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Background Combining HSTnT (high sensitive troponin T) values at low levels with composite risk scores may improve early safe, discharge in suspected acute coronary syndromes (ACS). We tested this hypothesis by a prospective study of 3016 consecutive patients with suspected ACS in 2 large hospitals. Methods Consecutive chest pain (CP) presentations with HSTnT sampled and ECG undertaken at presentation were prospectively defined in 2 time periods (2011-12, n=1642 [derivation] 2018, n=1376 [validation]). The HstnT input was modified: dichotomous HSTnT input was lowered to 14 = 2 [99th percentile]). All biomarker positive CP index and re-admissions to any regional hospital (catchment population 2.6 million) were independently adjudicated for MI by 2 experienced physicians. Primary outcome was MACE (adjudicated type 1 MI, unplanned coronary revascularisation and all cause death) at 6 weeks. Results In the 2 cohorts demographic factors were similar: median age 59 and 56, male 52% and 52%, previous MI 20% and 14% for 2011-12 and 2018 respectively. At 6 weeks 180 (11%) and 75 (5.4%) suffered type 1 MI and 211 (12.9%) and 92 (6.7%) patients suffered MACE in the 2011-12 and 2018 cohorts respectively. Only Mod HEART ≤3 and undetectable HSTnT, with a nonischaemic ECG, achieved prespecified NPV of >99.5% in both derivation and validation cohorts (table). However Modified HEART ≤3 score could discharge approximately 12% more patients as compared to undetectable HSTnT strategy. Conclusion Modified HEART score ≤3, with the use of a single HSTnT, appears the optimum early discharge strategy for suspected ACS Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Liverpool university Hospitals, North-West Educational Cardiac Group

Health-related quality of life (HRQoL) is impaired in patients with stable angina but patients often present with other forms of chest pain. The aim of this study was to compare the pre-diagnostic HRQoL in patients with suspected coronary artery disease (CAD) according to angina type, gender, and presence of obstructive CAD.From the pilot study for the European DISCHARGE trial, we analysed data from 24 sites including 1263 patients (45.9% women, 61.1 ± 11.3 years) who were clinically referred for invasive coronary angiography (ICA; 617 patients) or coronary computed tomography angiography (CTA; 646 patients). Prior to the procedures, patients completed HRQoL questionnaires: the Short Form (SF)-12v2, the EuroQoL (EQ-5D-3 L) and the Hospital Anxiety and Depression Scale.Fifty-five percent of ICA and 35% of CTA patients had typical angina, 23 and 33% had atypical angina, 18 and 28% had non-anginal chest discomfort and 5 and 5% had other chest discomfort, respectively. Patients with typical angina had the poorest physical functioning compared to the other angina groups (SF-12 physical component score; 41.2 ± 8.8, 43.3 ± 9.1, 46.2 ± 9.0, 46.4 ± 11.4, respectively, all age and gender-adjusted p 0.01), and highest anxiety levels (8.3 ± 4.1, 7.5 ± 4.1, 6.5 ± 4.0, 4.7 ± 4.5, respectively, all adjusted p 0.01). On all other measures, patients with typical or atypical angina had lower HRQoL compared to the two other groups (all adjusted p 0.05). HRQoL did not differ between patients with and without obstructive CAD while women had worse HRQoL compared with men, irrespective of age and angina type.Prior to a diagnostic procedure for stable chest pain, HRQoL is associated with chest pain characteristics, but not with obstructive CAD, and is significantly lower in women.Clinicaltrials.gov, NCT02400229.

Background: Health-related quality of life (HRQoL) is impaired in patients with stable angina but patients often present with other forms of chest pain. The aim of this study was to compare the pre-diagnostic HRQoL in patients with suspected coronary artery disease (CAD) according to angina type, gender, and presence of obstructive CAD.Methods: From the pilot study for the European DISCHARGE trial, we analysed data from 24 sites including 1263 patients (45.9% women, 61.1 ± 11.3 years) who were clinically referred for invasive coronary angiography (ICA; 617 patients) or coronary computed tomography angiography (CTA; 646 patients). Prior to the procedures, patients completed HRQoL questionnaires: the Short Form (SF)-12v2, the EuroQoL (EQ-5D-3 L) and the Hospital Anxiety and Depression Scale.Results: Fifty-five percent of ICA and 35% of CTA patients had typical angina, 23 and 33% had atypical angina, 18 and 28% had non-anginal chest discomfort and 5 and 5% had other chest discomfort, respectively. Patients with typical angina had the poorest physical functioning compared to the other angina groups (SF-12 physical component score; 41.2 ± 8.8, 43.3 ± 9.1, 46.2 ± 9.0, 46.4 ± 11.4, respectively, all age and gender-adjusted p p p Conclusions: Prior to a diagnostic procedure for stable chest pain, HRQoL is associated with chest pain characteristics, but not with obstructive CAD, and is significantly lower in women.Trial registration: Clinicaltrials.gov, NCT02400229.

ObjectiveTo educate providers to recognize the clinical presentation of neurofibromatosis 2 (NF2) in young children.MethodsA retrospective analysis of 22 children with NF2 from 4 tertiary care NF referral centers was performed. Age and signs/symptoms at initial presentation, age at NF2 diagnosis, family history, clinical/radiographic NF2 features, NF2 genetic testing results, and treatments were assessed.ResultsThe average age at initial clinical presentation was 48.1 months, while the average age at NF2 diagnosis was 77.2 months. Children with a family history of NF2 (23%) tended to present earlier (mean 39.2 vs 50.7 months) and have shorter times to NF2 diagnosis (mean 1.6 vs 37.2 months). Vision/eye complaints (n = 9; 41%) were the most commonly reported presenting signs/symptoms. Meningiomas (n = 7; 32%) and ocular abnormalities (n = 5; 23%) were the most frequently identified initial NF2 features. Vestibular (n = 17; 77%) and peripheral (n = 15; 68%) schwannomas were the most common abnormalities encountered over the study period. Seventeen (77%) children required treatment, most frequently for vestibular schwannomas (n = 9; 41%), peripheral schwannomas (n = 7; 32%), and meningiomas (n = 7; 32%). Genetic testing was available for 13 individuals, in whom nonsense mutations were most commonly identified (n = 7; 54%).ConclusionsAlthough uncommon, a substantial number of individuals with NF2 come to medical attention in early childhood. The finding of meningioma or characteristic ocular abnormalities (retinal hamartomas and epiretinal membranes) in young children should raise clinical suspicion for NF2 and prompt immediate referral to appropriate specialists for diagnosis and management.

In 1980, several new species of dinoflagellate cyst taxa were validly published and named from the Kimmeridge Clay of England as part of a larger study on Kimmeridgian-Valanginian dinoflagellate cyst assemblages (Fisher & Riley, 1980); this study was originally presented at the IV International Palynological Conference, Lucknow in 1976–77. This note, necessitated by the long publication delay and numerous printing errors, comprises taxonomic re-allocations, taking account of subsequent studies (Norris, 1978; Stover & Evitt, 1978; Davey, 1979; Riley, 1979) and corrects inadvertent taxonomic errors.

QUESTION: Does Nitisinone prevent the clinical progression of the Alkaptonuria? FINDINGS: In this observational study on 39 patients, 2 mg of daily nitisinone inhibited ochronosis and significantly slowed the progression of AKU over a three-year period. MEANING: Nitisinone is a beneficial therapy in Alkaptonuria. BACKGROUND: Nitisinone decreases homogentisic acid (HGA), but has not been shown to modify progression of Alkaptonuria (AKU). METHODS: Thirty-nine AKU patients attended the National AKU Centre (NAC) in Liverpool for assessments and treatment. Nitisinone was commenced at V1 or baseline. Thirty nine, 34 and 22 AKU patients completed 1, 2 and 3 years of monitoring respectively (V2, V3 and V4) in the VAR group. Seventeen patients also attended a pre-baseline visit (V0) in the VAR group. Within the 39 patients, a subgroup of the same ten patients attended V0, V1, V2, V3 and V4 visits constituting the SAME Group. Severity of AKU was assessed by calculation of the AKU Severity Score Index (AKUSSI) allowing comparison between the pre-nitisinone and the nitisinone treatment phases. RESULTS: The ALL (sum of clinical, joint and spine AKUSSI features) AKUSSI rate of change of scores/patient/month, in the SAME group, was significantly lower at two (0.32 ± 0.19) and three (0.15 ± 0.13) years post-nitisinone when compared to pre-nitisinone (0.65 ± 0.15) (p

Background: We tested the hypothesis that a single high sensitivity troponin at limits of detection (LOD HSTnT) (Methods: In a prospective cohort study, risk scores were computed in consecutive patients with suspected acute coronary syndrome presenting to the Emergency Room of a large English hospital. Adjudication of myocardial infarction, as per third universal definition, involved a two-physician, blinded, independent review of all biomarker positive chest pain re-presentations to any national hospital. The primary and secondary outcome was a composite of type 1 myocardial infarction, unplanned coronary revascularisation and all cause death (MACE) at six weeks and one year. Results: Of 3054 consecutive presentations with chest pain 1642 had suspected acute coronary syndrome (52% male, median age 59 years, 14% diabetic, 20% previous myocardial infarction). Median time from chest pain to presentation was 9.7 h. Re-presentations occurred in eight hospitals with 100% follow-up achieved. Two hundred and eleven (12.9%) and 279 (17%) were adjudicated to suffer MACE at six weeks and one year respectively. Only HEART ≤3 (negative predictive value MACE 99.4%, sensitivity 97.6%, %discharge 53.4) and LOD HSTnT strategy (negative predictive value MACE 99.8%, sensitivity 99.5%, %discharge 36.9) achieved pre-specified negative predictive value of >99% for MACE at six weeks. For type 1 myocardial infarction alone the negative predictive values at six weeks and one year were identical, for both HEART ≤3 and LOD HSTnT at 99.8% and 99.5% respectively. Conclusion: HEART ≤3 or LOD HSTnT strategy rules out short and medium term myocardial infarction with ≥99.5% certainty, and short-term MACE with >99% certainty, allowing for early discharge of 53.4% and 36.9% respectively of suspected acute coronary syndrome. Adoption of either strategy has the potential to greatly reduce Emergency Room pressures and minimise follow-up investigations. Very early presenters (

Colorectal cancer, the third most common cancer in U.S. adults, can be detected early through colonoscopy. Thorough bowel preparation facilitates successful colonoscopy. Effectiveness, tolerability, and costs of 3 bowel preparations were compared in patients undergoing outpatient screening colonoscopy. In this prospective, randomized, single-blind study, comparing three preparation protocols, 209 of 276 consented subjects completed (Protocol [N = 67] = HalfLytely© 1 L × 2 doses and bisacodyl 5 mg delayed release tablets × 2 tablets; Protocol 2 [N = 74] = MiraLAX® 5 tablespoons × 2 doses and bisacodyl 5 mg tablets × 2 tablets; and Protocol 3 [N = 68] = MoviPrep 1 L × 2 doses). Patients completed symptom diaries and a gastroenterologist rated effectiveness. Most subjects were White females, aged 59 years (mean). Protocol 1 was the most effective regimen, but Protocol 2 was the most tolerable and cost-effective. While the three bowel protocol differences were not statistically significant for all outcomes measured, there were clinically meaningful differences. As Protocol 1 was most effective, HalfLytely© and bisacodyl is recommended for patients prior to colonoscopy. For patients who cannot tolerate HalfLytely© or MoviPrep, or with financial concerns, Protocol 2 (MiraLAX® & bisacodyl) is alternatively recommended.

The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration was established with the goal to develop consensus recommendations for the use of endpoints in neurofibromatosis (NF) clinical trials. This supplement includes the first series of REiNS recommendations for the use of patient-reported, functional, and visual outcomes, and for the evaluation of imaging response in NF clinical trials. Recommendations for neurocognitive outcome measures, the use of whole-body MRI in NF, the evaluation of potential biomarkers of disease, and the comprehensive evaluation of functional and patient-reported outcomes in NF are in development. The REiNS recommendations are made based on current knowledge. Experience with the use of the recommended endpoints in clinical trials, development of new tools and technologies, new knowledge of the natural history of NF, and advances in the methods used to analyze endpoints will likely lead to modifications of the currently proposed guidelines, which will be shared with the NF research community through the REiNS Web site www.reinscollaboration.org. Due to the clinical complexity of NF, there is a need to seek expertise from multiple medical disciplines, regulatory agencies, and industry to develop trial endpoints and designs, which will lead to the identification and approval of effective treatments for NF tumor and nontumor manifestations. The REiNS Collaboration welcomes anyone interested in providing his or her expertise toward this effort.

The cardiovascular manifestations of alkaptonuria relate to deposition of ochronotic pigment within heart valves, endocardium, aortic intima and coronary arteries. We assessed 16 individuals with alkaptonuria for cardiovascular disease, including full electrocardiographic and echocardiographic assessment. The self reported prevalence of valvular heart disease and coronary artery disease was low. There was a significant burden of previously undiagnosed aortic valve disease, reaching a prevalence of over 40% by the fifth decade of life. The aortic valve disease was found to increase in both prevalence and severity with advancing age. In contrast to previous reports, we did not find a significant burden of mitral valve disease or coronary artery disease. These findings are important for the clinical follow-up of patients with alkaptonuria and suggest a role for echocardiographic surveillance of patients above 40 years old.

Proteome maps of hepatopancreas (midgut gland) and ovarian tissues of the crustacean, Cancer pagurus (Decapoda; edible crab) have been produced by 2D-PAGE and identification of proteins, following trypsin proteolysis, by electrospray MS/MS and database searching. Owing to the lack of sequence information on proteins and fully sequenced genomes amongst the decapod crustaceans and given the evolutionary distance to the nearest full genome database (Daphnia), it was necessary to adopt a non-conventional identification approach. Thus, a strategy was developed for effective identification of decapod proteins by sequence similarity, homology-based cross-species database searching, using various algorithms and a combination of NCBI Crustacea and Arthropoda databases, together with the Arthropoda PartiGene database (Blaxter, University of Edinburgh). In both hepatopancreas and ovary tissues, the largest group of proteins identified were a variety of enzymes, followed by a smaller number of storage/transport proteins [including vitellogenin (yolk protein), several subunits of hemocyanin, cryptocyanin, ferritin and calreticulin], with fewer structural proteins (actin, tubulin) and heat-shock proteins, in addition to a number of proteins of miscellaneous functions. Such protein identifications allow the development of tools, such as antibodies and RNA/DNA probes, to investigate the functions of the proteins in specific tissues during development.

Purpose Atypical teratoid rhabdoid tumor (ATRT) of the CNS is a highly malignant neoplasm primarily affecting young children, with a historic median survival ranging from 6 to 11 months. Based on a previous pilot series, a prospective multi-institutional trial was conducted for patients with newly diagnosed CNS ATRT. Patients and Methods Treatment was divided into five phases: preirradiation, chemoradiation, consolidation, maintenance, and continuation therapy. Intrathecal chemotherapy was administered, alternating intralumbar and intraventricular routes. Radiation therapy (RT) was prescribed, either focal (54 Gy) or craniospinal (36 Gy, plus primary boost), depending on age and extent of disease at diagnosis. Results Between 2004 and 2006, 25 patients were enrolled; 20 were eligible for evaluation. Median age at diagnosis was 26 months (range, 2.4 months to 19.5 years). Gross total resection of the primary tumor was achieved in 11 patients. Fourteen patients had M0 disease at diagnosis, one patient had M2 disease, and five patients had M3 disease. Fifteen patients received radiation therapy: 11 focal and four craniospinal. Significant toxicities, in addition to the expected, included radiation recall (n = 2) and transverse myelitis (n = 1). There was one toxic death. Of the 12 patients who were assessable for chemotherapeutic response (pre-RT), the objective response rate was 58%. The objective response rate observed after RT was 38%. The 2-year progression-free and overall survival rates are 53% ± 13% and 70% ± 10%, respectively. Median overall survival has not yet been reached. Conclusion This intensive multimodality regimen has resulted in a significant improvement in time to progression and overall survival for patients with this previously poor-prognosis tumor.

BACKGROUND Because few reports on outcome in patients with pediatric malignant gliomas during the magnetic resonance imaging era were available, the authors studied the outcomes of children with these tumors at their institution. METHODS The medical records of 39 patients with nonbrainstem, malignant gliomas who were treated at the Hospital of the University of Pennsylvania/Children's Hospital of Philadelphia between February 1, 1989 and December 31, 2000 were reviewed retrospectively. Magnetic resonance imaging was used to assess tumors at presentation and at follow-up. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan–Meier method. Univariate and multivariate analyses were performed using a Cox proportional hazards model. RESULTS The median follow-up for the 14 surviving patients was 47.6 months. The median PFS for all patients was 12.2 months, and the median OS for all patients was 21.3 months. The extent of surgery was the strongest prognostic factor for predicting outcomes in these patients, with a median survival of 122.2 months in patients who underwent macroscopic total resection compared with 14.1 months in patients who had significant residual disease after surgery. In univariate analyses, other than the extent of surgery, only the absence of visual symptoms at diagnosis significantly predicted improved OS. Local control was improved for patients who underwent better resection and had smaller tumors. In multivariate analyses, although the extent of surgery continued to predict outcomes significantly, histologic grade, which was not significant in the univariate analysis, also was significant. CONCLUSIONS Children with malignant gliomas appeared to fare better than their adult counterparts. Because the extent of resection was one of the strongest predictors of outcome, the authors concluded that the optimal therapy for these patients would include the maximal possible resection. Cancer 2004. © 2004 American Cancer Society.

Administration of the nonsteroidal ecdysteroid agonist RH-5849 or 20-hydroxyecdysone to final larval instar tobacco hornworm, Manduca sexta, has been shown to induce an ecdysteroid inactivation enzyme, ecdysteroid 26-hydroxylase, and the cytosolic inactivation enzymes ecdysone oxidase and ecdysteroid phosphotransferase. In this work, we show that induction of ecdysteroid 26-hydroxylase by the ecdysteroid agonists RH-5849, RH-5992 (tebufenozide), and RH-0345 (halofenozide) appears universal in lepidopteran species that show susceptibility to the agonists. Interestingly, the waxmoth, Galleria mellonella, which shows very low susceptibility to the agonists but whose ecdysteroid receptor is capable of binding the agonist, shows no induction of a 26-hydroxylase activity. It appears that the more potent ecdysteroid agonists in Lepidoptera, RH-5992 and RH-0345, show in general a greater induction of 26-hydroxylase than RH-5849. Feeding RH-5849 to the dipteran housefly Musca domestica results in the induction of an ecdysteroid phosphotransferase. The low toxicity of these ecdysteroid agonists in orthopteran and coleopteran orders also correlates with a lack of induction of ecdysteroid 26-hydroxylase activity. We propose that in species where ecdysteroid agonists are effective in stimulating an untimely premature molt, a response to a state of hyperecdysonism elicited by the agonists is induction of enzymes of ecdysteroid inactivation.

The diadenosine polyphosphates are a group of long-lasting compounds, released into the bloodstream by platelet degranulation. They mediate endothelium-dependent vasodilatation in several animal vascular systems via P2Y receptors coupled to increases in cytoplasmic calcium ([Ca2+]c). However, there is little evidence of diadenosine-mediated vasodilatation in the human vasculature, and a direct interaction with natively expressed P2Y receptors on human endothelium has not been demonstrated. We have therefore studied the effects of diadenosines on primary cultures of human saphenous vein endothelial cells (HSVECs) and related this to the expression of P2Y receptors. HSVECs were loaded with the calcium-sensitive dye fura-2, and nucleotide-stimulated [Ca2+]c responses were recorded. HSVECs responded to 10 µM UTP, ATP and 2-methylthio-ATP but not to UDP. Consistent with the recorded [Ca2+]c responses, RT-PCR analysis of HSVEC RNA amplified specific products for the P2Y1 and P2Y2 receptors but not the P2Y4 and P2Y6 receptors. HSVECs responded to Ap3A with a rise in [Ca2+]c, but none of the other diadenosines tested elicited a response. Therefore natively expressed human P2Y1 and P2Y2 receptors are insensitive to diadenosine polyphosphates with the exception of Ap3A. We would therefore predict that the diadenosine polyphosphates have only a limited vasodilatory role in human saphenous veins.

Aims—To study the eVect of prenatal glucocorticoid treatment on endothelial nitric oxide synthase (eNOS) expression in rats with congenital diaphragmatic hernia (CDH). Methods—CDH was induced in fetal rats by the maternal administration of nitrofen on day 9.5 of gestation. Dexamethasone was administered on days 18.5 and 19.5 before delivery of the fetuses on days 20.5 and 21.5. Pulmonary eNOS protein expression was studied by western immunoblotting and immunohistochemistry. Results—On day 20.5, eNOS expression was significantly reduced in CDH pups compared with normal control rats. Dexamethasone treated CDH pups had eNOS concentrations equivalent to those of normal animals. By day 21.5, however, there was no detectable diVerence in eNOS expression between the experimental groups. Conclusions—eNOS is deficient in near term (day 20.5) CDH rats. Dexamethasone restores eNOS expression in these animals to that seen in normal rat lungs. At term, the precise role of eNOS in the pathophysiology of CDH remains uncertain. (Arch Dis Child Fetal Neonatal Ed 1998;78:F204‐F208)

Neonates with congenital diaphragmatic hernia (CDH) have a high morbidity and mortality rate caused by pulmonary hypoplasia associated with pulmonary hypertension (PH). In experimental CDH, antenatal glucocorticoid therapy improves surfactant biochemical immaturity, enhances lung compliance, and induces morphological maturation in CDH rats. The effects of steroid therapy on preventing or treating PH in this condition have not been studied. Angiotensin converting enzyme (ACE), which is produced by the vascular endothelium, is implicated in the pathogenesis of pulmonary hypertension. The aim of this study was to evaluate the effect of antenatal glucocorticoid therapy on ACE activity and expression in CDH rat lungs.CDH was induced in fetal rats by the maternal administration of 100 mg nitrofen on day 9.5 of gestation (term, day 22). Dexamethasone (Dex) (0.25 mg/kg) was given by intraperitoneal injection on days 18.5 and 19.5 before delivery of the fetuses by cesarean section on day 21.5. Control animals received olive oil (OO) by gavage and normal saline (NS) as vehicle injection. ACE activity was measured spectrophotometrically in the lungs of rats from four treatment groups: CDH-NS, non-CDH-NS, CDH-Dex, and OO-NS controls. Total lung ACE activity (mU per lung) was significantly lower in CDH-NS (P = .002) and CDH-Dex (P = .004) rats compared with non-CDH-NS and OO-NS controls (9.1 +/- 1.0 and 10.7 +/- 1.3 v 16.2 +/- 1.6 and 15.4 +/- 1.7). When specific ACE activity (mU/mg protein) was derived by expressing ACE activity per milligram of lung protein, CDH-NS animals showed elevated specific ACE activity (P = .05) compared with OO-NS controls (6.31 +/- 1.1 v 4.4 +/- 0.4). CDH-Dex animals had a significantly lower specific ACE activity (P = .01) compared with CDH-NS and Non-CDH-NS rats (4.0 +/- 0.4 v 6.31 +/- 1.1 and 5.83 +/- 0.54). The specific ACE activity levels of CDH-Dex rats were equivalent to those seen in the lungs of OO-NS controls (P = .24).Antenatal steroid therapy, by suppressing pulmonary ACE activity, may reduce the risk of pulmonary hypertension developing in human newborns with antenatally diagnosed CDH.

Diadenosine polyphosphates released into the extracellular environment influence a variety of metabolic and other cellular activities in a wide range of target tissues. Here we have studied the impact of these novel nucleotides on gluconeogenesis in isolated rat proximal tubules. Gluconeogenesis was stimulated following exposure of isolated proximal tubules to a range of adenine-containing nucleotides including ADP, ATP, Ap3A, Ap4A, Ap5A and Ap6A. The concentration-dependence of ATP-, Ap3A- and Ap4A-mediated stimulation of gluconeogenesis was similar and was consistent with a role for these agents in the physiological control of renal metabolism. Nucleotide-stimulated gluconeogenesis was diminished in the presence of agents that interfere with phospholipase C activation or intracellular Ca2+ metabolism, indicative of a role for polyphosphoinositide-mediated Ca2+ mobilization in the mechanism of action of ATP, Ap3A and Ap4A. The characteristics of binding of [2-3H]Ap4 A to renal plasma-membrane preparations suggest that Ap4A mediates its effects on proximal tubule gluconeogenesis via interaction with P2y-like purinoceptor(s) also recognized by extracellular ATP.

The neurofibromatoses (NF)--including neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis--are related tumor-suppressor syndromes characterized by a predisposition to multiple tumor types and other disease manifestations, which often result in functional disability, reduced quality of life, pain, and, in some cases, malignancy. With increasing knowledge of the biology and pathogenesis of NF, clinical trials with targeted agents directed at NF tumors have become available. Most clinical trials for patients with NF have used designs and endpoints similar to oncology trials. However, differences in the disease manifestations and natural history of NF (compared to cancers) require the development of new designs and endpoints to perform meaningful NF clinical trials. The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration was established in 2011 at the Children's Tumor Foundation meeting to achieve consensus within the NF community about the design of future clinical trials, with a specific emphasis on endpoints. The REiNS Collaboration includes 7 working groups that focus on imaging of tumor response; functional, visual, patient-reported, and neurocognitive outcomes; whole-body MRI; and disease biomarkers. This supplement includes the first series of recommendations by the REiNS Collaboration. The hope is that these recommendations will be used by members of the group and by researchers outside of the REiNS International Collaboration to standardize the measurement of outcomes and thus improve clinical trials for patients with NF. Ultimately, we plan to engage industry partners and national regulatory agencies in this process to facilitate the approval of drugs for patients with NF.

Since it was first described 20 years ago in Japan, takotsubo cardiomyopathy has received considerable interest from the medical community around the world, particularly in recent years. Although takotsubo cardiomyopathy was originally described as a transient, stress-induced dysfunction of the left ventricular apex, other morphological subtypes have now been described. The pathogenesis of this disorder is likely to be catecholamine mediated myocyte damage and microvascular dysfunction; however, a number of possible alternative theories have been suggested. These include oxidative stress, transient coronary obstruction and oestrogen deficiency, the last explaining the high prevalence of takotsubo cardiomyopathy in women. The treatment remains largely supportive; however, a number of agents have been implicated in the acute stage and long term. Although most of the patients show complete recovery, there is a high risk of complications at the initial presentation requiring intense support.

Erythroid progenitor cells isolated from patients with polycythemia vera (PV) proliferate and differentiate in methylcellulose in the absence of exogenous erythropoietin (EPO). To investigate the potential role of the erythropoietin receptor (EPO-R) in the pathogenesis of PV, we cultured bone marrow-derived or peripheral blood-derived erythroid progenitors in the presence of neutralizing monoclonal antibodies (MoAbs) specific for EPO or EPO-R. Mononuclear cells were obtained from 9 healthy adults and 9 PV patients by Ficoll-Hypaque gradients and cultured with or without EPO in methylcellulose for 12 days under standard or serum-free conditions. Neutralizing anti-EPO and anti-EPO-R MoAbs, added to cultures at day 0, caused dose-dependent growth inhibition of all normal burst-forming units-erythroid (BFU-E) derived from health adult controls. The MoAbs had no effect on the growth of nonerythroid progenitor cells under the same culture conditions. In contrast, neutralizing antibodies distinguished two classes of BFU-E derived from PV patients. Class I BFU-E from PV patients were EPO- dependent. These progenitors, like those derived from healthy adults, had normal EPO dose-dependent growth characteristics and showed a normal period of EPO requirement in vitro that extended 6 days after the initiation of culture. These results indicate that EPO exerts its critical effect early during erythroid differentiation; the addition of neutralizing antibodies to normal progenitors after 6 days had no effect on the subsequent size or maturation of the colonies. Class II BFU-E from PV patients were EPO-independent. They proliferated and differentiated even in the presence of high concentrations of neutralizing anti-EPO or anti-EPO-R MoAbs. We conclude that the class II BFU-E from PV patients are independent of free EPO.

We have generated six high affinity monoclonal antibodies (MoAbs) to the human erythropoietin receptor (hEPO-R) polypeptide. All six MoAbs bind to the extracytoplasmic domain of the hEPO-R, and all immunoprecipitate 35S-labeled hEPO-R from metabolically labeled Ba/F3- hEPO-R cells. Four of the MoAbs neutralize the EPO-dependent growth of Ba/F3-hEPO-R cells, whereas two MoAbs are non-neutralizing. None of the MoAbs inhibit the EPO-dependent growth of Ba/F3 cells expressing the murine EPO-R (mEPO-R), even though the hEPO-R and mEPO-R share 82% amino acid identity. All six of the anti-EPO-R MoAbs bind to the cell surface human EPO-R but none bind to the cell surface murine EPO-R. Of the four neutralizing MoAbs, the one-half maximal inhibition occurs at MoAb concentrations ranging from 1 nmol/L to 50 nmol/L. These MoAbs also compete with radiolabeled EPO for hEPO-R binding. The two non- neutralizing MoAbs fail to inhibit EPO-dependent growth or compete with EPO-binding, even at antibody concentrations as high as 500 nmol/L. The four neutralizing MoAbs, designated group I, compete with each other for an epitope of the hEPO-R polypeptide required for EPO-binding. The two non-neutralizing MoAbs recognize discrete epitopes, and are designated group II and group III MoAbs. In conclusion, this is the first description of MoAbs specific for the hEPO-R. The MoAbs, which recognize three discrete epitopes, may be useful in characterizing the spectrum of cells that display the hEPO-R and in further defining the role of EPO in hematopoiesis.

The ability of purine nucleotides (e.g. ATP) to cause a dose-dependent activation of glycogen phosphorylase in isolated liver cells is well known known. These agents mediate their effects through interaction with specific P2-purinoceptors in the plasma membrane. We have investigated the ability of a range of synthetic and naturally occurring adenine dinucleotides to cause a similar stimulation of glycogen phosphorylase activity in isolated rat liver cells. Our results indicate that Ap3A and Ap4A, the most abundant naturally occurring adenine dinucleotides, cause a dose-dependent activation of glycogen phosphorylase similar to that observed with ATP. Similar responses were seen with Ap5A, Ap6A and a series of phosphorothioate analogues. In contrast, the response to phosphonate analogues depended on the position of the P-C-P bridged. The dinucleotides appear to exert their effects directly, rather than through hydrolytic products such as adenosine and/or ATP. The possibility that adenine dinucleotides are physiologically significant extracellular purinergic effectors is discussed in the light of these observations.

The coronary microcirculation regulates blood flow by responding to increased cardiac metabolic demands. Despite this important role, study of the microcirculation has been neglected for many years. This is because it is difficult to evaluate the function of this compartment, and doing so conflicts with the current clinical practice of many cardiologists, who are more familiar with dealing with the disease processes that affect the large epicardial arteries. The clinical importance of microvascular function is emerging because of attempts to develop techniques which allow for the objective assessment of microvascular function while in the catheter lab. In addition, there is a growing body of evidence to suggest that the microvascular compartment may show early changes in patients who are at risk of coronary artery disease. It is also possible that the microcirculation is responsible for the poor response to revascularisation in certain patients, potentially in the form of the no reflow phenomenon and peri-procedural myocardial infarction, which may be observed following percutaneous coronary intervention. Pathological microvascular changes could explain the significant midterm morbidity and mortality associated with these complications. The aim of this review is to provide an overview of the physiological mechanisms responsible for the regulation of the coronary microcirculation and to focus on the pathological processes which affect the microcirculation, particularly in relation to coronary angioplasty. We will also discuss potential mechanisms and therapeutic options which could improve microvascular perfusion in this group of patients.

Nocturnal gastro-oesophageal reflux may be important in the pathogenesis of reflux oesophagitis. This study aimed to determine whether: (1) gastro-oesophageal reflux occurs during sleep in patients with reflux oesophagitis and, if so, to explore the mechanism, and (2) the sleep pattern of patients with oesophagitis is different from that of control subjects. After a standard evening meal, simultaneous manometric, oesophageal pH, and polysomnographic recordings were obtained in 11 patients with endoscopic oesophagitis and 11 control subjects. Patients with gastrooesophageal reflux disease had significantly more total reflux episodes throughout the nocturnal monitoring period than control subjects (105 v 6). Ninety two of 105 episodes of gastro-oesophageal reflux in patients occurred during the awake state and 10 during sleep stage II. A number of reflux episodes occurred during brief periods of arousal from the various sleep stages. Of the 105 reflux events recorded in patients, 42 were induced by transient lower oesophageal sphincter relaxation, 20 by stress reflux, 22 by free reflux mechanisms, and in 21 the mechanism was unclear. The sleep pattern and the time spent in each sleep stage was not different between the two groups. It is concluded that the awake state is crucial for the occurrence of nocturnal reflux episodes in normal subjects as well as in patients with reflux oesophagitis and that the difference between the frequency of gastro-oesophageal reflux between normal subjects and patients cannot be explained by different sleep patterns.

Electrical and mechanical correlates of crural diaphragm activity during swallow-induced and transient lower esophageal sphincter relaxation were monitored in 12 healthy subjects. Simultaneous esophageal manometric, pH, and crural diaphragm electromyogram recordings were performed for 1 hour in the postprandial period. Swallow-induced lower esophageal sphincter relaxation was associated with minimal inhibition of the crural diaphragm, but transient lower esophageal sphincter relaxation was accompanied by marked inhibition of the crural diaphragm. The degree of lower esophageal sphincter relaxation appeared to correlate with the degree of crural diaphragm inhibition during transient lower esophageal sphincter relaxation. Inhibition of crural diaphragm during transient lower esophageal sphincter relaxation may play an important role in facilitating flow across the gastroesophageal junction.

Purpose: Spinal cord injury and the resultant postoperative paraplegia are devastating complications of thoracic aortic surgery, for which no widely accepted protective interventions exist. We hypothesized that retrograde venous perfusion-cooling of the spinal cord with a hypothermic saline and adenosine solution would protect it from ischemic injury caused by thoracic aortic occlusion. Methods: Adult domestic swine of either sex (weight range, 20 to 30 kg) were intubated and ventilated. A left thoracotomy was performed. The accessory hemiazygous vein was divided, and a catheter was inserted distally. The aorta was clamped at the left subclavian artery. The venous catheter was not used in the animals in the control group (n = 7); in the animals in the experimental group (n = 7), a cold (4°C) saline and adenosine solution was infused into the accessory hemiazygous vein. After 30 minutes, the clamp and catheter were removed, and the chest was closed. A blinded observer evaluated the animals' hind-leg motor activity 24 hours later. The Tarlov scale was used: 0, complete paralysis; 1, minimal movement; 2, stands with assistance; 3, stands alone; 4, weak walk; 5, normal gait. The animals' rectal temperatures were measured at the end of the experiment, and blood pressure was measured throughout. Two other groups were studied to assess the effect of the intervention on spinal cord temperature. Results: The animals in the control group had a mean Tarlov score of 1.7 ± 0.6; the animals in the experimental group had a mean Tarlov score of 4.9 ± 0.1 (P

Paraplegia remains a devastating complication following thoracic aortic operation. We hypothesized that retrograde perfusion of the spinal cord with a hypothermic, adenosine-enhanced solution would provide protection during periods of ischemia due to temporary aortic occlusion.In a rabbit model, a 45-minute period of spinal cord ischemia was produced by clamping the abdominal aorta and vena cava just below the left renal vessels and at their bifurcations. Four groups (n = 8/group) were studied: control, warm saline, cold saline, and cold saline with adenosine infusion. In the experimental groups, saline or saline plus adenosine was infused into the isolated cavae throughout the ischemic period. Clamps were removed and the animals to recovered for 24 hours before blinded neurological evaluation.Tarlov scores (0 = paraplegia, 1 = slight movement, 2 = sits with assistance, 3 = sits alone, 4 = weak hop, 5 = normal hop) were (mean +/- standard error of the mean): control, 0.50 +/- 0.50; warm saline, 1.63 +/- 0.56; cold saline, 3.38 +/- 0.26; and cold saline plus adenosine, 4.25 +/- 0.16 (analysis of variance for all four groups, p0.00001). Post-hoc contrast analysis showed that cold saline plus adenosine was superior to the other three groups (p0.0001).Retrograde venous perfusion of the spinal cord with hypothermic saline and adenosine provides functional protection against surgical ischemia and reperfusion.

Diadenosine polyphosphates present in the extracellular environment can, through interaction with appropriate purinoceptors, influence a range of cellular activities. Here we have investigated the nature of the ligand:receptor interactions involved in diadenosine 5′,5″-P1,P4-tetraphosphate (Ap4A)-mediated stimulation of glycogen breakdown in isolated rat liver cells. [2-3H]Ap4A showed specific binding to both intact isolated liver cells and plasma membrane fractions prepared from isolated liver cells. HPLC analysis confirmed that binding was mediated by intact Ap4A and not by potential breakdown products (e.g. ATP, adenosine etc). Binding of [2-3H]Ap4A, to isolated liver cell plasma membrane preparations, was successfully displaced by a range of both naturally occurring and synthetic diadenosine polyphosphates with the rank order potency Ap4A ⩾Ap5A > Ap6A > Ap3A > Ap2A. [2-3H]Ap4A binding was not displaced by P1 effectors but was successfully displaced by a range of P2 effectors with the rank order potency 2-methylthio-ATP > ATP > ADP ⩾adenosine 5′-[αβ-methylene]triphosphate > adenosine 5′-[βγ-methylene]triphosphate. These findings are consistent with the interaction of Ap4A with a P2y-like subclass of purinoceptor and are discussed in relation to (1) the known purinoceptor populations in liver cell plasma membranes and (2) observations concerning the binding of diadenosine polyphosphates to purinoceptors in other tissues.

We have characterized the immediate (465 bp) 5'-flanking region of the rat phenylalanine hydroxylase (PAH)-encoding gene. This sequence shows considerable similarity to the 5'-flanking region of the human PAH gene [Konecki et al., Biochemistry 31 (1992) 8363–8368]. Both sequences lack obvious TATA elements; however, putative regulatory sites, including a potential cyclic AMP-response element and glucocorticoid response elements, are present.

Single rat hepatocytes microinjected with aequorin respond to Cal’-mobilizing agonists, including ADP and ATP, with oscillations in cytosolic free Cal’. We show here that single rat hepatocytes also respond to the adenine dinucleotides Ap,A and Ap.,A with Cal’ oscillations which resemble those induced by ADP and ATP. Ca*’ oscillation; Adenine dinucleotide; Purinoceptor; Single hepatocyte

Evidence is presented for the reversible activation-inactivation of the microsomal ecdysone 20-monooxygenase from fat body of the cotton leafworm, Spodoptera littoralis, in a manner commensurate with reversible changes in its phosphorylation state. The activity of the monooxygenase was higher following preincubation with fluoride (an inhibitor of phosphoprotein phosphatases) than in its absence. Preincubation with alkaline phosphatase or with cAMP-dependent protein kinase resulted in appreciable diminution or enhancement, respectively, in monooxygenase activity. Activation of ecdysone 20-monooxygenase activity could also be effected by incubation with a cytosolic fraction in the presence of cAMP, ATP, and fluoride; this activation was prevented by a cAMP-dependent protein kinase inhibitor. Similarly, inactivation of the monooxygenase was achieved by preincubation with cytosol, the effect being enhanced by Ca2+-calmodulin or by Mg2+ ions. The combined results provide indirect evidence that the microsomal ecdysone 20-monooxygenase exists in an active phosphorylated form and an inactive dephosphorylated form, interconvertible by a cAMP-dependent protein kinase and a phosphoprotein phosphatase.

The impact of experimentally induced diabetes on the expression of rat liver phenylalanine hydroxylase has been investigated. A significant elevation in maximal enzymic activity was observed in diabetes. This was associated with significant increases in the amount of enzyme, the phenylalanine hydroxylase-specific translational activity of hepatic RNA and the abundance of phenylalanine hydroxylase-specific mRNA. These changes in phenylalanine hydroxylase expression were not observed when diabetes was controlled by daily injections of insulin. These results are discussed in relation to the hormonal control of phenylalanine hydroxylase gene expression.

The total activity of three key enzymes and the flux through eight steps of aromatic amino acid metabolism have been determined in liver cells isolated from rats fed either control or pyridoxine-free diet for 5–6 weeks. The pyridoxine-free diet caused a decrease in the catabolism of tyrosine and phenylalanine because of a drop in the flux through tyrosine aminotransferase. This decrease of expressed cellular tyrosine aminotransferase activity can be fully explained in terms of loss of cofactor. Larger decreases in the catabolism of tryptophan were seen after pyridoxine deprivation. The decreased extent of tryptophan catabolism can be solely attributed to loss of cofactor or increased degradation of kynureninase. Inhibition of tryptophan 2,3dioxygenase was seen in pyridoxine deficiency, probably because of the buildup of the kynurenine metabolites. The control strength of kynureninase, for flux through kynureninase, was calculated to be less than or equal to 0.004, but 0.41 after pyridoxine deprivation. The sensitivity of the three pathways to pyridoxine deprivation is interpreted and discussed in terms of the different affinities for pyridoxal phosphate and the control strengths of the pyridoxal phosphate-dependent enzymes, tyrosine aminotransferase and kynureninase.

Upper Triassic continental strata in the United States contain rare horizons which yield pollen assemblages. The Dockum Group and Chinle Formation of the American Southwest, as well as certain rock units within the Deep River, Richmond, and Taylorsville Basins of the Newark Group, contain palynomorphs which exhibit stratigraphically restricted ranges in Europe. The presence of Vallasporites ignacii, Camerosporites secatus and Ovalipollis ovalis in the Dockum Group, Chinle Formation, Cumnock Formation of the Deep River Basin, Vinita Formation of the Richmond Basin, and unnamed units in the Taylorsville Basin suggest that all these units are approximately contemporaneous. The occurrence of these and other stratigraphically diagnostic pollen taxa, particularly Patinasporites densus, further indicates a Middle to Late Karnian age for these units. The palynostratigraphy also implies that the Pekin Formation of the Deep River Basin is slightly older than the above mentioned units.

Liver cells from fed Sprague-Dawley rats metabolized phenylalanine, tyrosine and tryptophan at rates consistent with the known kinetic properties of the first enzymes of each pathway. Starvation of rats for 48 h did not increase the maximal activities of phenylalanine hydroxylase, tryptophan 2,3-dioxygenase and tyrosine aminotransferase in liver cell extracts, when results were expressed in terms of cellular DNA. Catabolic flux through the first two enzymes was unchanged; that through the aminotransferase was elevated relatively to enzyme activity. This is interpreted in terms of changes in the concentrations of 2-oxoglutarate and glutamate. Cells from tryptophan-treated animals exhibited significant increases in the catabolism of tyrosine and tryptophan, but not of phenylalanine. The activities of tyrosine aminotransferase and tryptophan 2,3-dioxygenase were also increased, although the changes in flux and enzyme activity did not correspond exactly. These results are discussed with reference to the control of aromatic amino acid catabolism in liver; the role of substrate concentration is emphasized.

Chronic (10-day) diabetes was associated with increased metabolic flux through phenylalanine hydroxylase in isolated liver cells. This flux was stimulated by 0.1 microM-glucagon, but not by 10 microM-noradrenaline; 0.1 microM-insulin affected neither basal nor glucagon-stimulated flux. The increased rate of phenylalanine hydroxylation in diabetes was accompanied by parallel increases in enzyme activity (as measured with artificial cofactor) and immunoreactive-enzyme-protein content. In contrast with total protein synthesis, which decreased, phenylalanine hydroxylase synthesis persisted at the control rate in cells from diabetic animals. These findings are discussed in relation to the hormonal regulation of the hydroxylase and the known metabolic consequences of chronic diabetes.

The adrenergic amines noradrenaline and adrenaline increased flux through phenylalanine hydroxylase by approx. 50%. This effect, which appears to be mediated by an alpha-adrenergic mechanism, was accompanied by a rapid increase in the phosphorylation of phenylalanine hydroxylase. Although ionophore A23187 mimicked the effects of the adrenergic amines, vasopressin was completely without effect on either phenylalanine hydroxylation or enzyme phosphorylation. Flux through phenylalanine hydroxylase in young rats (80 g) was insensitive to alpha-adrenergic, but sensitive to beta-adrenergic, agents. Consistent with previous observations [Fisher & Pogson (1984) Biochem. J. 219, 79-85] the present data indicate a close correlation between phosphorylation state and flux rate (i.e. enzyme activity).

B. S., a white maIe age fifty, was admitted to the Maimonides HospitaI on December 4, 1947. He stated that about four hours prior to admission he stepped from his bath, went to stoo1, was frightened whiIe pIaying with his dog, causing him to faI1 from the toiIet seat onto a gIass of the type used for oId fashioned cocktaiIs which was on the floor nearby. The gIass entered the rectum. The patient was a we11 nourished individua1 in exceIIent physica condition but in obvious distress. BIood pressure, puIse and respirations were within norma Iimits. The bIadder was emptied of 1,000 cc. of cIear urine which upon microscopic examination was not unusua1. Prior to his admission the patient had taken a Iarge dose of castor oil and now compIained of severe abdomina1 cramps, tenderness in the Iower abdomen and moderate distention, Under spina anesthesia of 150 mg. of procaine the examining surgeon was abie to paIpate the rim of the gIass, but repeated attempts to remove it were unsuccessfu1, severa pieces being broken, resuIting in Iacerations of the recta1 mucosa. Packing was inserted to check hemorrhage. On the foIIowing day because of severe abdomina pain and marked abdomina1 distention, a coIostomy was performed through a Ieft Iower rectus muscIe spIitting incision, using a spina anesthetic of 150 mg. of procaine. The gIass couId be paIpated through the abdomen but couId not be moved. A Penrose drain was passed through the mesentery and the sigmoid coIon opened. A tube was inserted and hxed with a purse-string suture. CIosure of the abdomina1 waI1 was done in the usua1 manner. The operation occupied onehaIf hour. Prior to operation the patient was given 50,000 units of peniciIIin every three hours and streptomycin (2 gm. daiIy) in eight divided doses. This medication was continued. During the next week two unsuccessftd attempts were made on the ward to remove the gIass by recta1 manipuIation. MeanwhiIe the edema of the mucosa increased about the rim of the gIass and the area became very tender. Seven days after admission the patient was again operated upon under a spina anesthetic being given 150 mg. of procaine. A Iubricated vagina1 specuIum was inserted in the ana canal, the gIass exposed and a stee1 pIunger pIaced in the center of the gIass, which was then IiIIed with a quick-setting pIaster of paris and aIIowed to harden. When traction was appIied to this, the pIaster of paris moId came out but the gIass did not move. At this point a proctoIogic consuItation was obtained. A proctoscope was inserted into the rectum and thus into the gIass and the area inspected. There were some minor Iacerations and a Iarge edematous ring of mucosa, quite hemorrhagic, into which the remaining rim was embedded. The proctoscope was sIowIy withdrawn and the edematous ring ffattened with the edge of the scope. A snub-nosed Yeomans biopsy punch was carefuIIy inserted between the rim of the gIass and the edematous, somewhat ffattened mucosa1 ring, then pIaced under the thick rim of the gIass. By gentIe Ieverage aIong the rim of the gIass the vacuum was broken. The gIass became movabIe but further manipuIation and rotation was necessary to avoid any further Iaceration from the jagged broken edges. In order to avoid injury to the operator a CriIe retractor was shaped and pIaced in position between the gIass and the recta1 waI1 and the gIoved hand inserted behind the retractor. It was then possibIe to grasp the base of the gIass between the fingers. The gIass was rotated and carefuIIy extracted. A combination gauze pack was inserted against the previousIy infected Iacerations. The glass measured 8 cm. in Iength, 4 cm. in diameter at the bottom and 7 cm. in diameter at the open end. Two days Iater the rectum was again inspected and the ring of edematous mucosa found to be considerabIy reduced. The patient was referred to his surgeon and the coIostomy Iater cIosed.

Salicylazosulfapyridine (Azulfidine) is an azo compound of salicylic acid and sulfapyridine first introduced in 1942 by Svartz1for the treatment of ulcerative colitis. In the early clinical trials with this medicament hypersensitivity reactions, particularly drug fever and rash, were noted in about 5% of patients.2Five instances of leukopenia were observed but no cases of agranulocytosis or nephrolithiasis. Bargen,3Morrison,4and others5have also noted the usefulness of salicylazosulfapyridine and its low incidence of hematological complications. The first reported instance of agranulocytosis after the use of salicylazosulfapyridine was described by Levy in 1949.6His patient recovered from a complicating staphylococcic septicemia after treatment with penicillin. We are aware of only one other occurrence of agranulocytosis associated with administration of this drug.7In view of the extensive use of salicylazosulfapyridine in the treatment of patients with ulcerative colitis, the following case of agranulocytosis is

Patients with severe acute pancreatitis are at risk of candidal infections carrying the potential risk of an increase in mortality. Since early diagnosis is problematic, several clinical risk scores have been developed to identify patients at risk. Such patients may benefit from prophylactic antifungal therapy while those patients who have a low risk of infection may not benefit and may be harmed. The aim of this study was to assess the validity and discrimination of existing risk scores for invasive candidal infections in patients with severe acute pancreatitis.Patients admitted with severe acute pancreatitis to the intensive care unit were analysed. Outcomes and risk factors of admissions with and without candidal infection were compared. Accuracy and discrimination of three existing risk scores for the development of invasive candidal infection (Candida score, Candida Colonisation Index Score and the Invasive Candidiasis Score) were assessed.A total of 101 patients were identified from 2003 to 2011 and 18 (17.8%) of these developed candidal infection. Thirty patients died, giving an overall hospital mortality of 29.7%. Hospital mortality was significantly higher in patients with candidal infection (55.6% compared to 24.1%, P=0.02). Candida colonisation was associated with subsequent candidal infection on multivariate analysis. The Candida Colonisation Index Score was the most accurate test, with specificity of 0.79 (95% confidence interval [CI] 0.68 to 0.88), sensitivity of 0.67 (95% CI 0.41 to 0.87), negative predictive value of 0.91 (95% CI 0.82 to 0.97) and a positive likelihood ratio of 3.2 (95% CI 1.9 to 5.5). The Candida Colonisation Index Score showed the best discrimination with area under the receiver operating characteristic curve of 0.79 (95% CI 0.69 to 0.87).In this study the Candida Colonisation Index Score was the most accurate and discriminative test at identifying which patients with severe acute pancreatitis are at risk of developing candidal infection. However its low sensitivity may limit its clinical usefulness.