI2, we develop a new approach, namely CMI2NI (CMI2-based network inference), for reverse-engineering GRNs. In CMI2NI, CMI2 is used to quantify the mutual information between two genes given a third one through calculating the Kullback–Leibler divergence between the postulated distributions of including and excluding the edge between the two genes. The benchmark results on the GRNs from DREAM challenge as well as the SOS DNA repair network in Escherichia coli demonstrate the superior performance of CMI2NI. Specifically, even for gene expression data with small sample size, CMI2NI can not only infer the correct topology of the regulation networks but also accurately quantify the regulation strength between genes. As a case study, CMI2NI was also used to reconstruct cancer-specific GRNs using gene expression data from The Cancer Genome Atlas (TCGA). CMI2NI is freely accessible at http://www.comp-sysbio.org/cmi2ni.     

Environmental and genetic variation in T-cell-mediated immune response of fledgling American kestrels

We investigated genetic and environmental components of variance in avian T-cell-mediated immune response (CMI) through a cross-fostering experiment conducted on wild American kestrels (Falco sparverius). CMI was evaluated in vivo by an experimental challenge with phytohaemagglutinin, a T-cell mitogen, injected intradermally in fledglings. Additionally, we assessed two measures of nutritional condition (body mass and circulating plasma proteins) which could influence the variance components of CMI. A two-way nested ANOVA indicated that CMI of fledgling kestrels was explained more by the nest where the bird was reared (33% of the explained variance) than by the nest of origin (12%). Body mass was explained equally by familial and environmental components, while plasma proteins were only related to the rearing environment. CMI of fledglings was not related to their circulating plasma proteins, but was positively correlated with their body mass. Fledgling body mass seemed to be influenced by pre-hatching or post-hatching maternal effects prior to manipulation since resemblance in body mass of sibships at the age of manipulation was high (h ²≤0.58), and body mass at this age predicted body mass at fledging. Therefore, pre-manipulation parental effects on body mass, such as investment in egg size, could have inflated the familial effects on body mass of fledglings and then on its correlated CMI. When controlling for body mass, most of the variation in CMI of fledglings was explained by the nest where the bird was reared (36.6%), while the variance explained by the nest of origin (4%) was not significant. This means that environmental influences are major determinants of offspring CMI. The low proportion of variance explained by the familial component may have been due to the high correlation of CMI to fitness. Received: 19 October 1999 / Accepted: 23 December 1999     

Lymphokines in sensitized rats. III. Influence of prednisolone treatment of lymph node and spleen architecture in sensitized rats and upon MIF release in vitro.

The influence of prednisolone (corticosteroid, C.S.) treatment upon established cell-mediated immunity (CMI) induced by complete Freund's adjuvant (CFA) has been studied in rats by using in vitro migration inhibitory factor (MIF) assays, type IV skin reactions, and regional lymph node and spleen histology. Additionally, changes in the mononuclear-polymorphonuclear ratio of peripheral blood and T-cell accumulation in bone marrow in response to C.S. treatment have been determined. These results have been evaluated by comparison with equivalent experiments upon animals treated with anti-rat lymphocyte serum (ALS), oxisuran, or 2-[(methylsulfinyl)-acetyl]pyridine, which selectively suppresses CMI. The results suggest the existence of a population of “educated” T-cells in the thymic cortex of sensitized rats, and they suggest that prolonged C.S. administration does not suppress T-effector cells involved in established CMI but, rather, affects lymphocyte and monocyte migration patterns, including the migration of educated T-cells from the thymic cortex into other tissue compartments.     

喘息的"度"与支气管哮喘阶梯治疗

目的:探讨掌握喘息"度"与支气管哮喘阶梯治疗的关系。方法:充分掌握支气管哮喘分级治疗方案和支气管哮喘病情,将喘息"度"细致化,与分级治疗用药"度"密切结合起来,对于完全理想的控制哮喘将会起到极大的指导作用,对于升阶梯和降阶梯治疗都会起到重要而细致的指导作用。必须将平喘治疗措施置于患者全身病情变化及总体治疗之下,会取得更加理想的哮喘控制效果。而强化支气管哮喘患者教育在支气管哮喘理想治疗中占据极为重要的地位,甚至直接关系到哮喘控制的持久性和稳定性。应得到高度重视。结果:喘息"度"与支气管哮喘的发作程度密切相关,准确把握并分级十分重要。结论:准确把握喘息"度"并与支气管哮喘分级治疗方法结合,将对稳定平息支气管哮喘起到意想不到的效果。     

Recovery of Adrenal Function after Substitution of Beclomethasone Dipropionate for Oral Corticosteroids

Of 16 steroid-dependent asthmatic patients oral treatment has been discontinued in six and reduced in four after the introduction of beclomethasone dipropionate. Substitution of inhaled beclomethasone for oral steroids was unsuccessful in the remaining six patients. Serial adrenal function studies in the patients whose oral treatment was discontinued showed progressive recovery, and five out of six had a normal response to tetracosactrin stimulation after two months.     

Assessment of the status of cell-mediated immunity in cytomegalovirus-infected renal allograft recipients.

Renal allograft recipients are unusually susceptible to cytomegalovirus (CMV) infections. Since humoral immunity to CMV is uncompromised in these patients, it was felt desirable to assess the competence of cell mediated immunity (CMI). Several parameters were used. On skin testing with candida, SK-SD, mumps, and PPD-5 antigens, 80.0% of patients and 5.0% of controls were unreactive. T-lymphocyte ratios (SRBC rosette test) were 18.7% in transplant patients, vs. 40.3% in controls. These differences are statistically significant. Lymphocyte stimulation assay ([³H] thymidine uptake) was developed to study CMI to CMV. Lymphocytes from all the normal seropositive subjects (10) had increased [³H]thymidine uptake on exposure to CMV antigens. There was no antigen specific stimulation of lymphocytes from the seronegative controls (five). Six of nine (67.7%) CMV infected renal allograft recipients, studied six or more months post-transplantation, had no evidence of CMI to CMV by this assay.     

Association of the biocide 5-chloro-2-methyl-isothiazol-3-one with Pseudomonas aeruginosa and Pseudomonas fluorescens

The biocide 5-chloro-2-methyl-isothiazol-3-one (CMI) associated rapidly with cells of Pseudomonas aeruginosa and Pseudomonas fluorescens with association being nearly complete within 10–15 min. The cells serve as a sink for CMI, concentrating it up to 400-fold. Kinetics of association are very similar amongst the strains examined. Examination of the relation of CMI concentration to the rate of association indicates that there are two kinetically distinguishable processes, with the breakpoint occurring around the transition from inhibitory to suprainhibitory levels of CMI. This suggests the rapid onset of toxic effects at suprainhibitory CMI concentrations affects the associative process. Discharging the proton motive force by treatment with uncoupling agents or selectively depleting it by treatment with inhibitors reduces the amount of CMI which associates with the cells. Selective depletion of the ATP pool has no effect. These results suggest that either the proton motive force (pmf) is involved directly in CMI association in an active transport process, or that an intact pmf is required for some facet of the cells metabolism which maintains the cells as a sink for CMI. The nonchlorinated analogue 2-methyl-isothiazol-3-one is a poor competitor for CMI association.     

Influence of sleep on lung volume in asthmatic patients and normal subjects

To assess the effect of sleep on functional residual capacity (FRC) in normal subjects and asthmatic patients, 10 adult subjects (5 asthmatic patients with nocturnal worsening, 5 normal controls) were monitored overnight in a horizontal volume-displacement body plethysmograph. With the use of a single inspiratory occlusion technique, we determined that when supine and awake, asthmatic patients were hyperinflated relative to normal controls (FRC = 3.46 +/- 0.18 and 2.95 +/- 0.13 liters, respectively; P less than 0.05). During sleep FRC decreased in both groups, but the decrease was significantly greater in asthmatic patients such that during rapid-eye-movement (REM) sleep FRC was equivalent between the asthmatic and normal groups (FRC = 2.46 +/- 0.23 and 2.45 +/- 0.09 liters, respectively). Specific pulmonary conductance decreased progressively and significantly in the asthmatic patients during the night, falling from 0.047 +/- 0.007 to 0.018 +/- 0.002 cmH2O-1.s-1 (P less than 0.01). There was a significant linear relationship through the night between FRC and pulmonary conductance in only two of the five asthmatic patients (r = 0.55 and 0.65, respectively). We conclude that 1) FRC falls during sleep in both normal subjects and asthmatic patients, 2) the hyperinflation observed in awake asthmatic patients is diminished during non-REM sleep and eliminated during REM sleep, and 3) sleep-associated reductions in FRC may contribute to but do not account for all the nocturnal increase in airflow resistance observed in asthmatic patients with nocturnal worsening.     

Is cell-mediated immunity related to the evolution of life-history strategies in birds?

According to life-history theory, the development of immune function should be balanced through evolutionary optimization of the allocation of resources to reproduction and through mechanisms that promote survival. We investigated interspecific variability in cell-mediated immune response (CMI), as measured by the phytohaemagglutinin (PHA) assay, in relation to clutch size, longevity and other life-history traits in 50 species of birds. CMI exhibited significant repeatability within species, and PHA responses in chicks were consistently stronger than in adults. Univariate tests showed a variety of significant relationships between the CMI of both chicks and adults with respect to size, development period and lifespan, but not clutch size or prevalence of blood parasites in adults. Multivariate analyses confirmed these patterns but independent variables were too highly correlated to isolate unique influences on CMI. The positive relationship of chick CMI to nestling period is further complicated by a parallel relationship of chick CMI to the age at testing. However, multivariate analysis showed that chick CMI varies uniquely with length of the nestling period. Adult CMI was associated with a strong life-history axis of body size, development rate and longevity. Therefore, adult CMI may be associated with prevention and repair mechanisms related to long lifespan, but it also may be allometrically related to body size through other pathways. Neither chick CMI nor adult CMI was related to clutch size, contradicting previous results linking parasite-related mortality to CMI and the evolution of clutch size (reproductive investment) in birds.     

Enhancement of delayed cutaneous hypersensitivity in untreated cancer patients given a short-term oral treatment with C 1821

Summary C 1821 is a purified glycoprotein extract of Klebsiella pneumoniae serotype 2 with immunomodulating properties in animals (in vivo and in vitro) and in humans (in vitro). The compound is devoid of any apparent toxicity when given orally. The aim of the present work was to evaluate the effects of a short term oral administration of C 1821 on delayed cutaneous hypersensitivity to recall antigens in untreated cancer patients (mostly lymphomas). Consecutive patients were alternately allocated to receive C 1821 or placebo for 14 days. C 1821 restored and significanty (P<0.02) enhanced skin reactions, as shown using the Multitest system.     

The presence of interleukin-2 receptor alpha in the serum of colorectal cancer patients is unlikely to result only from T cell up-regulation

It is unclear whether the presence of interleukin-2 soluble receptor alpha (IL-2 sRalpha) in the serum of colorectal cancer patients is solely due to T cell activation. In this study, we therefore investigated whether T cell activation, indicated by the up-regulation of the CD25 and HLA-DR markers, or cell-mediated immunity (CMI) were associated with increased serum levels of IL-2 sRalpha in patients with advanced colorectal carcinoma. The levels of serum IL-2 sRalpha and the proportion of T cells expressing HLA-DR (DR(+) T cells) were measured as markers for chronic activation. CMI was assessed by delayed-type hypersensitivity reaction (DTH) to intradermal injections of recall antigens. Eighty-seven colorectal liver metastases (CLM) patients and 23 'cancer-free' control subjects were studied. DR(+) T cells were found to be more prevalent ( P<0.0001) in CLM patients (median: 21.1%) than in controls (median: 3.4%), but DR(+) T cell up-regulation was not correlated with serum IL-2 sRalpha levels. CMI positivity was significantly reduced ( P=0.002) in CLM patients compared with controls, and this reduction was significantly associated ( P=0.05) with an increase in the number of DR(+) T cells. Although survival was significantly shorter ( P=0.0003) in patients with increased serum IL-2 sRalpha levels than in subjects with normal levels, no association was found between survival and DR(+) T cell up-regulation. These findings were consistent with the hypothesis of an additional source of serum IL-2 sRalpha other than T cell up-regulation in CLM patients -- either from other immune cells, or from tumour products.