The HLA-B 3906 allele imparts a high risk of diabetes only on specific HLA-DR/DQ haplotypes.

AIMS/HYPOTHESIS: We investigated the risk associated with HLA-B*39 alleles in the context of specific HLA-DR/DQ haplotypes. METHODS: We studied a readily available dataset from the Type 1 Diabetes Genetics Consortium that consists of 2,300 affected sibling pair families genotyped for both HLA alleles and 2,837 single nucleotide polymorphisms across the major histocompatibility complex region. RESULTS: The B*3906 allele significantly enhanced the risk of type 1 diabetes when present on specific HLA-DR/DQ haplotypes (DRB1 0801-DQB1 0402: p = 1.6 × 10(-6), OR 25.4; DRB1 0101-DQB1 0501: p = 4.9 × 10(-5), OR 10.3) but did not enhance the risk of DRB1 0401-DQB1 0302 haplotypes. In addition, the B 3901 allele enhanced risk on the DRB1 1601-DQB1 0502 haplotype (p = 3.7 × 10(-3), OR 7.2). CONCLUSIONS/INTERPRETATION: These associations indicate that the B 39 alleles significantly increase risk when present on specific HLA-DR/DQ haplotypes, and HLA-B typing in concert with specific HLA-DR/DQ genotypes should facilitate genetic prediction of type 1 diabetes, particularly in a research setting.

Statistical analysis of Peptide electron transfer dissociation fragmentation mass spectrometry.

It is well established that protein sequence determination may be achieved by mass spectrometric analysis of protonated tryptic peptides subjected to collisional activation. When separated by nanoflow HPLC, a high percentage of peptides from complex mixtures of proteins can usually be identified. Recently, alternative, radical-driven fragmentation approaches of electron capture dissociation and the more common electron transfer dissociation (ETD) have been introduced and made widely available. In order to utilize these techniques in large scale proteomics studies, it is important to characterize the performance of these fragmentation processes on peptides formed by a range of enzymatic cleavages. In this study, we present a statistical analysis of the ion types that are observed from peptides produced by different enzymes and highlight the different characteristics of ETD spectra of doubly charged precursors in comparison to precursors of higher charge states.

Detection and quantification of protein adduction by electrophilic fatty acids: mitochondrial generation of fatty acid nitroalkene derivatives.

Nitroalkene fatty acid derivatives manifest a strong electrophilic nature, are clinically detectable, and induce multiple transcriptionally regulated anti-inflammatory responses. At present, the characterization and quantification of endogenous electrophilic lipids are compromised by their Michael addition with protein and small-molecule nucleophilic targets. Herein, we report a trans-nitroalkylation reaction of nitro-fatty acids with beta-mercaptoethanol (BME) and apply this reaction to the unbiased identification and quantification of reaction with nucleophilic targets. Trans-nitroalkylation yields are maximal at pH 7 to 8 and occur with physiological concentrations of target nucleophiles. This reaction is also amenable to sensitive mass spectrometry-based quantification of electrophilic fatty acid-protein adducts upon electrophoretic resolution of proteins. In-gel trans-nitroalkylation reactions also permit the identification of protein targets without the bias and lack of sensitivity of current proteomic approaches. Using this approach, it was observed that fatty acid nitroalkenes are rapidly metabolized in vivo by a nitroalkene reductase activity and mitochondrial beta-oxidation, yielding a variety of electrophilic and nonelectrophilic products that could be structurally characterized upon BME-based trans-nitroalkylation reaction. This strategy was applied to the detection and quantification of fatty acid nitration in mitochondria in response to oxidative inflammatory conditions induced by myocardial ischemia-reoxygenation.

Molecular species composition of rat liver phospholipids by ESI-MS/MS: the effect of chromatography.

Using electrospray ionization tandem mass spectrometry (ESI-MS/MS) this study shows that the loss of glycerophospholipid (GPL) after chromatography was unevenly distributed across the GPL molecular species. Both TLC and HPLC caused a preferential loss of GPL with 0 to 3 double bonds: 20% and 7.2% for choline glycerophosphates (PC) and 19.7% and 7.5% for ethanolamine glycerophosphates (PE), respectively. A consequence of these losses was that GPLs containing fatty acids with four or more double bonds had a greater contribution to the total after chromatography. ESI-MS/MS analysis also showed that PC molecular species with four or more double bonds migrated at the front of the TLC band of PCs. GPLs extracted from TLC plates occasionally contained PCs that were smaller than those in the original extract. These low molecular mass PCs were easily reduced to alcohols and formed derivatives with 2,4-dinitrophenylhydrazine, suggesting that aldehydes were generated by the oxidation of unsaturated fatty acids. Directly analyzing lipid extracts by ESI-MS/MS without preliminary chromatographic separation gives an accurate distribution of GPL molecular species in lipid mixtures. However, the ionization of the phospholipids in the electrospray jet maximized at relatively low concentrations of GPL. There was a linear response between phospholipid mass and ion intensity for concentrations around 1-2 nmol/ml for both PC and PE. The total ion intensity continued to increase with concentrations above 1-2 nmol/ml, but the response was non-linear.

The natural history of renal disease in Australian Aborigines. Part 1. Changes in albuminuria and glomerular filtration rate over time.

BACKGROUND: The purpose of this study was to describe changes over time in albuminuria and glomerular filtration rate (GFR) in a cohort of Australian Aborigines from a community with high rates of renal disease and renal failure. METHODS: Participants were 486 adult community members (20+ years at first exam) who were screened for renal disease and related factors on at least two occasions (mean 2.7 occasions), at least a year apart, between 1990 and 1997. Renal function was assessed by the albumin:creatinine ratio (ACR; g/mol) on a random urine specimen and by the GFR estimated from the Cockcroft-Gault formula. Evolution over time was expressed as the average annual changes in these parameters. RESULTS: On baseline examination, 70% of participants had albuminuria (ACR 1.1+ g/mol) There was a significant net increase in ACR and a fall in GFR in the cohort over time. Among individuals, however, changes were strongly correlated with ACR levels at baseline. There was no loss of GFR in persons with normal renal parameters at baseline and a rapid loss of GFR in those with substantial levels of albuminuria at baseline. Other factors significantly correlated with progression of ACR included age, baseline body mass index and systolic blood pressure, the presence of diabetes (or levels of fasting glucose), and elevated levels of serum gamma glutamyl transferase. Factors significantly associated with loss of GFR included body mass index, diabetes, systolic and diastolic blood pressures, microscopic hematuria, and marginally high cholesterol levels. CONCLUSION: Albuminuria progresses and GFR is lost over time in individuals in this community, at rates that are strongly dependent on levels of pre-existing albuminuria. Much loss of GFR and all renal failure should be avoided by preventing the development of albuminuria and minimizing its progression. This depends on improving the weight, blood pressure, and metabolic profile of the entire community and reducing infections. Modification of the course in people with established disease depends on vigorous control of blood pressure and the metabolic profile and the specific use of angiotensin-converting enzyme inhibitors.

The natural history of renal disease in Australian Aborigines. Part 2. Albuminuria predicts natural death and renal failure.

BACKGROUND: The purpose of this study was to describe the relationship of albuminuria and glomerular filtration rate (GFR) with natural death and renal failure in an Australian Aboriginal community with high rates of renal disease. METHODS: Study subjects were 825 adults (18+ years, mean 33.6 years) or 88% of adults in a remote community who participated in a health screening program offered between 1990 and 1997. The urinary albumin:creatinine ratio (ACR; g/mol) was used as the renal disease marker. Participants were followed for 1.0 to 9.8 years (mean 5.8 years) until renal failure, death, the start of systematic antihypertensive/renal-protective treatment or June 30, 2000. RESULTS: Sixty-five people reached a terminal end point of renal failure or natural death. Sixteen people developed terminal renal failure, all of whom had an ACR of 34+ at baseline exam. There were 49 other natural deaths, which were also strongly correlated with increasing ACR and decreasing GFR over a wide range. This was observed in people without diabetes and in people with normal and elevated blood pressures. It applied to deaths associated with cardiovascular disease and to deaths without an assigned primary or underlying cardiovascular or renal cause. With adjustment for age, the association with death was more robust with ACR than GFR. When compared with people with an ACR <3.4, the hazard ratio (HR; 95% CI) for nonrenal natural death of persons with an ACR 3.4 to 33 was 3.0 (1.1 to 8.4), with an ACR 34 to 99, it was 5.4 (1.8 to 15.9), and with an ACR 100+, it was 6.5 (2.0 to 21). Regression equations predicted that each tenfold increase in the ACR was associated with a 3.7-fold increase in all-cause natural death: a> 400-fold increase in renal deaths, a 4-fold increase in cardiovascular deaths, and a 2.2-fold increase in nonrenal noncardiovascular deaths. Eighty-four percent of all-cause natural death was associated with pathologic albuminuria. CONCLUSION: All renal failure develops out of a background of persistent albuminuria in this population. More important, albuminuria and, inversely, GFR are powerful markers of risk for nonrenal natural death, including, but not restricted to, cardiovascular deaths. Most of the risk for premature death can be assessed by a simple urine test, and interventions that prevent development and progression of albuminuria and loss of GFR should not only prevent renal insufficiency, but powerfully reduce mortality from natural causes as well.

Reducing premature death and renal failure in Australian aboriginals. A community-based cardiovascular and renal protective program.

OBJECTIVE: To describe results of a systematic treatment program to modify renal and cardiovascular disease in an Aboriginal community whose rates of renal failure and cardiovascular deaths are among the highest in Australia. DESIGN: Longitudinal survey of people during treatment, and comparison of rates of natural death and renal failure with those in a historical control group. SETTING: Tiwi Islands (population, about 1800), November 1995 to December 1998. PARTICIPANTS: All adults with blood pressure > or = 140/90, with diabetes and urinary albumin/creatinine ratio (ACR) > or = 3.4 g/mol (microalbuminuria threshold), or with progressive overt albuminuria (ACR > or = 34 g/mol) were eligible for treatment. The historical control group comprised 229 people who satisfied these criteria in the pretreatment period 1992-1995. INTERVENTIONS: Perindopril, combined with calcium-channel blockers and diuretics if needed to achieve blood pressure goals; attempts to improve control of blood glucose and lipid levels; health education. MAIN OUTCOME MEASURES: Blood pressure, ACR, serum creatinine level and glomerular filtration rate (GFR) over two years of treatment; rates of renal failure and natural death compared with control group (analysed on intention-to-treat basis). RESULTS: 258 people enrolled in the program, and 118 had complete data for two years of treatment. In these 118, blood pressures fell significantly, while ACR and GFR stabilised. Rates of the combined endpoints of renal failure and natural death per 100 person-years were 2.9 for the treatment group (95% CI, 1.7-4.6) and 4.8 for the control group (95% CI, 3.3-7.0). After adjustment for baseline ACR category, the relative risk of the treatment group versus the control group for these combined endpoints was 0.47 (95% CI, 0.25-0.86; P = 0.013). Treatment benefit was especially marked in people with overt albuminuria or hypertension and in non-diabetic people. The estimates of benefit were supported by a fall in community rates of death and renal failure. CONCLUSIONS: Aboriginal people can participate enthusiastically in chronic disease management, with rapid, dramatic improvement in clinical profiles and mortality. Similar programs should be introduced urgently into other Aboriginal communities nationwide.

Development of an assay for the simultaneous determination of sildenafil (Viagra) and its metabolite (UK-103,320) using automated sequential trace enrichment of dialysates and high-performance liquid chromatography.

The development of the ASTED (automated sequential trace enrichment of dialysates) system to prepare plasma samples prior to high-performance liquid chromatography (HPLC) of sildenafil and its demethylated metabolite (UK-103,320) is described. Investigations to elucidate potential pitfalls of the ASTED on-line sample preparation system prior to separation of the analytes by HPLC are presented. The procedure is shown to be selective for sildenafil and UK-103,320, and linear over the range 1.00-250 ng/ml. The intra-batch imprecision (C.V.) of the method at plasma analyte concentrations of 1.00, 5.00, 50.0 and 200 ng/ml was 11.2, 3.10, 1.50, and 1.30%, respectively, and the corresponding inter-batch imprecision was estimated to be 13.5, 7.09, 3.69, and 5.43%. At these plasma analyte concentrations the overall inaccuracy (% bias) of the procedure ranged from 3.6 to 8.4%. The method showed similar assay performance for the estimation of the metabolite, UK-103,320. The application of the assay to a pharmacokinetic investigation during a clinical study is presented.

Expression of oestrogen receptor and oestrogen-inducible genes in pancreatic cancer.

BACKGROUND: Previous studies have not been able to demonstrate convincingly whether the human pancreas expresses oestrogen receptor and whether there is any benefit from antioestrogen therapy in advanced pancreatic cancer. METHODS: Oestrogen receptor expression was assessed in normal human pancreas and pancreatic cancer tissue by enzyme immunoassay, Northern blot analysis, in situ hybridization and immunohistochemistry. The expression of the oestrogen-inducible proteins, progesterone receptor, pS2 and ERD5 was also examined. RESULTS: A mean of 1.0 (range 0-2.4) fmol oestrogen receptor per mg protein was detected in normal pancreas and 0.5 (range 0-1.2) fmol mg-1 in pancreatic cancer. Messenger RNA for oestrogen receptor was detected in both normal and cancerous pancreas. In situ hybridization and immunohistochemistry, however, failed to localize oestrogen receptor expression. Mean (range) expression of progesterone receptor in normal and neoplastic pancreas was 1.9 (0.5-3.5) and 2.5 (0.3-9.3) fmol mg-1 respectively. pS2 and ERD5 were also expressed in normal tissue and pancreatic cancer, and expression was localized to ductular epithelium. CONCLUSION: The amount of oestrogen receptor detected in pancreatic tissue was small, and may account for previous difficulties in its detection. The extent to which it is functional in both the normal and malignant pancreas warrants further investigation.

Determination of the two major human metabolites of tipredane in human urine by high-performance liquid chromatography with column switching.

An automated method based on column-switching reversed-phase in high-performance liquid chromatography the heart-cutting mode has been developed for the simultaneous determination of the two major human metabolites of tipredane, FPL 66365XX and FPL 66366XX, in human urine. The limit of quantification of the method was 25 ng/ml for both analytes from a urine injection volume of 100 microl. The intra- and inter-assay precision and accuracy were acceptable between 25 and 5000 ng/ml. No significant interferences were observed from either tipredane or a selection of its putative metabolites, or urine constituents in samples from male and female volunteers. Both analytes were found to be stable in human urine when stored at room temperature for two days, at 4 degrees C for six days, in a freezer at or below -20 degrees C for three weeks, and when the urine samples were subjected to three freeze-thaw cycles The method was unusual in that the initial separation was performed on a non-polar, octadecylsilane, column and the final separation on a more polar, trimethylsilane column. These columns were selected only after the investigation of a wide range of reversed-phase columns. The method's success was based on the greatly differing selectivities shown towards the two analytes by the organic modifiers, methanol and acetonitrile, present in the mobile phases used for the extraction and analytical stages

Determination of a major metabolite of tipredane in rat urine by high-performance liquid chromatography with column switching.

An automated method, based on column-switching reversed-phase high-performance liquid chromatography, has been developed for the determination of a major metabolite of tipredane in rat urine. Samples are injected directly onto a cyanopropyl extraction column. The portion of eluate containing the metabolite is switched, via an injection loop, onto an octadecylsilane analytical column. The limit of quantification of the method was 25 ng/ml for a 20 microl injection volume of urine. The intra-assay precision (0.7-4.8%) and accuracy (94-105%), and the inter-assay precision (2.7-12.6%) and accuracy (94-105%), were acceptable. The analyte was found to be stable in rat urine when stored at room temperature for six days, in a freezer at or below -20 degrees C for twelve weeks, and when the samples were subjected to two freeze-thaw cycles. No significant interference was observed from tipredane and its major human metabolites, or urine constituents in male and female rats. The method was successfully used to analyse samples from a long-term toxicology study.

Proteinase inhibitors reduce basement membrane degradation by human breast cancer cell lines.

The relative importance of different proteinases, and their inhibition, in the breakdown of human endothelial basement membrane (BM) by MDA-MB-231 and MCF7ADR human breast cancer cell lines has been studied using 35S-labelled BM-coated 96-well culture plates. Basement membrane degradation (BMD) was independent of cell proliferation above the seeding density. Inhibitors of aspartic (pepstatin and PD 134678-0073) and cysteine proteinases (E64) had little effect on BMD under normal culture conditions, suggesting that cathepsins D, B and L have only a minor role. In contrast, inhibitors of urokinase-type plasminogen activator (uPA) and/or plasminogen activation to plasmin (aprotinin, amiloride, EACA, tranexamic acid, anti-uPA antibody) all reduced BMD by MDA-MB-231 cells by approximately 30-40%, but only in the presence of serum or plasminogen. BB94, an inhibitor of matrix metalloproteinases (MMPs), also reduced BMD by about 30% under these conditions but was similarly effective in serum-free medium. Combinations of BB94 with any of the uPA/plasminogen activation inhibitors in serum-containing medium had additive effects, while BB94 with pepstatin and E64 under serum-free conditions reduced BMD to 16% of control. Serum-containing conditioned medium exhibited appreciable BMD, largely due to aprotinin-inhibitable activity. Although small reductions in cell proliferation were seen with some inhibitors, the combination of BB94 with E64 or E64d reduced the cell population by about 60% under serum-containing conditions. These in vitro observations suggest that combinations of proteinase inhibitors, particularly of uPA/plasminogen activation and MMPs, may merit clinical evaluation as potential antimetastatic therapy for breast cancer.

Fluorogenic compound hydrolysis as a measure of toxicity-induced cytoplasmic viscosity and pH changes.

If a fluorogenic compound, such as fluorescein diacetate, is added to a water solution containing living cells it becomes hydrolyzed by intracellular esterases into a fluorochrome whose fluorescence can be used to monitor the cytoplasmic pH and the cytoplasmic viscosity of the cells. In this paper we have used this technique to measure the effects of different concentrations of Co2+ and Cd2+ ions on the cytoplasmic pH and the cytoplasmic viscosity of a single cell culture. Our results indicate that the observed decrease in the efficiency of the intracellular hydrolyzation of fluorogenic substances in the presence of different concentrations of heavy metals could be caused by both a decrease in the cytoplasmic pH and an increase in the cytoplasmic viscosity. A decrease in cytoplasmic pH would decrease the effectiveness of the intracellular enzymes, whereas an increase in cytoplasmic viscosity would decrease diffusion which would also reduce the effectiveness of the reaction. The dependence of the reciprocal of the cytoplasmic viscosity on the concentration of these metals correlates well with published results on their toxicity.

Impact of patient with patient interaction on perceived rheumatoid arthritis overall disease status.

To determine whether patient interaction impacts on perceived disease severity and ability to cope with rheumatoid arthritis (RA) forty RA patients were assessed using joint counts, clinician global assessment, patient global assessment (PGA), VAS pain scale and Health Assessment Questionnaire (HAQ). All participants had six one-on-one conversations about their disease activity and the effect of RA on their lives. Follow-up questionnaires asked about recall of pre-conversation PGA; post-conversation PGA; change in PGA; and change in ability to cope as a result of the conversations. 87.5% of the questionnaires were returned. Pre- and post-conversation PGA were statistically reliable; PGA score improved (P = 0.004); 60.0% of participants felt their ability to cope with their disease improved as a result of this interaction. RA patients benefit from sharing information with like patients. Support groups may be an integral part of treatment strategy in patients with RA.

Automated high-performance liquid chromatographic method for the determination of nedocromil sodium in human urine using bimodal column switching.

An automated HPLC method is described for the determination of nedocromil sodium in human urine. An HPLC autosampler is used to inject urine samples onto a short reversed-phase column. This column acts as a concentration column and performs a preliminary extraction. The concentration column is automatically back-flushed onto an ion-exchange column where final separation of nedocromil sodium from urine constituents occurs. Recovery, accuracy, precision, sensitivity and specificity were investigated. The method has been applied to urine samples from clinical studies, and the results were compared to those obtained using a radioimmunoassay developed previously.

Determination of dopexamine hydrochloride in human blood by high-performance liquid chromatography with electrochemical detection.

A method is described for the determination of dopexamine hydrochloride at concentrations of 5 to 100 ng/ml in human blood using electrochemical detection. The method uses a Hypersil ODS column and a mobile phase containing heptane sulphonate, orthophosphoric acid, diisopropylamine and disodium EDTA. Blood samples are stabilised immediately after collection by the use of dipotassium EDTA and a high concentration of sodium metabisulphite. The sample preparation procedure consists of a simple de-proteinisation with perchloric acid. The method is accurate, with inter-assay accuracies ranging from 100 to 104%, and is free of interference by blood from different individuals. Known and potential metabolites of dopexamine hydrochloride and a wide range of drugs do not interfere with the method. The method is precise with inter-assay coefficients of variation of 10.6% at 5 ng/ml and of less than 4.2% at higher concentrations. Stabilised blood samples may be stored for over six months at -25 degrees C prior to analysis.

Oestrogen and progesterone receptors in colorectal cancer and human colonic cancer cell lines.

Receptors for oestrogen (ER) and progesterone (PR) were assayed in tissue from 17 patients with colorectal cancer and five colonic cancer cell lines using enzyme immunoassays. ERs and PRs were detected in 15 and 17 cancers respectively, although the levels detected were low: median (range) ER 1.3 (0-11.3) and PR 3.9 (0.3-10.2) fmol per mg protein. These values were not significantly different from median (range) levels of ER (1.1 (0.6-3.0) fmol/mg) and PR (1.9 (0.5-3.2) fmol/mg) detected in normal mucosa. There were significant positive correlations between the levels of ER and PR for cancer tissue (tau = 0.56, P < 0.005; r(log transform) = 0.68, P < 0.003; n = 17) but not for mucosa, and between levels of ER in cancer tissue and mucosa (tau = 0.55, P < 0.05; r(log transform) = 0.70, P < 0.025; n = 10) but not between the corresponding PR values. In maintenance media, which contained phenol red and unstripped fetal calf serum, the median (range) concentration of ER was 1.9 (1.2-10.4) fmol/mg and that for PR 24.3 (9.1-63.2) fmol/mg in the five cell lines studied (HT-29, LS174T, SW620, LoVo, COLO 320DM). The addition of oestradiol (10 nmol/l) to phenol red-free medium containing 5 per cent dextran-coated charcoal-treated fetal calf serum had little effect on the concentration of ERs or PRs in SW620, LoVo and COLO 320DM cells after 7 days' culture. It is concluded that ERs and PRs are expressed in malignant and normal colonic mucosa. ERs appear to be a feature of the colonic mucosa rather than the malignant process, but in carcinoma may regulate synthesis of PRs, suggesting a degree of oestrogen responsiveness.

A method for achieving consensus on rheumatoid arthritis outcome measures: the OMERACT conference process.

We describe the process used during the international Conference on Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT). The objectives of the conference were (1) to broaden consensus on the minimum number of outcome measures to be included in all RA clinical trials in rheumatoid arthritis (RA); (2) to achieve consensus on criteria for (a) minimum clinically important improvement in patients with RA and (b) minimum important differences between treatment groups in RA clinical trials; and (3) to decide whether aggregate outcome measures (indices) are useful in the assessment of patients and trials. A combination of plenary sessions and structured nominal groups were employed during the conference. Simulated patient profiles and clinical trial profiles were used to generate discussion. The objective of the nominal group exercises was to capture each participant's judgments of the relative importance of each outcome measure and the degree of change required to indicate clinical improvement. Considerable discussion ensued on the content of the core set of outcome measures. An electronic interactive voting machine was used to obtain participants' views on a core set of outcome measures and methodological issues. To permit further discussion of outcome measures, the group explored the use of aggregate outcome measures (indices) in patient care and trials only in a preliminary way. A final plenary session dealt with patient perceptions of minimum important differences, a new classification of antirheumatic drugs, and a repeat of part of the preconference questionnaire. Concluding statements and future plans were developed at the conclusion of the meeting.

Minimum important difference between patients with rheumatoid arthritis: the patient's perspective.

OBJECTIVE: To determine the point at which differences in clinical assessment scores on physical ability, pain and overall condition are sufficiently large to correspond to a subjective perception of a meaningful difference from the perspective of the patient. METHODS: Forty patients with a diagnosis of rheumatoid arthritis participated in an evening of clinical assessment and one-on-one conversations with each other regarding their arthritic condition. The assessments included tender and swollen joint counts, clinician and patient global assessments, participant assessment of pain and the Health Assessment Questionnaire (HAQ) on physical ability. After each conversation, participants rated themselves relative to their conversational partner on physical ability, pain and overall condition. These subjective comparative ratings were compared to the differences of the individual clinical assessments. RESULTS: In total there were 120 conversations. Generally participants judged themselves as less disabled than others. They rated themselves as "somewhat better" than their conversation partner when they had a (mean) 7% better score on the HAQ, 6% less pain, and 9% better global assessment. In contrast, they rated themselves as "somewhat worse" when they had a (mean) 16% worse score on the HAQ, 16% more pain, and 29% worse global assessment. CONCLUSIONS: Patients view clinically important differences in an asymmetric manner. These results can provide guidance in interpreting results and planning clinical trials.

Faecal unconjugated bile acids in patients with colorectal cancer or polyps.

The unconjugated faecal bile acid profiles of 14 patients with colorectal cancer, nine patients with polyps and 10 controls were compared using gas liquid chromatography, controlling for such confounding variables as cholecystectomy, gall stones and hepatic function. Patients with adenomatous polyps had a higher concentration of faecal bile acids (5.23 mumol/g, 2.16-13.67 (median, range) v 1.96, 0.91-6.97; p = 0.016) lithocholic acid (2.41, 0.88-3.22 v 1.07, 0.38-2.03; p = 0.013) and total secondary bile acids (5.23, 2.16-13.4 v 1.96, 0.73-6.63; p = 0.02) compared with control subjects. Patients with colorectal cancer had an increased (p = 0.029) proportion of secondary faecal bile acids (mol%) compared with controls (100, 96.5-100 v 95.19, 81.73-100) and the ratios of the primary bile acids, cholic and chenodeoxycholic acid, to their respective derivatives (secondary bile acids) were significantly lower in cancer patients compared with control and patients with polyps (p = 0.034 to 0.004). This study lends further support to the theory that bile acids may play a role in the development of polyps and colorectal cancer.