Proton pump inhibitor use and progression to major adverse renal events: a competing risk analysis.

BACKGROUND: Proton pump inhibitors (PPIs) are associated with acute tubulointerstitial nephritis and there are reports associating their use with the development of chronic kidney disease (CKD). AIM: To determine if PPI use is associated with major adverse renal events (MARE) in patients with CKD. DESIGN: Observational cohort study comprising patients with CKD attending secondary care renal clinics from 1 January 2006 until 31 December 2016. METHODS: We collated baseline clinical, socio-demographic and biochemical data at start of PPI (PPI group) or study inception (control group). MARE was considered a composite of doubling of creatinine or end-stage renal disease. Association between PPI exposure and progression to MARE was assessed by cause-specific hazards competing risk survival analysis. RESULTS: There were 3824 patients with CKD included in the analyses of whom 1195 were prescribed a PPI. The PPI group was younger (64.8 vs. 67.0 years, P < 0.001), with lower estimated glomerular filtration rate (eGFR) (30 vs. 35 ml/min, P < 0.001) and more proteinuria (64 vs. 48 mg/mmol, P < 0.001). PPI use was associated with progression to MARE on multivariable adjustment (hazard ratio 1.13 [95% confidence interval 1.02-1.25], P = 0.021). Other factors significantly associated with progression to MARE were higher systolic blood pressure, lower eGFR, greater proteinuria, congestive cardiac failure and diabetes. Hypomagnesaemia was more common in the PPI group (39.5 vs. 18.9%, P < 0.001). CONCLUSION: PPI use was associated with progression to MARE, but not death in patients with CKD after adjusting for factors known to predict declining renal function, including lower eGFR, proteinuria and comorbidities. A prospective cohort study is required to validate these findings.

Eye Tracking Effort Expenditure and Autonomic Arousal to Social and Circumscribed Interest Stimuli in Autism Spectrum Disorder.

The social communicative deficits and repetitive behaviours seen in Autism Spectrum Disorder (ASD) may be affected by altered stimulus salience and reward attribution. The present study used eye tracking and a behavioural measure to index effort expenditure, arousal, and attention, during viewing of images depicting social scenes and subject-specific circumscribed interests in a group of 10 adults with ASD (mean age 25.4 years) and 19 typically-developing controls (mean age 20.7 years) Split-plot and one-way repeated measures ANOVAs were used to explore results. A significant difference between the ASD and control group was found in the amount of effort expended to view social and circumscribed images. The ASD group also displayed significant differences in pupillary response to social and circumscribed images, indicative of changes in autonomic arousal. Overall, the results support the social motivation hypothesis in ASD (Chevallier et al., Trends Cogn Sci 16(4):231-239, 2012) and suggest a role for autonomic arousal in the ASD symptom dyad.

Indices of repetitive behaviour are correlated with patterns of intrinsic functional connectivity in youth with autism spectrum disorder.

The purpose of the current study was to examine how repetitive behaviour in Autism Spectrum Disorder (ASD) is related to intrinsic functional connectivity patterns in a number of large-scale, neural networks. Resting-state fMRI scans from thirty subjects with ASD and thirty-two age-matched, typically developing control subjects were analysed. Seed-to-voxel and ROI-to-ROI functional connectivity analyses were used to examine resting-state connectivity in a number of cortical and subcortical neural networks. Bivariate correlation analysis was performed to examine the relationship between repetitive behaviour scores from the Repetitive Behaviour Scale - Revised and intrinsic functional connectivity in ASD subjects. Compared to control subjects, ASD subjects displayed marked over-connectivity of the thalamus with several cortical sensory processing areas, as well as over-connectivity of the basal ganglia with somatosensory and motor cortices. Within the ASD group, significant correlations were found between functional connectivity patterns and total RBS-R scores as well as one principal component analysis-derived score from the RBS-R. These results suggest that thalamocortical resting-state connectivity is altered in individuals with ASD, and that resting-state functional connectivity is associated with ASD symptomatology.

Collection and determinants of patient reported outcome measures in haemodialysis patients in Scotland.

BACKGROUND/INTRODUCTION: Patient reported outcome measures (PROMs) can evaluate the quality of health in patients with established renal failure. There is limited experience of their use within national renal registries. AIM: To describe the Scottish Renal Registry's (SRR) experience of collecting PROMS in the haemodialysis population and correlate PROMS to demographic and clinical parameters. DESIGN: Retrospective observational cross-sectional study. METHODS: Haemodialysis patients in Scotland were invited to complete the KDQOL™-36 questionnaire on the day of the annual SRR census in 2015 and 2016. Questionnaires were linked to census demographic and clinical variables. RESULTS: In 2016, 738 questionnaires were linked to census data (39% of prevalent haemodialysis population). Response rates differed with age (≥ 65 years 42%, < 65 years 36%) [χ2P = 0.006]; duration of renal replacement therapy (<1 year 46%, ≥1 < 5 years 38%, ≥ 5 years 33%) [χ2P = 0.002] and social class (Scottish Index of Multiple Deprivation (SIMD) Class 1 32%, Class 2 41%, Class 3 40%, Class 4 48%, Class 5 40%) [χ2P < 0.001]. There were significant differences in PROMs with age, SIMD quintile and primary renal diagnosis. Achieving a urea reduction ratio of >65% and dialysing through arteriovenous access were associated with significantly higher PROMs. PROMs were not affected by haemoglobin or phosphate concentration. DISCUSSION/CONCLUSIONS: Routine collection of PROMs is feasible and can identify potentially under-recognized and treatable determinants to quality of life. The association between attaining recommended standards of care and improved PROMs is striking. Individual and population-wide strategies are required to improve PROMs.

Positive allosteric modulators of the µ-opioid receptor: a novel approach for future pain medications.

UNLABELLED: Morphine and other agonists of the µ-opioid receptor are used clinically for acute and chronic pain relief and are considered to be the gold standard for pain medication. However, these opioids also have significant side effects, which are also mediated via activation of the µ-opioid receptor. Since the latter half of the twentieth century, researchers have sought to tease apart the mechanisms underlying analgesia, tolerance and dependence, with the hope of designing drugs with fewer side effects. These efforts have revolved around the design of orthosteric agonists with differing pharmacokinetic properties and/or selectivity profiles for the different opioid receptor types. Recently, µ-opioid receptor-positive allosteric modulators (µ-PAMs) were identified, which bind to a (allosteric) site on the µ-opioid receptor separate from the orthosteric site that binds an endogenous agonist. These allosteric modulators have little or no detectable functional activity when bound to the receptor in the absence of orthosteric agonist, but can potentiate the activity of bound orthosteric agonist, seen as an increase in apparent potency and/or efficacy of the orthosteric agonist. In this review, we describe the potential advantages that a µ-PAM approach might bring to the design of novel therapeutics for pain that may lack the side effects currently associated with opioid therapy. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

End-stage renal disease and survival in people with diabetes: a national database linkage study.

BACKGROUND: Increasing prevalence of diabetes worldwide is projected to lead to an increase in patients with end-stage renal disease (ESRD) requiring renal replacement therapy (RRT). AIM: To provide contemporary estimates of the prevalence of ESRD and requirement for RRT among people with diabetes in a nationwide study and to report associated survival. METHODS: Data were extracted and linked from three national databases: Scottish Renal Registry, Scottish Care Initiative-Diabetes Collaboration and National Records of Scotland death data. Survival analyses were modelled with Cox regression. RESULTS: Point prevalence of chronic kidney disease (CKD)5 in 2008 was 1.63% of 19 414 people with type 1 diabetes (T1DM) compared with 0.58% of 167 871 people with type 2 diabetes (T2DM) (odds ratio for DM type 0.97, P = 0.77, on adjustment for duration. Although 83% of those with T1DM and CKD5 and 61% of those with T2DM and CKD5 were receiving RRT, there was no difference when adjusted for age, sex and DM duration (odds ratio for DM type 0.83, P = 0.432). Diabetic nephropathy was the primary renal diagnosis in 91% of people with T1DM and 58% of people with T2DM on RRT. Median survival time from initiation of RRT was 3.84 years (95% CI 2.77, 4.62) in T1DM and 2.16 years (95% CI: 1.92, 2.38) in T2DM. CONCLUSION: Considerable numbers of patients with diabetes continue to progress to CKD5 and RRT. Almost half of all RRT cases in T2DM are considered to be due to conditions other than diabetic nephropathy. Median survival time for people with diabetes from initiation of RRT remains poor. These prevalence data are important for future resource planning.

Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists.

Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse.

The delivery of renal replacement therapy in Scotland--why the geographic variation?

BACKGROUND: The incidence of patients starting renal replacement therapy (RRT) for established renal failure (ERF) in Scotland has fallen from 2005 to 2011 due to a reduction in older patients starting RRT; there are significant differences between NHS Health board areas. AIM: To understand the apparent inequality in provision of RRT between NHS board areas in Scotland. DESIGN: Retrospective population analysis of Scottish renal registry (SRR) data, population statistics and quality outcomes framework summary statistics. RESULTS: The incidence of patients starting RRT for ERF in Scotland fell from 123 per million population (pmp) in 2005 to 96 pmp in 2011. The incidence of ≥75 year olds fell from 406 to 274 pmp. There are significant differences between NHS board areas when standardized for age and social deprivation. There is no relationship between the population prevalence of CKD as reported by QOF and the incidence of RRT for ERF. Those areas with high incidence rates of ≥75 year olds have higher 90-day [Spearman's rank correlation: coefficient = 0.662; P = 0.03] and 1-year [Spearman's rank correlation: coefficient = 0.776; P = 0.003] mortality rates. CONCLUSION: The significant variation in provision of RRT for ERF between Scottish NHS Board areas is not explained by age or social deprivation. There is evidence of change in practice towards RRT for patients aged ≥75 years but variation between NHS Board areas. This disparity must be further investigated to ensure equity of access to RRT for those who will benefit from it, and to non-dialytic care for those who would not.

Vascular access type and risk of mortality in a national prospective cohort of haemodialysis patients.

BACKGROUND: Central venous catheters (CVC) are a potential source of bacteraemia and have been associated with increased mortality in haemodialysis patients. We aimed to investigate the relationships between haemodialysis vascular access, taking into account changes in vascular access type during patients' lives, and cause specific mortality risk in a national cohort of dialysis patients. METHODS: Prospective cohort study including all patients receiving haemodialysis in Scotland at annual cross sectional surveys in 2009, 2010 and 2011. Data were collected through the Scottish Renal Registry and by a structured review of case records following death. Cox proportional hazards regression and multivariable logistic regression were used to model survival and risk of death from septicaemia respectively. RESULTS: Of a cohort of 2666 patients, 873 (32%) died during follow-up. After case-mix adjustment, patients using only tunnelled CVC during follow-up had a higher risk of all cause mortality across all strata of prior renal replacement therapy exposure [adjusted hazard ratio (HR): 1.83-2.08]. Case-mix adjusted risks of cardiovascular death (adjusted HR: 2.20-2.95) and infection-related death (adjusted HR: 3.10-3.63) were also higher in this group. Patients using tunnelled CVCs during follow-up and prior to death had 6.9-fold higher odds of death from septicaemia compared with those using only arteriovenous fistulae or grafts. CONCLUSION: Compared with an arteriovenous fistula or graft, sustained use of tunnelled CVCs for vascular access is associated with higher risks of all-cause, cardiovascular and infection-related mortality.

Stratifying risk in chronic kidney disease: an observational study of UK guidelines for measuring total proteinuria and albuminuria.

BACKGROUND: Proteinuria predicts poor renal and cardiovascular outcomes. Some guidelines recommend measuring proteinuria using albumin:creatinine ratio (ACR), while others recommend total protein:creatinine ratio (TPCR). AIM: To compare renal outcomes and mortality in the populations identified by these different recommendations. DESIGN: Retrospective longitudinal cohort study. METHODS: Baseline ACR and TPCR measurements were obtained from 5586 patients with chronic kidney disease (CKD) attending a Scottish hospital nephrology clinic. The cohort was divided into three groups with concordant results by ACR and TPCR (no proteinuria; low proteinuria; significant proteinuria) and one group with discordant results (significant proteinuria with TPCR, but not ACR). Outcomes were assessed using Kaplan-Meier plots and Cox proportional hazards models. RESULTS: Median follow-up was 3.5 years [interquartile range (IQR) 2.1-6.0]; 844 (15%) died at 3.0 years (IQR 1.8-4.7) and 468 (8%) started renal replacement therapy (RRT) at 1.7 years (IQR 0.6-3.4). Proteinuria was associated with a substantially increased risk of RRT and death. Patients with significant proteinuria by TPCR, but not ACR (n = 231) had high renal risk, and the highest all-cause mortality (log-rank P < 0.001). With multivariate analysis the risk fell below those with significant proteinuria with concordant results by ACR and TPCR but remained considerably higher than those without significant proteinuria. CONCLUSION: Proteinuria screening with TPCR identifies an additional 16% of patients with significant proteinuria, not identified using ACR. This subgroup has high renal risk, and high risk of all-cause mortality and therefore warrant identification. Guideline recommendations on proteinuria screening in CKD should be reconsidered.

The prevalence of chronic kidney disease in rheumatology outpatients.

BACKGROUND: The introduction of routine reporting of estimated glomerular filtration rate coupled with a new definition of chronic kidney disease (CKD) has led to an unprecedented focus on kidney disease in many patient groups. In light of this, we performed an audit of patients attending the rheumatology clinics to assess the prevalence of CKD in this population. METHODS: Over a four week period, we reviewed the renal function of all patients attending the rheumatology clinics and day ward at our hospital (n=351). Renal function was assessed using the 4-variable MDRD formula. We then interviewed those patients with estimated glomerular filtration rate (eGFR) of 59 ml/min or lower. RESULTS: We found a prevalence rate of 18% for stage 3 CKD or lower in our audit population. Surprisingly, 60.3% of patients in this category were not aware of any problems with their kidneys (n=38). CONCLUSIONS: The prevalence rate of 18% for stage 3 CKD or lower is significantly higher than the five per cent reported within the general population. As a result of this audit, we now plan to ensure that these patients undergo measurement of blood pressure, eGFR, and urinalysis on a six to twelve monthly basis.

14 beta-O-cinnamoylnaltrexone and related dihydrocodeinones are mu opioid receptor partial agonists with predominant antagonist activity.

14-O-Cinnamoyl esters of naltrexone (6) were synthesized and evaluated in isolated tissue assays in vitro and in vivo in mouse antinociceptive assays. Their predominant opioid receptor activity was mu receptor (MOR) antagonism, but the unsubstituted cinnamoyl derivative (6a) had partial MOR agonist activity in vitro and in vivo. When compared to the equivalent 14-cinnamoylaminomorphinones (5), the cinnamoyloxy morphinones (6) as MOR antagonists had a shorter duration of action and were less effective as pseudoirreversible antagonists. The antinociceptive activity of the cinnamoyloxycodeinones (7) was not significantly greater than that of the morphinones (6), but they exhibited no evidence of any pseudoirreversible MOR antagonism. In both respects, these profiles differed from those of the equivalent 14-cinnamoylaminocodeinones (4).

Neutral antagonist activity of naltrexone and 6beta-naltrexol in naïve and opioid-dependent C6 cells expressing a mu-opioid receptor.

BACKGROUND AND PURPOSE: Adenylyl cyclase sensitization occurs on chronic agonist activation of mu-opioid receptors and is manifested by an increase in cAMP levels (overshoot) on challenge with antagonist. It has been proposed that a long lasting constitutively active receptor is formed on chronic mu-opioid exposure and that antagonists with inverse agonist activity rapidly return the receptor to a basal state causing a cAMP overshoot and a more severe withdrawal response in vivo. This hypothesis depends on an accurate characterization of neutral and inverse agonist properties of opioid antagonists. EXPERIMENTAL APPROACH: C6 glioma and HEK293 cells expressing mu-opioid receptors were used. Opioid antagonists were examined for their ability to induce a cAMP overshoot following chronic treatment with the agonist DAMGO ([D-Ala(2),N-Me-Phe(4),Glyol(5)]-enkephalin). The compounds were also characterized as agonists, inverse agonists or neutral antagonists by using assays for competitive binding, [(35)S]GTPgammaS (guanosine-5'-O-(3-[(35)S]thio)triphosphate) binding and changes in cell surface receptor expression. KEY RESULTS: Naltrexone, 6beta-naltrexol and naloxone were indistinguishable to the mu-opioid receptor in the opioid-naïve or dependent state and acted as neutral antagonists. The delta-opioid receptor inverse agonist RTI-5989-25 [(+)-N-[trans-4'-(2-methylphenyl)-2'-butenyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine], a 3,4-dimethyl-4-(3-hydroxyphenyl)-piperidine, was an inverse agonist at the mu-opioid receptor, and the peptide antagonist CTAP (H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)) showed variable, assay-dependent properties. All the antagonists precipitated the same degree of cAMP overshoot in opioid-dependent cells. CONCLUSIONS AND IMPLICATIONS: Antagonists at the mu-opioid receptor may be neutral or show inverse agonist activity. Formation of a constitutively active mu-opioid receptor is not a requirement for the development or expression of adenylyl cyclase sensitization.

Endogenous regulators of G protein signaling differentially modulate full and partial mu-opioid agonists at adenylyl cyclase as predicted by a collision coupling model.

Regulator of G protein signaling (RGS) proteins accelerate the endogenous GTPase activity of Galpha(i/o) proteins to increase the rate of deactivation of active Galpha-GTP and Gbetagamma signaling molecules. Previous studies have suggested that RGS proteins are more effective on less efficiently coupled systems such as with partial agonist responses. To determine the role of endogenous RGS proteins in functional responses to mu-opioid agonists of different intrinsic efficacy, Galpha(i/o) subunits with a mutation at the pertussis toxin (PTX)-sensitive cysteine (C351I) and with or without a mutation at the RGS binding site (G184S) were stably expressed in C6 glioma cells expressing a mu-opioid receptor. Cells were treated overnight with PTX to inactivate endogenous G proteins. Maximal inhibition of forskolin-stimulated adenylyl cyclase by the low-efficacy partial agonists buprenorphine and nalbuphine was increased in cells expressing RGS-insensitive Galpha(o)(CIGS), Galpha(i2)(CIGS), or Galpha(i3)(CIGS) compared with their Galpha(CI) counterparts, but the RGS-insensitive mutation had little or no effect on the maximal inhibition by the higher efficacy agonists DAMGO and morphine. The potency of all the agonists to inhibit forskolin-stimulated adenylyl cyclase was increased in cells expressing RGS-insensitive Galpha(o)(CIGS), Galpha(i2)(CIGS), or Galpha(i3)(CIGS), regardless of efficacy. These data are comparable with predictions based on a collision coupling model. In this model, the rate of G protein inactivation, which is modulated by RGS proteins, and the rate of G protein activation, which is affected by agonist intrinsic efficacy, determine the maximal agonist response and potency at adenylyl cyclase under steady state conditions.

A comparison of the physiological, behavioral, neurochemical and microglial effects of methamphetamine and 3,4-methylenedioxymethamphetamine in the mouse.

3,4-Methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) are amphetamine analogues with similar persistent neurochemical effects in the mouse which some have described as neurotoxicity. We attempted to identify dose regimens of MDMA and METH with similar effects on behavioral and physiological variables in the mouse, then quantified the effects of these dose regimens on neurochemistry and microglial markers. Four discrete injections of saline, MDMA (10, 20, or 30 mg/kg), or METH (5 or 10 mg/kg) were administered to mice at 2 h intervals. Body weight was quantified immediately before each injection, and 2 h after the last injection, while core temperature and locomotor activity were continuously monitored via radiotelemetry. Mice were killed 72 h after the final injection and brains were rapidly dissected on ice. Dopamine content in various brain regions was quantified via high pressure liquid chromatography (HPLC), and microglial activation was assessed by saturation binding of the peripheral benzodiazepine receptor (PBR) ligand 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide ([(3)H]PK11195). Specific dose regimens of MDMA and METH induced similar reductions in body weight, depletions of dopamine and its metabolites, and similar hyperthermic and locomotor stimulant effects, but only METH activated microglia in striatum. These results suggest that repeated high doses of MDMA and METH that produce hyperthermia, locomotor stereotypy, weight loss and neurochemical depletion are not consistently accompanied by microglial activation. The finding that METH, but not MDMA, induces microglial effects in the striatum consistent with neurotoxicity might imply different mechanisms of toxic action for these two psychostimulants.

Gastric carcinoid: germline and somatic mutation of the neurofibromatosis type 1 gene.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominantly inherited conditions. A range of complications has been described, including gastrointestinal manifestations. Gastric carcinoid tumours are associated with multiple endocrine neoplasia, atrophic gastritis and pernicious anaemia but have not been reported in NF1 in the absence of other predisposing factors. We report the occurrence and investigation of a gastric carcinoid tumour in a 23-year-old woman with previously uncomplicated NF1. Analysis of the tumour tissue revealed loss of heterozygosity at the NF1 gene locus but a normal karyotype and an absence of microsatellite instability. A germline NF1 gene nonsense mutation in exon 37 was detected by denaturing high-performance liquid chromatography and DNA sequence analysis. This is the first reported occurrence of a gastric carcinoid tumour in a patient with NF1 in the absence of other predisposing factors such as pernicious anaemia. The analyses indicate that the carcinoid arose through NF1 gene inactivation but in the absence of an inherited NF1 gene microdeletion. This case adds to the range of gastrointestinal tumours that may be encountered in patients with NF1, particularly in those who present with upper gastrointestinal haemorrhage.

The relationship between serum creatinine and estimated glomerular filtration rate: implications for clinical practice.

INTRODUCTION: A new classification of chronic kidney disease (CKD) has been widely adopted that stratifies patients into 5 'stages' according to estimated glomerular filtration rate (eGFR). In adults the most commonly used formulae to calculate eGFR are the Cockcroft and Gault (C and G) and Modification of Diet in Renal Disease (MDRD) formulae. The UK Renal Association has recommended calculation of MDRD eGFR to screen for reduced kidney function in primary and secondary care. AIM: The aim of this study was to explore the implication of using these predictive formulae. METHODS: We searched for patients currently attending a renal clinic who have ever had a serum creatinine (SCr) of exactly 100 micromol/L, 150 micromol/L or 200 micromol/L. The C and G and MDRD eGFRs corresponding to that SCr were calculated. The proportion of patients in each stage of the CKD classification was determined. RESULTS: For a SCr of 100 micromol/L mean eGFR was 86.5 ml/min (range 31.0 - 192.8) by C and G and 63.8 ml/min (range 39.7 - 99.9) by MDRD (p < 0.0001; t-test of mean). For SCr 150 micromol/L mean eGFR was 51.7 ml/min (18.0 - 110.4) by C and G and 38.0 ml/min (20.7 - 54.8) by MDRD (p < 0.0001). For SCr of 200 micromol/L mean eGFR was 34.4 ml/min (12.6 - 89.5) by C and G and 27.3 ml/min (16.7 - 41.3) by MDRD (p < 0.0001). Using MDRD eGFR 46.5% patients with a SCr of 100 micromol/L have stage 3 CKD (GFR 30-60 ml/min) and all patients with a SCr of 150 micromol/L or 200 micromol/L have CKD 3 or worse. 8.6% of males with SCr 100 micromol/L had stage 3 CKD or worse compared with 86.8% females. 70.2% patients > 65 years old with SCr 100 micromol/L had stage 3 CKD. CONCLUSIONS: Targeted screening of patients at-risk for CKD will identify a large number of patients who require management of CKD and potential referral to nephrology services even at levels of SCr regarded as 'normal' or mildly.

Design of high affinity cyclic pentapeptide ligands for kappa-opioid receptors.

Using results from our previously reported cyclic opioid peptide series and reliable models for mu-, delta-, and kappa-opioid receptors (MOR, DOR, and KOR, respectively) and their complexes with peptide ligands, we have designed and synthesized a series of cyclic pentapeptides of structure Tyr-C[D-Cys-Phe-Phe-X]-NH2, cyclized via disulfide, methylene, or ethylene dithioethers, and where X = D- or L-Cys; or D- or L-penicillamine (Pen; beta,beta-dimethylcysteine). Determination of binding affinities to MOR, DOR, and KOR revealed that members of this series with X = D- or L-Cys display KOR affinities in the low nanomolar range, demonstrating that a 'DPDPE-like' tetrapeptide scaffold is suitable not only for DOR and MOR ligands, but also for KOR ligands. The cyclic pentapeptides reported here are not, however, selective for KOR, rather they display significant selectivity and high affinity for MOR. Indeed, peptide 8, Tyr-C[D-Cys-Phe-Phe-Cys]-NH2-cyclized via a methylene dithioether, shows picomolar binding affinity for MOR ( = 16 pm) with more than 100-fold selectivity for MOR vs. DOR or KOR, and may be of interest as a high affinity, high selectivity MOR ligand. Nonetheless, the high affinity KOR peptides in this series represent excellent leads for the development of structurally related, selective KOR ligands designed to exploit structurally specific features of KOR, MOR, and DOR.

Assessing the utility of the stop dialysate flow method in patients receiving haemodiafiltration.

BACKGROUND: The stop dialysate flow (SDF) method of post-dialysis urea sampling is the most commonly used method in the UK. It can also be used with a published formula to predict 30 min equilibrated urea accurately. The method has not been validated in patients undergoing haemodiafiltration (HDF). Given the increased use of HDF across Europe, we felt it prudent to assess the utility of the SDF method and prediction equation in this modality. METHODS: Fourteen patients from two renal units were studied. Blood samples were taken at 1 min intervals from the arterial side of the dialysis circuit in the first 5 min after HDF had ceased whilst blood circulation continued. A peripheral sample was taken from the contralateral arm immediately after HDF had ceased and a 30 min sample was taken from the arterial needle. These samples were used to assess the utility of 5 min arterial blood urea and the 30 min prediction formula, respectively. RESULTS: Blood urea measured from the arterial circuit at 5 min correlated closely with the contralateral sample taken immediately post-HDF, with no significant difference (6.45+/-2.11 vs 6.52+/-2.19 mmol/l, P = 0.39). The use of 5 min arterial blood urea and prediction formula allowed an accurate prediction of 30 min urea (R2 = 0.96). CONCLUSIONS: The use of the SDF method with a 5 min post-HDF arterial sample is valid in patients receiving HDF. The previously published prediction formula for estimating 30 min urea is also valid using the 5 min post-HDF sample.