Laparoscopic-assisted ERCP following RYGB: a 12-year assessment of outcomes and learning curve at a high-volume pancreatobiliary center.

INTRODUCTION: Treatment of pancreaticobiliary pathology following Roux-en-Y gastric bypass (RYGB) poses significant technical challenges. Laparoscopic-assisted endoscopic retrograde cholangiopancreatography (LA-ERCP) can overcome those anatomical hurdles, allowing access to the papilla. Our aims were to analyze our 12-year institutional outcomes and determine the learning curve for LA-ERCP. METHODS: A retrospective review of cases between 2007 and 2019 at a high-volume pancreatobiliary unit was performed. Logistic regression was used to identify predictors of specific outcomes. To identify the learning curve, CUSUM analyses and innovative methods for standardizing the surgeon's timelines were performed. RESULTS: 131 patients underwent LA-ERCP (median age 60, 81% females) by 17 surgeons and 10 gastroenterologists. Cannulation of the papilla was achieved in all cases. Indications were choledocholithiasis (78%), Sphincter of Oddi dysfunction/Papillary stenosis (18%), management of bile leak (2%) and stenting/biopsy of malignant strictures (2%). Median total, surgical and ERCP times were 180, 128 and 48 min, respectively, and 47% underwent concomitant cholecystectomy. Surgical site infection developed in 9.2% and post-ERCP pancreatitis in 3.8%. Logistic regression revealed multiple abdominal operations and magnitude of BMI decrease (between RYGB and LA-ERCP) to be predictive of conversion to open approach. CUSUM analysis of operative time demonstrated a learning curve at case 27 for the surgical team and case 9 for the gastroenterology team. On binary cut analysis, 3-5 cases per surgeon were needed to optimize operative metrics. CONCLUSION: LA-ERCP is associated with high success rates and low adverse events. We identify outcome benchmarks and a learning curve for new adopters of this increasingly performed procedure.

A single dose of self-transcribing and replicating RNA-based SARS-CoV-2 vaccine produces protective adaptive immunity in mice.

A self-transcribing and replicating RNA (STARR)-based vaccine (LUNAR-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 full-length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolongs SARS-CoV-2 spike glycoprotein expression. A single prime vaccination in mice led to robust antibody responses, with neutralizing antibody titers increasing up to day 60. Activation of cell-mediated immunity produced a strong viral antigen-specific CD8+ T lymphocyte response. Assaying for intracellular cytokine staining for interferon (IFN)γ and interleukin-4 (IL-4)-positive CD4+ T helper (Th) lymphocytes as well as anti-spike glycoprotein immunoglobulin G (IgG)2a/IgG1 ratios supported a strong Th1-dominant immune response. Finally, single LUNAR-COV19 vaccination at both 2 µg and 10 µg doses completely protected human ACE2 transgenic mice from both mortality and even measurable infection following wild-type SARS-CoV-2 challenge. Our findings collectively suggest the potential of LUNAR-COV19 as a single-dose vaccine.

Hair analysis to monitor adherence to prescribed chronic inhaler drug therapy in patients with asthma or COPD.

BACKGROUND: Poor adherence to inhaled drug therapy in individuals with asthma and/or chronic obstructive pulmonary disease (COPD) may be associated with suboptimal therapeutic outcomes. Measurement of drug residues in hair samples has been employed to assess oral medication use over time. Here, we test the feasibility of analyzing hair samples from patients with asthma and/or COPD for assessing adherence to prescribed inhaled medication. METHODS: In total, 200 male and female subjects, ≥ 18 years of age, with stable asthma and/or COPD who were receiving an acceptable standard of care daily inhaled product consistently, were recruited. Head hair samples were taken during a single visit to the clinical site and grouped by hair color according to the Fischer-Saller scale. Drug residues were extracted from milled hair samples using solid-phase extraction and analyzed using liquid chromatography-tandem mass spectrometry. RESULTS: Inhaled drugs were detected in hair for 72% of subjects from whom it was possible to analyze hair samples (n = 157/200). Most hair samples obtained from subjects receiving formoterol or vilanterol had amounts of drug present that allowed determination of a quantifiable concentration, and demonstrated a dose response. Drugs were detected in all hair colors, with higher concentrations of formoterol observed in dark-haired versus light-haired individuals. CONCLUSIONS: This is the first study to demonstrate that inhaled medication can be measured in hair samples from subjects with asthma and/or COPD. The results show that hair drug concentration data could potentially provide a record of historical adherence to inhaled therapeutics.

Device-assisted enteroscopy in the UK: description of a large tertiary case series under conscious sedation.

OBJECTIVE: Device-assisted enteroscopy (DAE) has developed rapidly, particularly with the advent of double-balloon enteroscopy (DBE). This study reports a case series from a UK tertiary centre for DAE across two modalities-DBE and spiral enteroscopy (SE)-under conscious sedation. DESIGN: Retrospective observational study of 257 enteroscopy procedures from 2008 to 2014. Data were collected on demographics, indications, diagnosis, sedation requirements, duration, complications, tolerance, therapy performed and completion rate. Procedures were performed under conscious sedation using a combination of midazolam, pethidine and fentanyl in a solely outpatient setting. RESULTS: Obscure gastrointestinal bleeding (OGIB) was the commonest indication for DAE (n=164, 63.8%). Overall, yield of DAE was 47.2% and varied significantly across the indications (p=0.003). There was a greater likelihood of positive findings if the indication was polyposis syndrome (75%), abnormal capsule endoscopy (67%) or OGIB (53%) and in older patients (mean age normal exam 60.3 vs abnormal exam 67.9 years, p<0.001). Higher mean doses of midazolam were used for DBE from above (5.4 mg, SD 2.24) and SE (5.6 mg, SD 2.9) to DBE from below (4.4 mg, SD 1.8). No serious complications were recorded. Tolerance of DAE was good with the majority (240/257, 93.4%) of procedures tolerated with comfort scores 0 or 1. Therapy was performed in 121/257 (47.1%) of procedures. The strongest predictor indications for therapy to be performed at DAE were abnormal capsule endoscopy (88.9%) and occult gastrointestinal (GI) bleeding (54.9%). Completion rates were higher in DBEb (91.8%) compared to DBEa (76.5%) and SE (81.6%). CONCLUSION: DAE under conscious sedation is safe and well tolerated. DAE has a high yield if performed for recognised indications and may be safely used to provide therapy where a diagnosis has been made using other modalities.

Spatial patterns and environmental constraints on ecosystem services at a catchment scale.

Improved understanding and prediction of the fundamental environmental controls on ecosystem service supply across the landscape will help to inform decisions made by policy makers and land-water managers. To evaluate this issue for a local catchment case study, we explored metrics and spatial patterns of service supply for water quality regulation, agriculture production, carbon storage, and biodiversity for the Macronutrient Conwy catchment. Methods included using ecosystem models such as LUCI and JULES, integration of national scale field survey datasets, earth observation products and plant trait databases, to produce finely resolved maps of species richness and primary production. Analyses were done with both 1×1km gridded and subcatchment data. A common single gradient characterised catchment scale ecosystem services supply with agricultural production and carbon storage at opposing ends of the gradient as reported for a national-scale assessment. Species diversity was positively related to production due to the below national average productivity levels in the Conwy combined with the unimodal relationship between biodiversity and productivity at the national scale. In contrast to the national scale assessment, a strong reduction in water quality as production increased was observed in these low productive systems. Various soil variables were tested for their predictive power of ecosystem service supply. Soil carbon, nitrogen, their ratio and soil pH all had double the power of rainfall and altitude, each explaining around 45% of variation but soil pH is proposed as a potential metric for ecosystem service supply potential as it is a simple and practical metric which can be carried out in the field with crowd-sourcing technologies now available. The study emphasises the importance of considering multiple ecosystem services together due to the complexity of covariation at local and national scales, and the benefits of exploiting a wide range of metrics for each service to enhance data robustness.

Guidelines for uniform reporting of body fluid biomarker studies in neurologic disorders.

OBJECTIVE: The aim of these guidelines is to make the process of reporting body fluid biomarker studies in neurologic disorders more uniform and transparent, in line with existing standards for reporting research in other biomedical areas. Although biomarkers have been around for decades, there are concerns over the high attrition rate of promising candidate biomarkers at later phases of development. METHODS: BioMS-eu consortium, a collaborative network working toward improving the quality of biomarker research in neurologic disorders, discussed the merits of standardizing the reporting of body fluid biomarker research. A checklist of items integrating the results of other published guidances, literature, conferences, regulatory opinion, and personal expertise was created to ultimately form a structured summary guidance incorporating the key features. RESULTS: The summary guidance is comprised of a 10-point uniform reporting format ranging from introduction, materials and methods, through to results and discussion. Each item is discussed in detail in the guidance report. CONCLUSIONS: To enhance the future development of body fluid biomarkers, it will be important to standardize the reporting of studies. This guideline by the BioMS-eu consortium is aimed at setting a standard for the reporting of future body fluid biomarker research studies in neurologic disorders. We anticipate that following these guidelines will help to accelerate the selection of biomarkers for clinical development.

Effects of an antisense oligonucleotide inhibitor of C-reactive protein synthesis on the endotoxin challenge response in healthy human male volunteers.

BACKGROUND: C-reactive protein (CRP) binds to damaged cells, activates the classical complement pathway, is elevated in multiple inflammatory conditions, and provides prognostic information on risk of future atherosclerotic events. It is controversial, however, as to whether inhibiting CRP synthesis would have any direct anti-inflammatory effects in humans. METHODS AND RESULTS: A placebo-controlled study was used to evaluate the effects of ISIS 329993 (ISIS-CRPR x) on the acute-phase response after endotoxin challenge in 30 evaluable subjects. Healthy adult males were randomly allocated to receive 6 injections over a 22-day period of placebo or active therapy with ISIS 329993 at 400- or 600-mg doses. Eligible subjects were subsequently challenged with a bolus of endotoxin (2 ng/kg). Inflammatory and hematological biomarkers were measured before and serially after the challenge. ISIS-CRPR x was well tolerated with no serious adverse events. Median CRP levels increased more than 50-fold from baseline 24 hours after endotoxin challenge in the placebo group. In contrast, the median increase in CRP levels was attenuated by 37% (400 mg) and 69% (600 mg) in subjects pretreated with ISIS-CRPR x (P<0.05 vs. placebo). All other aspects of the acute inflammatory response were similar between treatment groups. CONCLUSION: Pretreatment of subjects with ISIS-CRPR x selectively reduced the endotoxin-induced increase in CRP levels in a dose-dependent manner, without affecting other components of the acute-phase response. These data demonstrate the specificity of antisense oligonucleotides and provide an investigative tool to further define the role of CRP in human pathological conditions.

Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis.

The choice of appropriate control group(s) is critical in cerebrospinal fluid (CSF) biomarker research in multiple sclerosis (MS). There is a lack of definitions and nomenclature of different control groups and a rationalized application of different control groups. We here propose consensus definitions and nomenclature for the following groups: healthy controls (HCs), spinal anesthesia subjects (SASs), inflammatory neurological disease controls (INDCs), peripheral inflammatory neurological disease controls (PINDCs), non-inflammatory neurological controls (NINDCs), symptomatic controls (SCs). Furthermore, we discuss the application of these control groups in specific study designs, such as for diagnostic biomarker studies, prognostic biomarker studies and therapeutic response studies. Application of these uniform definitions will lead to better comparability of biomarker studies and optimal use of available resources. This will lead to improved quality of CSF biomarker research in MS and related disorders.

Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study.

BACKGROUND: The CC-chemokine receptor 4 (CCR4) is thought potentially to play a critical role in asthma pathogenesis due to its ability to recruit type 2 T-helper lymphocytes to the inflamed airways. Therefore, CCR4 provides an excellent target for anti-inflammatory therapy. METHODS: The safety, tolerability, pharmacokinetics and pharmacodynamics of the CCR4 antagonist GSK2239633, N-(3-((3-(5-chlorothiophene-2-sulfonamido)-4-methoxy-1H-indazol-1-yl)methyl)benzyl)-2-hydroxy-2-methylpropanamide, were examined in healthy males. Two studies were performed: 1) an open-label, study in which six subjects received a single intravenous infusion of [14C]-GSK2239633 100 µg (10 kBq) (NCT01086462), and 2) a randomised, double-blind, placebo-controlled, cross-over, ascending dose study in which 24 subjects received single oral doses of GSK2239633 150-1500 mg (NCT01371812). RESULTS: Following intravenous dosing, plasma GSK2239633 displayed rapid, bi-phasic distribution and slow terminal elimination (t½: 13.5 hours), suggesting that GSK2239633 was a low to moderate clearance drug. Following oral dosing, blood levels of GSK2239633 reached Cmax rapidly (median tmax: 1.0-1.5 hours). Estimated GSK2239633 bioavailability was low with a maximum value determined of only 16%. Food increased GSK2239633 systemic exposure (as assessed by AUC and Cmax). Increases in AUC and Cmax were less than dose proportional. Adverse events were reported by three subjects (50%) following intravenous administration, and by 19 subjects (79%) following oral administration; most (46/47; 98%) events were mild/moderate in intensity. GSK2239633 1500 mg inhibited thymus- and activation-regulated chemokine-induced (TARC) actin polymerisation reaching a mean CCR4 occupancy of 74%. CONCLUSION: In conclusion, GSK2239633 was well-tolerated and capable of inhibiting TARC from activating the CCR4 receptor.

Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy.

Transthyretin (TTR)-associated amyloidosis is a late-onset autosomal-dominant genetic disease. Over 100 amyloidogenic mutations have been identified in TTR which destabilize the TTR tetramer thereby inducing the formation of amyloid fibrils in tissues such as the heart and peripheral nerves. This disease mainly affects peripheral nerves, causing familial amyloid polyneuropathy (FAP) or heart, causing familial amyloid cardiomyopathy (FAC). Circulating TTR is predominantly produced by liver, and the only widely available clinical treatment for FAP is orthotopic liver transplantation (OLT), whereas no treatment currently exists for FAC. Using second-generation antisense technology, we identified an antisense oligonucleotide (ASO) targeting TTR, ISIS-TTR(Rx), for the treatment of TTR-associated amyloidosis. When tested in a human TTR transgenic mouse model (hTTR Ile84Ser), ISIS-TTR(Rx) showed a dose-dependent reduction of human TTR (up to >80%) at both the mRNA and protein levels. In cynomolgus monkeys, ISIS-TTR(Rx) treatment produced a time-dependent reduction in plasma TTR levels. After 12 weeks of treatment in monkey, liver TTR mRNA and plasma TTR protein levels were reduced by ~80%. As expected, treatment with ISIS-TTR(Rx) also produced a significant decrease in plasma RBP4 levels that correlated with reductions in TTR levels. ISIS-TTR(Rx) treatment was well tolerated in both rodents and monkeys and produced a PK/PD profile consistent with prior experiences using this chemistry platform. ISIS-TTR(Rx) is currently under evaluation in a Phase 1 clinical trial in normal healthy volunteers, and interim results of this trial will be presented.

Multiple sources of contamination in samples from patients reported to have XMRV infection.

Xenotropic murine leukemia virus (MLV)-related retrovirus (XMRV) was reported to be associated with prostate cancer by Urisman, et al. in 2006 and chronic fatigue syndrome (CFS) by Lombardi, et al. in 2009. To investigate this association, we independently evaluated plasma samples from 4 patients with CFS reported by Lombardi, et al. to have XMRV infection and from 5 healthy controls reported to be XMRV uninfected. We also analyzed viral sequences obtained from supernatants of cell cultures found to contain XMRV after coculture with 9 clinical samples from 8 patients. A qPCR assay capable of distinguishing XMRV from endogenous MLVs showed that the viral sequences detected in the CFS patient plasma behaved like endogenous MLVs and not XMRV. Single-genome sequences (N = 89) from CFS patient plasma were indistinguishable from endogenous MLVs found in the mouse genome that are distinct from XMRV. By contrast, XMRV sequences were detected by qPCR in 2 of the 5 plasma samples from healthy controls (sequencing of the qPCR product confirmed XMRV not MLV). Single-genome sequences (N = 234) from the 9 culture supernatants reportedly positive for XMRV were indistinguishable from XMRV sequences obtained from 22Rv1 and XMRV-contaminated 293T cell-lines. These results indicate that MLV DNA detected in the plasma samples from CFS patients evaluated in this study was from contaminating mouse genomic DNA and that XMRV detected in plasma samples from healthy controls and in cultures of patient samples was due to cross-contamination with XMRV (virus or nucleic acid).

Consensus Guidelines for CSF and Blood Biobanking for CNS Biomarker Studies.

There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in cerebrospinal fluid (CSF) are being used in clinical practice. Anti-aquaporin-4 antibodies in serum are currently useful for the diagnosis of neuromyelitis optica (NMO), but we could expect novel CSF biomarkers that help define prognosis and response to treatment for this disease. One of the most critical factors in biomarker research is the inadequate powering of studies performed by single centers. Collaboration between investigators is needed to establish large biobanks of well-defined samples. A key issue in collaboration is to establish standardized protocols for biobanking to ensure that the statistical power gained by increasing the numbers of CSF samples is not compromised by pre-analytical factors. Here, consensus guidelines for CSF collection and biobanking are presented, based on the guidelines that have been published by the BioMS-eu network for CSF biomarker research. We focussed on CSF collection procedures, pre-analytical factors and high quality clinical and paraclinical information. Importantly, the biobanking protocols are applicable for CSF biobanks for research targeting any neurological disease.

Phase 1/2 study of lumiliximab combined with fludarabine, cyclophosphamide, and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia.

Preclinical data demonstrate enhanced antitumor effect when lumiliximab, an anti-CD23 monoclonal antibody, is combined with fludarabine or rituximab. Clinical data from a phase 1 trial with lumiliximab demonstrated an acceptable toxicity profile in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). We therefore pursued a phase 1/2 dose-escalation study of lumiliximab added to fludarabine, cyclophosphamide, and rituximab (FCR) in previously treated CLL patients. Thirty-one patients received either 375 mg/m(2) (n = 3) or 500 mg/m(2) (n = 28) of lumiliximab in combination with FCR for 6 cycles. The toxicity profile was similar to that previously reported for FCR in treatment of relapsed CLL. The overall response rate was 65%, with 52% of patients achieving a complete response (CR), which compares favorably with the CR rate previously reported for the FCR regimen alone in relapsed CLL. The estimated median progression-free survival for all responders was 28.7 months. The addition of lumiliximab to FCR therapy is feasible, achieves a high CR rate, and does not appear to enhance toxicity in previously treated patients with CLL. A randomized trial comparing lumiliximab plus FCR with FCR alone is underway to define the benefit of this combination in relapsed CLL. This trial was registered at clinicaltrials.gov as NCT00103558.

Cost-effectiveness analyses of natalizumab (Tysabri) compared with other disease-modifying therapies for people with highly active relapsing-remitting multiple sclerosis in the UK.

BACKGROUND: Natalizumab (Tysabri) is a new disease-modifying therapy that has been shown to be clinically effective in patients with relapsing-remitting multiple sclerosis (RRMS) and has been licensed for use in patients with highly active RRMS (HARRMS). These patients are those who experience higher relapse rates and faster disability progression than the general RRMS population. OBJECTIVES: To estimate the cost effectiveness of natalizumab compared with interferon-beta, glatiramer acetate and best supportive care from various UK cost perspectives. METHODS: A 30-year Markov model was developed, based on previously published models for multiple sclerosis, to estimate transition between disability states and the probability of relapse within disability states. The model was parameterized with data from the UK Multiple Sclerosis (MS) Survey 2005 and data from the AFFIRM study, a 2-year multicentre, randomized, double-blind, placebo-controlled trial of natalizumab in RRMS patients. Additional data were sourced from the literature. A UK societal cost perspective was used in the base case, with additional cost perspectives considered in the sensitivity analysis. The baseline characteristics for the patient group were taken from the patient population in the AFFIRM study (mean age 36 years, mean time since diagnosis 5 years and a mean Kurtzke Extended Disability Status Scale [EDSS] score of 2.5). The model and its parameterization were designed and developed to support a reimbursement application for natalizumab submitted to the UK National Institute for Health and Clinical Excellence (NICE). Efficacies for natalizumab and glatiramer acetate were taken from clinical trial data, and for interferon-beta from a meta-analysis of clinical trial data. Disutilities from adverse events for each comparator were also included in the model. Outcomes and costs were discounted at 3.5% per anum. Costs for interferon-beta and glatiramer acetate were based on published prices (year 2006 values) under the UK Risk Sharing Scheme, and for natalizumab the UK NHS list price was used. Diagnostic, administration and adverse event costs were also included. The incremental cost-effectiveness ratios (ICERs) were calculated for the base case, and a probabilistic sensitivity analysis was performed to assess the probability of cost effectiveness at different willingness-to-pay thresholds. RESULTS: The ICER for natalizumab compared with interferon-beta was 2300 pound per QALY. Compared with glatiramer acetate, it was 2000 pound per QALY, and compared with best supportive care it was 8200 pound per QALY. From a health and social care cost perspective, the ICERs were 18,700 pound, 20,400 pound and 25,500 per QALY, respectively. At a willingness-to-pay threshold of 30,000 pound per QALY, the probability of natalizumab being cost effective against any comparator from a societal perspective was >89%. CONCLUSION: If UK society is willing to pay more than 8200 pound per QALY, or Health and Social Services are willing to pay more than 26,000 pound per QALY, this analysis suggests that natalizumab is likely to be a cost-effective treatment for all patients with HARRMS.

Opinion piece: genomics and crop plant science in Europe.

Recent report reviews and funding initiatives in the field of plant genomic research are considered in the context of their translation into practical and economic value via plant breeding. It is concluded that there is a deficit in investment and that a change in working styles towards knowledge sharing and connectivity is required.

Polo-like kinase 1-mediated phosphorylation of the GTP-binding protein Ran is important for bipolar spindle formation.

Polo-like kinase functions are essential for the establishment of a normal bipolar mitotic spindle, although precisely how Plk1 regulates the spindle is uncertain. In this study, we report that the small GTP/GDP-binding protein Ran is associated with Plk1. Plk1 is capable of phosphorylating co-immunoprecipitated Ran in vitro on serine-135 and Ran is phosphorylated in vivo at the same site during mitosis when Plk1 is normally activated. Cell cultures over-expressing a Ran S135D mutant have significantly higher numbers of abnormal mitotic cells than those over-expressing either wild-type or S135A Ran. The abnormalities in S135D mutant cells are similar to cells over-expressing Plk1. Our data suggests that Ran is a physiological substrate of Plk1 and that Plk1 regulates the spindle organization partially through its phosphorylation on Ran.

Soluble reactive phosphorus levels in rainfall, cloud water, throughfall, stemflow, soil waters, stream waters and groundwaters for the Upper River Severn area, Plynlimon, mid Wales.

Soluble reactive phosphorus (SRP) data are presented for rainfall, cloud water, soil waters, stream waters and groundwaters at the Plynlimon catchments in mid Wales to examine the hydrochemical functioning of inorganic phosphorus for an acidic and acid sensitive area characteristic of much of the UK uplands. In general, stream water concentrations are low compared to lowland areas. Average concentrations of SRP in rainfall and cloud water (0.3 and 0.9 microM l(-1), respectively) are higher than in stream water with wider ranges in concentration (0-19.3 and 0-20.9 microM l(-1), respectively). Throughfall and stemflow is enriched in SRP compared to rain and cloud water by a factor of approximately twofold and sixfold, respectively: the average concentrations and ranges are 0.73 and 0-6.61 microM l(-1) for throughfall and 2.12 and 0-18.61 microM l(-1) for stemflow. Soil water SRP concentrations measured in the surface layers of representative areas of podzol and gley soils, are further enriched with respect to inputs. Average concentrations and ranges for the L/F and Oh horizons in the podzols are 3.1 microM l(-1) (range: 0.03-17.2 microM l(-1)) and 0.75 microM l(-1) (range: 0.03-2.64 microM l(-1)), respectively. Correspondingly, the average values and ranges for the L/F and Oh horizons in the gley are 2 microM l(-1) (range: 0.03-16.65 microM l(-1)) and 0.4 microM l(-1) (range: 0.03-8.61 microM l(-1)). SRP concentrations in stream and ground water are lower than in atmospheric inputs and surface soil waters and show marked spatial variability. This variability is linked to three catchment features. (1) For streams draining podzolic soils, most of the SRP is retained by the catchment. For this situation, stream and ground waters have average concentrations of approximately 0.05 microM l(-1) with a range of 0-1.47 microM l(-1). There is no clear stream or groundwater SRP response to felling despite a large release of SRP from felling debris (brash) and the forest floor (L/F horizon) with average post-felling concentrations of 11.02 microM l(-1) (0.40-155.0 microM l(-1)) and 23.60 microM l(-1) (0.26-172.23 microM l(-1)), respectively. (2) For forested catchments with gley soils, stream water SRP concentrations are more variable with, in one case, much higher concentrations than for the podzol counterparts (range in average 0.05-0.46 microM l(-1)). (3) For the streams draining gley soils, felling results in a mixed SRP response. At the local scale (ditch drainage), there is a marked enrichment in SRP concentration (average concentrations increase from 0.05 to 1.31 microM l(-1), with a peak concentration of 4.0 microM l(-1)). This response is consistent with the observed mobilisation of SRP from brash and forest floor material (post-felling mean concentrations of 9.39 and 11.94 microM l(-1), respectively). However, stream water concentrations are an order of magnitude lower than observed in the soil waters implying considerable immobilisation of SRP between the soils and the stream. At the larger catchment scale, no discernable enrichment in SRP is observed following felling. The results are related to input-output budgets and the findings interpreted in terms of the dominant hydrogeochemical processes operative and environmental management issues.