In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus–based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1.
We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc).
All patients received bone marrow–derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2 , MECOM, and other lymphoid proto-oncogenes in our patients.
This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.)
Active tuning and switching of electromagnetic properties of materials is of great importance for controlling their interaction with electromagnetic waves. In spite of their great promise, previously demonstrated reconfigurable metamaterials are limited in their operation bandwidth due to their resonant nature. Here, we demonstrate a new class of meta-surfaces that exhibit electrically-induced switching in their scattering parameters at room temperature and over a broad range of frequencies. Structural configuration of the subwavelength meta-molecules determines their electromagnetic response to an incident electromagnetic radiation. By reconfiguration of the meta-molecule structure, the strength of the induced electric field and magnetic field in the opposite direction to the incident fields are varied and the scattering parameters of the meta-surface are altered, consequently. We demonstrate a custom-designed meta-surface with switchable scattering parameters at a broad range of terahertz frequencies, enabling terahertz intensity modulation with record high modulation depths and modulation bandwidths through a fully integrated, voltage-controlled device platform at room temperature.
Ritonavir therapy is not generally considered nephrotoxic. We report a case of acute kidney injury secondary to ritonavir, with kidney biopsy demonstrating extensive acute tubular injury. This is the first report of a kidney biopsy and pathology in acute kidney injury associated with ritonavir. A review of published medical literature on the topic is also presented.
ritonavir; acute renal failure; kidney biopsy; human immunodeficiency virus
In this work, we introduce a modified Holzapfel-Ogden hyperelastic constitutive model for ventricular myocardium that accounts for residual stresses, and we investigate the effects of residual stresses in diastole using a magnetic resonance imaging–derived model of the human left ventricle (LV). We adopt an invariant-based constitutive modelling approach and treat the left ventricular myocardium as a non-homogeneous, fibre-reinforced, incompressible material. Because in vivo images provide the configuration of the LV in a loaded state even in diastole, an inverse analysis is used to determine the corresponding unloaded reference configuration. The residual stress in this unloaded state is estimated by two different methods. One is based on three-dimensional strain measurements in a local region of the canine LV, and the other uses the opening angle method for a cylindrical tube. We find that including residual stress in the model changes the stress distributions across the myocardium and that whereas both methods yield qualitatively similar changes, there are quantitative differences between the two approaches. Although the effects of residual stresses are relatively small in diastole, the model can be extended to explore the full impact of residual stress on LV mechanical behaviour for the whole cardiac cycle as more experimental data become available. In addition, although not considered here, residual stresses may also play a larger role in models that account for tissue growth and remodelling.
Residual stress; Left ventricle; Finite strain ; Finite stress
Cyclosporin is an immunosuppressant that has recently been proposed as a treatment to prevent reperfusion injury in acute myocardial infarction (MI). We aimed to determine the overall efficacy of cyclosporin in experimental studies of acute reperfused MI. We conducted a systematic review and stratified meta-analysis of published studies describing the efficacy of cyclosporin in experimental models of acute reperfused MI. We included all in vivo publications of cyclosporin where infarct size was measured. A literature search identified 29 potential studies of which 20 fulfilled the eligibility criteria. In these studies (involving four species of animals), cyclosporin reduced myocardial infarct size by a standardized mean (95% confidence interval) difference of −1.60 (−2.17, −1.03) compared with controls. Cyclosporin failed to demonstrate a convincing benefit in studies involving pigs. Despite this observation, the overall efficacy of cyclosporin did not differ across species (P= 0.358). The dose of cyclosporin given did not affect final infarct size (P= 0.203). Funnel plots of these data suggested heterogeneity among the studies. Cyclosporin had variable effects on infarct size compared with placebo. Cyclosporin had no effect on myocardial infarct size in swine, raising a question over the potential cardioprotective effects of cyclosporin in man.
review article; cardiovascular pharmacology; methods and techniques
Muscle spindle afferent (MSA) neurons can show rapid and sustained firing. Immunostaining for the α3 isoform of the Na+/K+-ATPase (α3) in some large dorsal root ganglion (DRG) neurons and large intrafusal fibres suggested α3 expression in MSAs (Dobretsov et al. 2003), but not whether α3-immunoreactive DRG neuronal somata were exclusively MSAs. We found that neuronal somata with high α3 immunointensity were neurofilament-rich, suggesting they have A-fibres; we therefore focussed on A-fibre neurons to determine the sensory properties of α3-immunoreactive neurons. We examined α3 immunointensity in 78 dye-injected DRG neurons whose conduction velocities and hindlimb sensory receptive fields were determined in vivo. A dense perimeter or ring of staining in a subpopulation of neurons was clearly overlying the soma membrane and not within satellite cells. Neurons with clear α3 rings (n = 23) were all MSAs (types I and II); all MSAs had darkly stained α3 rings, that tended to be darker in MSA1 than MSA2 units. Of 52 non-MSA A-fibre neurons including nociceptive and cutaneous low-threshold mechanoreceptive (LTM) neurons, 50 had no discernable ring, while 2 (Aα/β cutaneous LTMs) had weakly stained rings. Three of three C-nociceptors had no rings. MSAs with strong ring immunostaining also showed the strongest cytoplasmic staining. These findings suggest that α3 ring staining is a selective marker for MSAs. The α3 isoform of the Na+/K+-ATPase has previously been shown to be activated by higher Na+ levels and to have greater affinity for ATP than the α1 isoform (in all DRG neurons). The high α3 levels in MSAs may enable the greater dynamic firing range in MSAs.
Differences in activation between spores from strains of Bacillus thuringiensis subsp. israelensis with and without the toxin-encoding plasmid pBtoxis are demonstrated. Following alkaline activation, the strain bearing pBtoxis shows a significantly greater germination rate. Expression of just three genes constituting a previously identified, putative ger operon from this plasmid is sufficient to produce the same phenotype and characterizes this operon as a genetic determinant of alkaline activation.
As the hormone gastrin promotes gastrointestinal (GI) cancer progression by triggering survival pathways, regulation of gastrin expression at the translational level was explored. Sequence within the 5′ untranslated region of a gastrin transcript expressed in GI cancer cells was investigated, then cloned into a bicistronic vector upstream of firefly luciferase and transfected into a series of GI cancer cell lines. Firefly luciferase activity was measured relative to that of a cap-dependent Renilla luciferase. A gastrin transcript that was different from that described in Ensembl was expressed in GI cancer cells. Its transcription appears to be initiated within the region designated as the gene's first intron. In GI cancer cells transfected with the bicistronic construct, firefly luciferase activity increased 8–15-fold compared with the control vector, and there was a further induction of the signal (up to 25-fold) following exposure of the cells to genotoxic stress or hypoxia, suggesting that the sequence acts as an internal ribosome entry site. These data suggest that the gastrin transcript within GI cancer cells contains an internal ribosome entry site that may allow continued expression of gastrin peptides when normal translational mechanisms are inactive, such as in hypoxia, thereby promoting cancer cell survival.
gastrin; translation; gastrointestinal; internal ribosome entry
brain natriuretic peptide; myocardial infarction; vascular surgery
Objective: To investigate how patients with heart failure with preserved left ventricular systolic function (LVSF) compare with patients with reduced LVSF.
Design: Cohort study.
Setting: Urban university hospital.
Patients: 528 index emergency admissions with heart failure during the year 2000. Information on LVSF and follow up was available for 445 (84%) of these patients.
Results: 130 (29%) patients had preserved LVSF (defined as an ejection fraction > 40%). The median follow up was 814 days (range 632–978 days). The average (SD) age was 72 (13) years. Women accounted for 62% and 45% of patients with preserved and reduced LVSF, respectively (p = 0.001). Patients with preserved LVSF (compared with those with reduced LVSF) had a higher prevalence of left ventricular hypertrophy (56% v 29%) and aortic valve disease (mean gradient > 20 mm Hg; 31% v 9%). Fewer patients with preserved LVSF received an angiotensin converting enzyme inhibitor (65% v 78%, p = 0.008) or spironolactone (12% v 21%, p = 0.027). Anaemia tended to occur more often in patients with preserved LVSF than in those with reduced LVSF (43% v 33% for women, p = 0.12; 59% v 49% for men, p = 0.22). There was a similarly high prevalence of significant renal dysfunction in both groups (estimated glomerular filtration rate < 60 ml/min/1.73 m2 in 68% with preserved and 64% with reduced LVSF, p = 0.40). Mortality was similar in both groups (preserved versus reduced 51 (39%) v 132 (42%), p = 0.51). Compared with patients with reduced LVSF, patients with preserved LVSF tended to have a lower risk of death or hospital admission for heart failure (56 (42%) v 165 (53%), p = 0.072) but a similar rate of death or readmission for any reason.
Conclusion: Patients with preserved LVSF had more co-morbid problems than those with reduced LVSF; however, prognosis was similar for both groups.
heart failure; hospitalisation; preserved systolic function; reduced systolic function
Objective: To evaluate the relation between pressure derived coronary collateral flow (PDCF) index and angiographic TIMI (thrombolysis in myocardial infarction) myocardial perfusion (TMP) grade, angiographic collateral grade, and subsequent recovery of left ventricular function after rescue percutaneous coronary intervention (PCI) for failed reperfusion in acute myocardial infarction.
Methods: The pressure wire was used as the guidewire in 38 consecutive patients who underwent rescue PCI between December 2000 and March 2002. Follow up angiography was performed at six months. Baseline and follow up single plane ventriculograms were analysed off line by an automated edge detection technique. A linear model was fitted to assess the relation between 0.1 unit increase in PDCF and change in left ventricular regional wall motion.
Results: Patients with TMP 0 grade had significantly higher mean (SD) PDCF than patients with TMP 1–3 (0.30 (0.11) v 0.15 (0.07), p < 0.0001, r = −0.5). A similar relation was observed between TMP grade and coronary wedge pressure (mean (SD) 28 (16) mm Hg with TMP 0 v 9 (7) mm Hg with TMP 1–3, p = 0.001, r = −0.4). Higher PDCF was associated with increased left ventricular end diastolic pressures (0.28 (0.14) with end diastolic pressure > 20 mm Hg v 0.22 (0.09) with end diastolic pressure < 20 mm Hg, p = 0.08, r = 0.2). No correlation was observed between PDCF and Rentrops collateral grade (0.26 (0.13) with grade 0 v 0.25 (0.11) with grades 1–3, p = 0.4, r = −0.06). No linear relation existed between changes in PDCF and changes in left ventricular regional wall motion.
Conclusion: PDCF in the setting of rescue PCI for failed reperfusion after thrombolysis does not predict improvement in left ventricular function. Increased PDCF and coronary wedge pressure in acute myocardial infarction reflect a dysfunctional microcirculation rather than good collateral protection.
pressure derived collateral flow; TMP grade; acute myocardial infarction; rescue percutaneous coronary intervention; left ventricular function
A review of patient confidentiality issues was commissioned and its findings published as the Caldicott Report in December 1997. It made 16 recommendations and formulated six principals. To help in remembering these principles the mnemonic FIONA C can be used: Formal justification of purpose; Information transferred only when absolutely necessary; Only the minimum required; Need to know access controls; All to understand their responsibilities; Comply with and understand the law. Since the Caldicott Report in 1997 the following acts have become law. Data Protection Act 1998, Human Rights Act 1998, Public Interest Disclosure Act 1998, Audit Commission Act 1998, Terrorism Act 2000, section 60 of the Health and Social Care Act 2001 and Regulation of Investigatory Powers Act 2000, and by 2005 The Freedom of Information Act 2000 will become law and affect the NHS. Consequently it can be seen that the role and responsibility of Caldicott guardians has grown significantly into what is now known as information governance.
Objective: To determine whether the plasma concentration of the putative new cardiac hormone relaxin is predictive of clinical outcome in patients with chronic heart failure (CHF).
Design: Plasma relaxin and N-terminal pro B type natriuretic peptide (NT pro BNP) concentrations were measured in 87 patients admitted in an emergency with CHF caused by left ventricular systolic dysfunction. These were related to death and death or readmission with CHF over the following year.
Setting: Western Infirmary, Glasgow, UK.
Main outcome measures: Plasma concentrations of relaxin and NT pro BNP; time to death or hospitalisation caused by heart failure.
Results: Plasma concentrations of both relaxin and NT pro BNP were greatly increased. Of the 43 patients with NT pro BNP above the group median concentration, 23 (53%) died and 30 (70%) died or were hospitalised with CHF. Among the 44 with concentrations below the median, these numbers were 5 (11%) and 12 (27%), respectively (p < 0.0001 and p < 0.0001, respectively). Plasma NT pro BNP concentration remained an independent predictor of an adverse clinical outcome in a multivariate analysis. Of the 42 patients with a relaxin concentration above the median, 13 (31%) died and 20 (48%) died or were hospitalised. Below the median, these numbers were 15 of 45 (33%) and 22 of 45 (49%) (p = 0.76 and p = 0.84, respectively).
Conclusions: NT pro BNP is a powerful and independent predictor of outcome in CHF, whereas relaxin, also secreted by the heart in increased amounts in CHF, is not.
natriuretic peptides; relaxin; heart failure; prognosis; survival; hospital admission
We have investigated regulatory sequences in noncoding human DNA that are associated with repression of an integrated human immunodeficiency virus type 1 (HIV-1) promoter. HIV-1 integration results in the formation of precise and homogeneous junctions between viral and host DNA, but integration takes place at many locations. Thus, the variation in HIV-1 gene expression at different integration sites reports the activity of regulatory sequences at nearby chromosomal positions. Negative regulation of HIV transcription is of particular interest because of its association with maintaining HIV in a latent state in cells from infected patients. To identify chromosomal regulators of HIV transcription, we infected Jurkat T cells with an HIV-based vector transducing green fluorescent protein (GFP) and separated cells into populations containing well-expressed (GFP-positive) or poorly expressed (GFP-negative) proviruses. We then determined the chromosomal locations of the two classes by sequencing 971 junctions between viral and cellular DNA. Possible effects of endogenous cellular transcription were characterized by transcriptional profiling. Low-level GFP expression correlated with integration in (i) gene deserts, (ii) centromeric heterochromatin, and (iii) very highly expressed cellular genes. These data provide a genome-wide picture of chromosomal features that repress transcription and suggest models for transcriptional latency in cells from HIV-infected patients.
Objectives: To determine whether patients with suspected heart failure but preserved systolic function, as determined by conventional echocardiographic measures (often said to have “diastolic heart failure), might have subtle left ventricular systolic dysfunction detectable by a new measure of left ventricular systolic function—left ventricular systolic atrioventricular plane displacement.
Design: Observational study.
Setting: Direct access echocardiography.
Patients: 147 patients with suspected heart failure referred by general practitioners.
Measurements: Echocardiographic assessment of conventional measures of left ventricular systolic function (fractional shortening, ejection fraction (by Simpson's biplane method) and “eyeball” assessment) and measurement of left ventricular systolic atrioventricular plane displacement.
Results: Between 21% and 33% of patients with “normal” left ventricular systolic function by conventional methods were found to have abnormal left ventricular systolic atrioventricular plane displacement.
Conclusions: Approximately one quarter of patients with suspected heart failure but preserved systolic function by conventional methods have abnormal atrioventricular plane displacement. These patients with suspected heart failure but preserved systolic function by conventional echocardiographic measures may have heart failure caused by subtle systolic dysfunction rather than isolated “diastolic heart failure”.
heart failure; diastole; systole; atrioventricular plane displacement
In patients with chronic heart failure, spironolactone added to conventional treatment may lead to serious and, occasionally, fatal hyperkalaemia. In some cases this seems to happen because spironolactone causes diarrhoea. Four cases involving men with New York Heart Association functional class III heart failure are presented. As these cases revealed, close monitoring of blood chemistry is mandatory after starting spironolactone, and patients should be advised to stop spironolactone immediately if diarrhoea develops.
Keywords: spironolactone; heart failure; hyperkalaemia
The goal of this study was to identify genes whose mRNA levels are differentially expressed in human cells with acquired cisplatin (cDDP) resistance. Using the parental UMSCC10b head and neck carcinoma cell line and the 5.9-fold cDDP-resistant subline, UMSCC10b/Pt-S15, two suppressive subtraction hybridization (SSH) cDNA libraries were prepared. One library represented mRNAs whose levels were increased in the cDDP resistant variant (the UP library), the other one represented mRNAs whose levels were decreased in the resistant cells (the DOWN library). Arrays constructed with inserts recovered from these libraries were hybridized with SSH products to identify truly differentially expressed elements. A total of 51 cDNA fragments present in the UP library and 16 in the DOWN library met the criteria established for differential expression. The sequences of 87% of these cDNA fragments were identified in Genbank. Among the mRNAs in the UP library that were frequently isolated and that showed high levels of differential expression were cytochrome oxidase I, ribosomal protein 28S, elongation factor 1α, α-enolase, stathmin, and HSP70. The approach taken in this study permitted identification of many genes never before linked to the cDDP-resistant phenotype. © 2000 Cancer Research Campaign
cisplatin resistance; suppression subtractive hybridization; high throughput screening; gene expression
Thrombin is a potent mitogenic agent. Clot-associated thrombin retains its amidolytic and pro-aggregant activity. We therefore studied the ability of fibrin clots to induce proliferation in CCL39 cells (Chinese hamster lung fibroblasts), in the absence and presence of the thrombin inhibitors PPACK, recombinant hirudin (rHV2 Lys47) and heparin:antithrombin III.Fibrin clots incubated for 48 h with CCL39 cells led to significant cell proliferation, which was dependent on the concentration of thrombin used to prepare the clots. Thus, clots prepared with 91 nmol l−1 thrombin produced a similar proliferation (231±21%) to that obtained with 50 nmol l−1 thrombin in solution (213±29%). Rabbit plasma clots led to a 499±41% increase in cell number under identical conditions.Fibrin clot-induced cell proliferation was inhibited by all three thrombin inhibitors with no difference in IC50 values compared to those obtained against thrombin in solution, suggesting that cell proliferation be due to thrombin leaching from the clots.We found a time-dependent increase in thrombin release from the clots attaining a plateau at 24 h (∼61% of the total thrombin used in clot formation). Clots separated from the cells using porous cell culture chamber inserts led to similar proliferation to that of clots in contact with the cells.Thus fibrin-clot induced CCL39 proliferation is due to thrombin released from the clots.
Fibrin clots; cell proliferation; mitogen; thrombin inhibitors
Strains of the periodontal pathogen Actinobacillus actinomycetemcomitans are variable with respect to display of phosphorylcholine (PC)-bearing antigens. We have examined strains of A. actinomycetemcomitans with and without PC to assess their ability to invade endothelial cells via the receptor for platelet-activating factor (PAF). Results of antibiotic protection assays indicate that PC-bearing A. actinomycetemcomitans invade human vascular endothelial cells by a mechanism inhibitable by CV3988, a PAF receptor antagonist, and by PAF itself. The invasive phenotype was verified by transmission electron microscopy. A PC-deficient strain of this organism was not invasive. This property, in addition to the established ability of A. actinomycetemcomitans to invade epithelial cells, may provide this organism with access to the systemic circulation. The ability of PC-bearing oral bacteria to access the circulation may also explain the elevated levels of anti-PC antibody in serum found in patients with periodontitis.
Elevated plasminogen activator inhibitor 1 (PAI-1) is a risk factor for thrombosis, and inhibitors of the interaction between PAI-1 and tissue plasminogen activator (t-PA) have antithrombotic and pro-thrombolytic activity in animals. We describe the antithrombotic effects in the rat of a monoclonal antibody (MA33H1) which converts PAI-1 to a non-inhibitory substrate.The activity of MA33H1 against rat PAI-1 was confirmed using two-chain t-PA and a chromogenic substrate. MA33H1 was evaluated in rat venous (thromboplastin+stasis in the abdominal vena cava) and arterial (electric current applied to a carotid artery) thrombosis models. The effects on tail-transection bleeding time were studied.MA33H1 at 100 ng ml−1 inhibited both human (44.1%) and rat PAI-1 (49.7%). This effect was concentration-dependent. Its effect on human PAI-1 was not significantly inhibited by 1 μg ml−1 fibrin or a ≈amp;7 fold molar excess of vitronectin (1 nM). Inhibition of rat PAI-1 was unchanged by fibrin, but vitronectin reduced inhibition from 0.5 nM.In the venous thrombosis model, MA33H1 significantly reduced thrombus weights by 38 and 58.6% at 50 and 100 μg kg−1 min−1 i.v. respectively. This effect was inhibited by tranexamic acid. In the arterial model, MA33H1 significantly increased the delay to occlusive thrombus formation by 58 and 142% at 50 and 100 μg kg−1 min−1 i.v., and did not affect bleeding time at 300 μg kg−1 min−1 i.v.Thus, a monoclonal antibody which transforms PAI-1 to a t-PA substrate prevents thrombus formation in the rat with no effect on bleeding time at a higher dose.
PAI-1 inhibition; plasminogen activators; rat venous thrombosis; arterial thrombosis; bleeding time
OBJECTIVE: To develop and validate a measure of contemporary life stressors. STUDY SETTING: Three interview studies: Study 1 (pilot), 32 caregivers receiving case management services for a child with chronic illness; Study 2 (validation), 311 caregivers of children receiving general pediatric care at a university clinic; Study 3 (reliability), 17 caregivers of children with a complex medical diagnosis. STUDY DESIGN: Study 1: item development via discussions with case managers; piloted with caregivers. Study 2 examined psychometric properties of the measure and correlated it with the CES-D, a measure of depressive symptomatology and the PRQ85-Part 2, a measure of perceived social support, to establish its convergent construct validity. Study 3 established the test-retest reliability of the measure over two weeks by correlating two administrations of the index. DATA COLLECTION: Face-to-face interviews in homes (Study 1) or in clinic waiting rooms (Studies 2 and 3) and by telephone (Study 3 retest). PRINCIPAL FINDINGS: The CRISYS is a flexible, multidimensional tool that demonstrates strong face, content, and construct validity, and excellent test-retest reliability. The format is easy to use and well accepted by respondents and is suitable for low-income populations. CONCLUSIONS: Researchers will find the CRISYS useful when evaluating the success of a clinical model or a healthcare system, and the effectiveness of an insurance plan or a government program. Clinicians may also find that the CRISYS is an effective screen for family needs.
This open-label, non-randomized, parallel-group trial investigated the pharmacokinetics of raltitrexed (Tomudex, formerly ZD1694) after a single intravenous dose of 3.0 mg m(-2), comparing eight cancer patients with mild to moderate renal impairment (creatinine clearance 25-65 ml min(-1)) with eight cancer patients with normal renal function (creatinine clearance >65 ml min(-1)). The primary end points were area under the plasma raltitrexed concentration-time curve from the start of the infusion to the last determined concentration (AUC(0-tldc)) and AUC to infinity (AUC(0-infinity)); secondary end points were peak concentrations of raltitrexed (Cmax) and elimination half-life (t(1/2gamma)). The groups were compared statistically using analysis of covariance. The AUCs were greater for patients with renal impairment than for patients with normal renal function (2452.2 compared with 1247.3 ng h ml(-1) for AUC(0-tldc) (ratio 1.97; 95% CI 1.36-2.84); 2961.5 compared with 1457.0 ng h ml(-1) for AUC(0-infinity) (ratio 2.03; 1.25-3.29). These differences were statistically significant (P = 0.002 and P = 0.008 for AUC(0-tldc) and AUC(0-infinity) respectively. Terminal half-life was longer for the renally impaired patients (271.2 compared with 143.3; P = 0.030). There was no significant statistical difference between the groups for Cmax (652.9 compared with 564.7 ng ml(-1) for patients with impaired and normal renal function respectively: ratio 1.16; 0.91-1.46; P = 0.204). There was a clear relationship between raltitrexed clearance and creatinine clearance. Adverse events, severe (WHO grade 3 or 4) toxicity and hospitalization due to adverse events were more frequent in the group with renal impairment. Therefore, a reduction in raltitrexed dose and increased interval between doses is recommended for patients with mild to moderate renal impairment.