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Competing Interests: Conflict of interest: None declared.

Neuromyelitis optica (NMO) is an autoimmune demyelinating disease of the central nervous system characterized by the presence of autoantibodies (called NMO-IgG) targeting aquaporin-4. Aquaporin-4 is expressed at the perivascular foot processes of astrocytes, in the glia limitans, but also at the ependyma. Most studies have focused on studying the pathogenicity of NMO-IgG on astrocytes, and NMO is now considered an astrocytopathy. However, periependymal lesions are observed in NMO suggesting that ependymal cells could also be targeted by NMO-IgG. Ependymal cells regulate CSF-parenchyma molecular exchanges and CSF flow, and are a niche for sub-ventricular neural stem cells. Our aim was to examine the effect of antibodies from NMO patients on ependymal cells. We exposed two models, i.e. primary cultures of rat ependymal cells and explant cultures of rat lateral ventricular wall whole mounts, to purified IgG of NMO patients (NMO-IgG) for 24 hours. We then evaluated the treatment effect using immunolabelling, functional assays, ependymal flow analysis and bulk RNA sequencing. For each experiment, the effects were compared with those of purified IgG from a healthy donors and non-treated cells. We found that: (i) NMO-IgG induced aquaporin-4 agglomeration at the surface of ependymal cells and induced cell enlargement in comparison to controls. In parallel, it induced an increase in gap junction connexin-43 plaque size; (ii) NMO-IgG altered the orientation of ciliary basal bodies and functionally impaired cilia motility; (iii) NMO-IgG activated the proliferation of sub-ventricular neural stem cells; (iv) treatment with NMO-IgG up-regulated the expression of pro-inflammatory cytokines and chemokines in the transcriptomic analysis. Our study showed that NMO-IgG can trigger an early and specific reactive phenotype in ependymal cells, with functional alterations of intercellular communication and cilia, activation of sub-ventricular stem cell proliferation and the secretion of pro-inflammatory cytokines. These findings suggest a key role for ependymal cells in the early phase of NMO lesion formation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Aims: Cardiac myosin-binding protein C (cMyC) demonstrated high diagnostic accuracy for the early detection of non-ST-elevation myocardial infarction (NSTEMI). Its dynamic release kinetics may enable a 0/1h-decision algorithm that is even more effective than the ESC hs-cTnT/I 0/1 h rule-in/rule-out algorithm., Methods and Results: In a prospective international diagnostic study enrolling patients presenting with suspected NSTEMI to the emergency department, cMyC was measured at presentation and after 1 h in a blinded fashion. Modelled on the ESC hs-cTnT/I 0/1h-algorithms, we derived a 0/1h-cMyC-algorithm. Final diagnosis of NSTEMI was centrally adjudicated according to the 4th Universal Definition of Myocardial Infarction. Among 1495 patients, the prevalence of NSTEMI was 17%. The optimal derived 0/1h-algorithm ruled-out NSTEMI with cMyC 0 h concentration below 10 ng/L (irrespective of chest pain onset) or 0 h cMyC concentrations below 18 ng/L and 0/1 h increase <4 ng/L. Rule-in occurred with 0 h cMyC concentrations of at least 140 ng/L or 0/1 h increase ≥15 ng/L. In the validation cohort (n = 663), the 0/1h-cMyC-algorithm classified 347 patients (52.3%) as 'rule-out', 122 (18.4%) as 'rule-in', and 194 (29.3%) as 'observe'. Negative predictive value for NSTEMI was 99.6% [95% confidence interval (CI) 98.9-100%]; positive predictive value 71.1% (95% CI 63.1-79%). Direct comparison with the ESC hs-cTnT/I 0/1h-algorithms demonstrated comparable safety and even higher triage efficacy using the 0h-sample alone (48.1% vs. 21.2% for ESC hs-cTnT-0/1 h and 29.9% for ESC hs-cTnI-0/1 h; P < 0.001)., Conclusion: The cMyC 0/1h-algorithm provided excellent safety and identified a greater proportion of patients suitable for direct rule-out or rule-in based on a single measurement than the ESC 0/1h-algorithm using hs-cTnT/I., Trial Registration: ClinicalTrials.gov number, NCT00470587., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Motivation: Statistical and machine-learning analyses of tumor transcriptomic profiles offer a powerful resource to gain deeper understanding of tumor subtypes and disease prognosis. Currently, prognostic gene-expression signatures do not exist for all cancer types, and most developed to date have been optimized for individual tumor types. In Galgo, we implement a bi-objective optimization approach that prioritizes gene signature cohesiveness and patient survival in parallel, which provides greater power to identify tumor transcriptomic phenotypes strongly associated with patient survival., Results: To compare the predictive power of the signatures obtained by Galgo with previously studied subtyping methods, we used a meta-analytic approach testing a total of 35 large population-based transcriptomic biobanks of four different cancer types. Galgo-generated colorectal and lung adenocarcinoma signatures were stronger predictors of patient survival compared to published molecular classification schemes. One Galgo-generated breast cancer signature outperformed PAM50, AIMS, SCMGENE and IntClust subtyping predictors. In high-grade serous ovarian cancer, Galgo signatures obtained similar predictive power to a consensus classification method. In all cases, Galgo subtypes reflected enrichment of gene sets related to the hallmarks of the disease, which highlights the biological relevance of the partitions found., Availability and Implementation: The open-source R package is available on www.github.com/harpomaxx/galgo., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Acute coronary syndrome (ACS) can be a life-threatening condition. However, identification of patients with ACS can be challenging, especially among women, and clinical presentation can often overlap with other medical entities., Case Summary: A 61-year-old woman with a history of stable bronchial asthma presented with worsening dyspnoea for spiroergometry. During bicycle exercise testing, she developed acute chest pain and her electrocardiogram showed significant ST-segment elevations. High-sensitivity cardiac troponin was elevated and a coronary angiography was performed showing normal coronary arteries. Cardiac magnetic resonance imaging showed no signs of myocardial infarction, myocarditis or Takotsubo cardiomyopathy but the incidental finding of a giant hiatal hernia impeding the filling of the left atrium. The giant hernia was surgically corrected, and the patient's exertional dyspnoea fully relieved during follow-up., Discussion: Hiatal hernia might compress cardiac structures, cause exertional dyspnoea and mimic ST-elevation myocardial infarction. 10.1093/ehjcr/ytz138&#95;audio1 ytz138&#95;audio1 6074443146001., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: We sought to evaluate diagnostic accuracy of a high-sensitivity cardiac troponin I (hs-cTnI) assay for acute coronary syndromes (ACS) in the emergency department (ED). The assay has high precision at low concentrations and can detect cTnI in 96.8% of healthy individuals., Methods: In successive prospective multicenter studies ("testing" and "validation"), we included ED patients with suspected ACS. We drew blood for hs-cTnI [Singulex Clarity ® cTnI; 99th percentile, 8.67 ng/L; limit of detection (LoD), 0.08 ng/L] on arrival. Patients also underwent hs-cTnT (Roche Elecsys) testing over ≥3 h. The primary outcome was an adjudicated diagnosis of ACS, defined as acute myocardial infarction (AMI; prevalent or incident), death, or revascularization within 30 days., Results: The testing and validation studies included 665 and 2470 patients, respectively, of which 94 (14.1%) and 565 (22.9%) had ACS. At a 1.5-ng/L cutoff, hs-cTnI had good sensitivity for AMI in both studies (98.7% and 98.1%, respectively) and would have "ruled out" 40.1% and 48.9% patients. However, sensitivity was lower for ACS (95.7% and 90.6%, respectively). At a 0.8-ng/L cutoff, sensitivity for ACS was higher (97.5% and 97.9%, ruling out 28.6% patients in each cohort). The hs-cTnT assay had similar performance at the LoD (24.6% ruled out; 97.2% sensitivity for ACS)., Conclusions: The hs-cTnI assay could immediately rule out AMI in 40% of patients and ACS in >25%, with similar accuracy to hs-cTnT at the LoD. Because of its high precision at low concentrations, this hs-cTnI assay has favorable characteristics for this clinical application., (© 2019 American Association for Clinical Chemistry.)

Background: Previous studies have indicated a correlation between heart failure, inflammation and poorer outcome. However, the pathogenesis and role of inflammation in acute heart failure (AHF) is incompletely studied and understood. The aim of our study was to explore the potential role of innate immunity - quantified by complement activation products (CAPs) - in pathophysiology, responses to treatment and impacts on long-term survival in AHF., Methods: In a prospective study enrolling 179 unselected patients with AHF, plasma concentrations of C4d, C3a and sC5b-9 were measured in a blinded fashion on the first day of hospitalisation and prior to discharge. The final diagnosis, including the AHF phenotype, was adjudicated by two independent cardiologists. Long-term follow-up was obtained. Findings in AHF were compared to that obtained in 75 healthy blood donors (control group)., Results: Overall, concentrations of all three CAPs were significantly higher in patients with AHF than in healthy controls (all p < 0.001). In an age-adjusted subgroup analysis, significant differences could be confirmed for concentrations of C4d and sC5b-9, and these parameters further increased after 6 days of in-hospital treatment ( p < 0.001). In contrast, C3a levels in AHF patients did not differ from those of the control group in the age-adjusted subgroup analysis and remained constant during hospitalisation. Concentrations of C4d, C3a and sC5b-9 were significantly higher when AHF was triggered by an infection as compared to other triggers ( p < 0.001). In addition, CAP levels significantly correlated with each other ( r = 0.64-0.76), but did not predict death within 2 years., Conclusions: Activation of complement with increased plasma levels of C4d and sC5b-9 at admission and increasing levels during AHF treatment seems to be associated with AHF, particularly when AHF was triggered by an infection. However, CAPs do not have a prognostic value in AHF.

Evaluation of quality of care is an integral part of modern healthcare, and has become an indispensable tool for health authorities, the public, the press and patients. However, measuring quality of care is difficult, because it is a multifactorial and multidimensional concept that cannot be estimated solely on the basis of patients' clinical outcomes. Thus, measuring the process of care through quality indicators (QIs) has become a widely used practice in this context. Other professional societies have published QIs for the evaluation of quality of care in the context of acute myocardial infarction (AMI), but no such indicators exist in Europe. In this context, the European Society of Cardiology (ESC) Acute Cardiovascular Care Association (ACCA) has reflected on the measurement of quality of care in the context of AMI (ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI)) and created a set of QIs, with a view to developing programmes to improve quality of care for the management of AMI across Europe. We present here the list of QIs defined by the ACCA, with explanations of the methodology used, scientific justification and reasons for the choice for each measure.

Background: Interpretation of serial high-sensitivity cardiac troponin (hs-cTn) measurements for the diagnosis of acute myocardial infarction (AMI) assumes random fluctuation of hs-cTn around an individual's homeostatic set point. The aim of this study was to challenge this diagnostic concept., Methods: Study 1 examined the presence of a diurnal hs-cTn rhythm by hourly blood sampling, day and night, in 24 individuals without a recent history of AMI. Study 2 assessed morning vs evening diagnostic accuracy of hs-cTnT and hs-cTnI in a prospective multicenter diagnostic study of 2782 unselected patients, presenting to the emergency department with acute chest pain., Results: In study 1, hs-cTnT, but not hs-cTnI, exhibited a diurnal rhythm, characterized by gradually decreasing concentrations throughout daytime, rising concentrations during nighttime, to peak concentrations in the morning (mean 16.2 ng/L at 8:30 AM and 12.1 ng/L at 7:30 PM). In study 2, the hs-cTnT rhythm was confirmed by higher hs-cTnT concentrations in early-morning presenters compared to evening presenters with an adjudicated diagnosis of noncardiac disease. The diagnostic accuracy [area under the receiver-operation characteristics curve (AUC)] of hs-cTnT at presentation, 1 h, and for the combination of absolute changes with presenting concentration, were very high and comparable among patients presenting early morning as compared to evening (all AUC >0.93). hs-cTnI exhibited no diurnal rhythm with no differences in AUC among early-morning and evening presenters., Conclusions: Rhythmic diurnal variation of hs-cTnT is a general phenomenon that is not seen with hs-cTnI. While the diurnal hs-cTnT rhythm does not seem to affect the diagnostic accuracy of hs-cTnT for AMI, it should be considered when using hs-cTnT for screening purposes., Clinical Trial Registration: 1. Circadian Variation of Cardiac Troponin, NCT02091427, www.clinicaltrials.gov/ct2/show/NCT02091427. 2. Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) Study, NCT00470587, www.clinicaltrials.gov/ct2/show/NCT00470587., (© 2016 American Association for Clinical Chemistry.)

Aims: High-sensitivity cardiac troponin (hs-cTn) assays provide higher diagnostic accuracy for acute myocardial infarction (AMI) when compared with conventional assays, but may result in increased use of unnecessary coronary angiographies due to their increased detection of cardiomyocyte injury in conditions other than AMI., Methods and Results: We evaluated the impact of the clinical introduction of high-sensitivity cardiac troponin T (hs-cTnT) on the use of coronary angiography, stress testing, and time to discharge in 2544 patients presenting with symptoms suggestive of AMI to the emergency department (ED) within a multicentre study either before (1455 patients) or after (1089 patients) hs-cTnT introduction. Acute myocardial infarction was more often the clinical discharge diagnosis after hs-cTnT introduction (10 vs. 14%, P < 0.001), while unstable angina less often the clinical discharge diagnosis (14 vs. 9%, P = 0.007). The rate of coronary angiography was similar before and after the introduction of hs-cTnT (23 vs. 23%, P = 0.092), as was the percentage of coronary angiographies showing no stenosis (11 vs. 7%, P = 0.361). In contrast, the use of stress testing was substantially reduced from 29 to 19% (P < 0.001). In outpatients, median time to discharge from the ED decreased by 79 min (P < 0.001). Mean total costs decreased by 20% in outpatients after the introduction of hs-cTnT (P = 0.002)., Conclusion: The clinical introduction of hs-cTn does not lead to an increased or inappropriate use of coronary angiography. Introduction of hs-cTn is associated with an improved rule-out process and thereby reduces the need for stress testing and time to discharge., Clinical Trial Registration Information: www.clinicaltrials.gov. Identifier, NCT00470587., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Patients presenting very early after chest pain onset may provide a diagnostic challenge even when using a high-sensitivity cardiac troponin (hs-cTnT). We hypothesized that in these patients the incremental value of copeptin in the early diagnosis of acute myocardial infarction (AMI) may be substantial., Methods: We aimed to investigate the incremental value of copeptin in a pre-specified subgroup analysis of patients presenting with suspected AMI to the emergency department within 2 hours of symptom onset in a multicenter study. Copeptin was measured in a blinded fashion. Two independent cardiologists adjudicated the final diagnosis using all available clinical informations, including high-sensitivity cardiac troponin T (hs-cTnT)., Results: Overall, 2000 patients were enrolled, of whom 519 (26%) arrived within 2 hours of symptom onset. Of these, 102 patients (20%) had an AMI. The additional use of copeptin did not increase diagnostic accuracy as quantified by the area under the receiver-operating characteristic curve (AUC) of hs-cTnT (0.87 (95% confidence interval (CI): 0.83-0.90) for hs-cTnT alone to 0.86 (95% CI: 0.82-0.90) for the combination; p = NS). Copeptin (using 9 pmol/L as a cut-off) increased the negative predictive value (NPV) of hs-cTnT (using 14 ng/L as a cut-off) alone from 93% (95% CI: 90-95%) to 96% (95% CI: 93-98%). The NPV for the combination of hs-cTnT and copeptin was lower in patients arriving in the first 2 hours than in those arriving after 2 hours: 96% (95% CI: 93-98%) versus 99% (95% CI: 99-100%), respectively., Conclusions: The additional use of copeptin on top of hs-cTnT seems to lead to a small increase in NPV, but no increase in AUC. Routine use of copeptin in early presenters does not seem warranted., (© The European Society of Cardiology 2016.)

Background: The early triage of patients toward rule-out and rule-in of acute myocardial infarction (AMI) is challenging. Therefore, we aimed to develop a 2-h algorithm that uses high-sensitivity cardiac troponin I (hs-cTnI)., Methods: We prospectively enrolled 1435 (derivation cohort) and 1194 (external validation cohort) patients presenting with suspected AMI to the emergency department. The final diagnosis was adjudicated by 2 independent cardiologists. hs-cTnI was measured at presentation and after 2 h in a blinded fashion. We derived and validated a diagnostic algorithm incorporating hs-cTnI values at presentation and absolute changes within the first 2 h., Results: AMI was the final diagnosis in 17% of patients in the derivation and 13% in the validation cohort. The 2-h algorithm developed in the derivation cohort classified 56% of patients as rule-out, 17% as rule-in, and 27% as observation. Resulting diagnostic sensitivity and negative predictive value (NPV) were 99.2% and 99.8% for rule-out; specificity and positive predictive value (PPV) were 95.2% and 75.8% for rule-in. Applying the 2-h algorithm in the external validation cohort, 60% of patients were classified as rule-out, 13% as rule-in, and 27% as observation. Diagnostic sensitivity and NPV were 98.7% and 99.7% for rule-out; specificity and PPV were 97.4% and 82.2% for rule-in. Thirty-day survival was 100% for rule-out patients in both cohorts., Conclusions: A simple algorithm incorporating hs-cTnI baseline values and absolute 2-h changes allowed a triage toward safe rule-out or accurate rule-in of AMI in the majority of patients., (© 2015 American Association for Clinical Chemistry.)

Background: Combined testing of high-sensitivity cardiac troponin T (hs-cTnT) and copeptin at presentation provides a very high-although still imperfect-negative predictive value (NPV) for the early rule-out of acute myocardial infarction (AMI). We hypothesized that a second copeptin measurement at 1 h might further increase the NPV., Methods: In a prospective diagnostic multicenter study, we measured hs-cTnT and copeptin concentrations at presentation and at 1 h in 1439 unselected patients presenting to the emergency department with suspected AMI. The final diagnosis was adjudicated by 2 independent cardiologists blinded to copeptin concentrations. We investigated the incremental value of 1-h copeptin in the rule-out setting (0-h hs-cTnT negative and 0-h copeptin negative) and the intermediate-risk setting (0-h hs-cTnT negative and 0-h copeptin positive)., Results: The adjudicated diagnosis was AMI in 267 patients (18.6%). For measurements obtained at presentation, the NPV in the rule-out setting was 98.6% (95% CI, 97.4%-99.3%). Whereas 1-h copeptin did not increase the NPV significantly, 1-h hs-cTnT did, to 99.6% (95% CI, 98.7%-99.9%, P = 0.008). Similarly, in the intermediate-risk setting (NPV 92.8%, 95% CI, 88.7%-95.8%), 1-h copeptin did not significantly increase the NPV (P = 0.751), but 1-h hs-cTnT did, to 98.6 (95% CI, 96%-99.7%, P < 0.001)., Conclusions: One-hour copeptin increased neither the safety of the rule-out process nor the NPV in the intermediate-risk setting. In contrast, the incremental value of 1-h hs-cTnT was substantial in both settings. ClinicalTrials.gov/NCT00470587., (© 2015 American Association for Clinical Chemistry.)

Background: In contrast to ST-elevation myocardial infarction (STEMI), in non-STEMI (NSTEMI) patients the need for continuous rhythm monitoring in a coronary care unit, respective incidence and timing of serious arrhythmias are poorly defined., Methods: We used a derivation-validation design and data from two independent prospective cohorts of consecutive haemodynamically stable NSTEMI patients to evaluate the incidence and timing of serious arrhythmias after successful early percutaneous revascularization. Serious arrhythmia was prospectively defined as any arrhythmia that requires immediate medical attention including persistent ventricular tachycardia (>30 s), ventricular fibrillation, asystole, and high degree atrioventricular (AV)-block requiring pacemaker insertion during hospitalization., Results: In the derivation cohort, among 228 NSTEMI patients who underwent successful early percutaneous revascularization, one patient (0.4%, 95% confidence interval 0.02-2.8%) had a serious arrhythmia which occurred 21 h after revascularization. In the validation cohort, among 293 NSTEMI patients who underwent successful early percutaneous revascularization, no patient (0%, 95% confidence interval 0-1.6%) had a serious arrhythmia after revascularization., Conclusion: The incidence of serious arrhythmias in NSTEMI patients after successful early revascularization seems to be very low., (© The European Society of Cardiology 2014.)

Aim: It is unknown whether cardiac troponin (cTn) I or cTnT is the preferred biomarker in the early diagnosis of acute myocardial infarction without ST segment elevation (NSTEMI)., Methods and Results: In a prospective multicentre study, we measured cTnI and cTnT using clinically available high-sensitivity assays (hs-cTnI Abbott and hs-cTnT Roche) and compared their diagnostic and prognostic accuracies in consecutive patients presenting to the emergency department with acute chest pain. The final diagnosis was adjudicated by two independent cardiologists using all information pertaining to the individual patient. The mean follow-up was 24 months. Among 2226 consecutive patients, 18% had an adjudicated final diagnosis of NSTEMI. Diagnostic accuracy at presentation as quantified by the area under the receiver-operating-characteristics curve (AUC) for NSTEMI was very high and similar for hs-cTnI [AUC: 0.93, 95% confidence interval (CI) 0.92-0.94] and hs-cTnT (0.94, 95% CI: 0.92-0.94) P = 0.62. In early presenters (<3 h since chest pain onset) hs-cTnI showed a higher diagnostic accuracy (AUC: 0.92, 95% CI: 0.89-0.94) when compared with hs-cTnT AUC (0.89, 95% CI: 0.86-0.91) (P = 0.019), while hs-cTnT was superior in late presenters [AUC hs-cTnT 0.96 (95% CI: 0.94-0.96)  vs. hs-cTnI 0.94 (95% CI: 0.93-0.95); P = 0.007]. The prognostic accuracy for all-cause mortality, quantified by AUC, was significantly higher for hs-cTnT (AUC: 0.80; 95% CI: 0.78-0.82) when compared with hs-cTnI (AUC: 0.75; 95% CI: 0.73-0.77; P < 0.001)., Conclusion: Both hs-cTnI and hs-cTnT provided high diagnostic and prognostic accuracy. The direct comparison revealed small but potentially important differences that might help to further improve the clinical use of hs-cTn., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: Several high-sensitivity cardiac troponin (hs-cTn) assays have recently been developed. It is unknown which hs-cTn provides the most accurate prognostic information and to what extent early changes in hs-cTn predict mortality., Methods and Results: In a prospective, international multicentre study, cTn was simultaneously measured with three novel [high-sensitivity cardiac Troponin T (hs-cTnT), Roche Diagnostics; hs-cTnI, Beckman-Coulter; hs-cTnI, Siemens] and a conventional assay (cTnT, Roche Diagnostics) in a blinded fashion in 1117 unselected patients with acute chest pain. Patients were followed up 2 years regarding mortality. Eighty-two (7.3%) patients died during the follow-up. The 2-year prognostic accuracy of hs-cTn was most accurate for hs-cTnT [area under the receivers operating characteristic curve (AUC) 0.78 (95% CI: 0.73-0.83) and outperformed both hs-cTnI (Beckman-Coulter, 0.71 (95% CI: 0.65-0.77; P = 0.001 for comparison), hs-cTnI (Siemens) 0.70 (95% CI: 0.64-0.76; P < 0.001 for comparison)] and cTnT 0.67 (95% CI: 0.61-0.74; P < 0.001 for comparison). Absolute changes of hs-cTnT were more accurate than relative changes in predicting mortality, but inferior to presentation values of hs-cTnT. Combining changes of hs-cTnT within the first 6 h with their presentation values did not further improve prognostic accuracy. Similar results were obtained for both hs-cTnI assays regarding the incremental value of changes. Hs-cTn concentrations remained predictors of death in clinically challenging subgroups such as patients with pre-existing coronary artery disease, impaired renal function, and patients older than 75 years., Conclusion: High-sensitivity cardiac Troponin T is more accurate than hs-cTnI in the prediction of long-term mortality. Changes of hs-cTn do not seem to further improve risk stratification beyond initial presentation values.

Background: An association between porphyria cutanea tarda (PCT) and diabetes mellitus (DM) is widely reported, but the pathogenetic link remains unknown., Objectives: To investigate the natural history of DM in the setting of PCT and to determine which PCT features and risk factors may be associated with the development of DM., Methods: This retrospective longitudinal study included 81 Spanish patients with PCT with at least 10 years of strict follow-up. Patients attended our Porphyria Unit for follow-up visits and the data were collected in the period 2004-2008. We classified patients into two groups: patients with glucose metabolism alterations (GMA: DM or impaired fasting glucose), and patients without. PCT features and PCT and DM risk factors were retrieved from clinical charts and compared between groups., Results: We identified 33 patients (41%) with GMA, of whom 27 (82%) developed GMA a long time after the diagnosis of PCT (mean 12·7 years). In bivariate analysis, these patients had significantly higher mean serum ferritin at diagnosis (651 vs. 405 ng mL(-1); P = 0·005), a higher prevalence of persistently elevated serum ferritin (52% vs. 15%; P < 0·001 for trend) and a higher prevalence of family history of DM (48% vs. 19%; P = 0·004). In multivariate analysis, persistently elevated serum ferritin [odds ratio (OR) 10·66, 95% confidence interval (CI) 1·95-58·19; P = 0·006] and family history of DM (OR 4·82, 95% CI 1·34-17·33; P = 0·016) remained significantly associated with the presence of GMA., Conclusions: GMA are highly prevalent in patients with PCT and mostly develop a long time after the diagnosis of PCT. Persistent hyperferritinaemia seems to be a risk biomarker of GMA in patients with PCT, probably in the setting of chronic iron overload and hepatic inflammation. Strict long-term monitoring of glucose metabolism and serum ferritin may be advisable in the routine follow-up of patients with PCT., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

Objectives: The antifungal drug susceptibilities of 351 isolates of Candida species, obtained through active laboratory-based surveillance in the period January 2002-December 2003, were determined (Candida albicans 51%, Candida parapsilosis 23%, Candida tropicalis 10%, Candida glabrata 9%, Candida krusei 4%)., Methods: The MICs of amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole and caspofungin were established by means of the broth microdilution reference procedure of the European Committee on Antibiotic Susceptibility Testing., Results and Conclusions: Amphotericin B and flucytosine were active in vitro against all strains. A total of 24 isolates (6.8%) showed decreased susceptibility to fluconazole (MIC > or = 16 mg/L) and 43 (12.3%) showed decreased susceptibility to itraconazole (MIC > or = 0.25 mg/L). Voriconazole and caspofungin were active in vitro against the majority of isolates, even those that were resistant to fluconazole.

Eighteen patients with lepromatous leprosy (LL) showed a significant reduction (P less than 0.001) of Langerhans cells (LC) irrespective of whether the biopsies were obtained from involved (398 +/- 186) or healthy skin (304 +/- 98). The cells showed morphological changes consisting mainly of loss of dendritic processes. Twenty-four controls (age, sex and race matched) had a mean number of LC of 632 +/- 138. In tuberculoid patients (TT) significant differences were observed, depending on the site of biopsy. Nine biopsies from involved skin had 993 +/- 206 LC, whereas 11 from healthy skin had 448 +/- 96 (P less than 0.001). This difference was confirmed in six additional borderline tuberculoid (BT) and TT patients in whom biopsies were simultaneously obtained from involved (973 +/- 179) and uninvolved skin (498 +/- 99). In 10 patients with indeterminate leprosy the LC density did not differ from the control population (630 +/- 261). The expression of LC numbers in BT and TT patients may represent migration of these cells from healthy skin to involved areas or mobilization of a central pool. The low density found in LL patients could interfere with adequate presentation of mycobacterial antigens leading to tolerance. Alternatively the presence of T helper cells in TT infiltrates may produce factors that recruit LC; their absence in LL lesions may account for the decrease in LC expression.