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Background Early heart failure prevention is central in patients with type 2 diabetes, and mineralocorticoid receptor antagonists (MRAs) have shown to improve prognosis. We investigated the effect of high-dose MRA, eplerenone, on cardiac function and structure in patients with type 2 diabetes and established or increased risk of cardiovascular disease but without heart failure. Methods In the current randomized, placebo-controlled clinical trial, 140 patients with high-risk type 2 diabetes were randomized to high-dose eplerenone (100–200 mg daily) or placebo as add-on to standard care for 26 weeks. Left ventricular systolic and diastolic function, indexed left ventricular mass (LVMi), and global longitudinal strain (GLS) were assessed using echocardiography at baseline and after 26 weeks of treatment. Results Of the included patients, 138 (99%) had an echocardiography performed at least once. Baseline early diastolic in-flow velocity (E-wave) indexed by mitral annulus velocity (e’) was mean (SD) 11.1 (0.5), with 31% of patients reaching above 12. No effect of treatment on diastolic function was observed measured by E/e’ (0.0, 95%CI [-1.2 to 1.2], P = 0.992) or E/A (-0.1, 95%CI [-0.2 to 0.0], P = 0.191). Mean left ventricular ejection fraction (LVEF) at baseline was 59.0% (8.0). No improvement in systolic function was observed when comparing groups after 26 weeks (LVEF: 0.9, 95%CI [-1.1 to 2.8], P = 0.382; GLS: -0.4%, 95%CI [-1.5 to 0.6], P = 0.422), nor in LVMi (-3.8 g/m2 95%CI [-10.2 to 2.7], P = 0.246). Conclusion In the present echo sub-study, no change in left ventricular function was observed following high-dose MRA therapy in patients with type 2 diabetes when evaluated by conventional echocardiography. Trial registration Date of registration 25/08/2015 (EudraCT number: 2015–002,519-14).

Objectives This study investigated the impact of the MR antagonist (MRA) eplerenone on LVM in type 2 diabetes patients at high risk for cardiovascular disease (CVD). Background MRA activat...

To investigate the effects of 13 weeks treatment with empagliflozin in patients with high-risk type-2 diabetes mellitus on echocardiographic measures of left ventricular (LV) structure and function compared to placebo. A total of 91 patients were randomized to treatment with empagliflozin (25 mg/day, n = 45) or matching placebo (n = 45) for 13 weeks. Left ventricular (LV) mass, volumes and geometry as well as measures of LV systolic and diastolic function were measured using echocardiography at baseline and follow up. Mean LV mass index (LVMi) was reduced by − 11.5 g/m2 (95% CI − 56.4; 33.4, p = 0.03) with empagliflozin compared to − 1.4 g/m2 (95% CI − 36.5; 33.8, p = 0.63) for placebo. The proportion of patients with LV hypertrophy was reduced by 16.3% (p = 0.04) in the empagliflozin group compared to 1.1% in the placebo group (p = 1.00). The proportion of patients with left atrial volume index > 34 mL/m2 was reduced by 20.0% (p = 0.02) with empagliflozin compared to 9.5% for placebo (p = 0.45) and the E/e′ ratio decreased (∆-0.8 (1.9) vs. ∆0.5 (2.0), p < 0.01). 13 weeks empagliflozin treatment in patients with type-2 diabetes at high CV risk significantly reduced LV mass, improved LV geometry and improved diastolic function compared to placebo.

Background Sodium–glucose cotransporter 2 inhibitors reduce hospitalizations for heart failure and cardiovascular death, although the underlying mechanisms have not been resolved. The SIMPLE trial (The Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus) investigated the effects of empagliflozin on myocardial flow reserve (MFR) reflecting microvascular perfusion, in patients with type 2 diabetes mellitus at high cardiovascular disease risk. Methods and Results We randomized 90 patients to either empagliflozin 25 mg once daily or placebo for 13 weeks, as add‐on to standard therapy. The primary outcome was change in MFR at week 13, quantified by Rubidium‐82 positron emission tomography/computed tomography. The secondary key outcomes were changes in resting rate‐pressure product adjusted MFR, changes to myocardial flow during rest and stress, and reversible cardiac ischemia. Mean baseline MFR was 2.21 (95% CI, 2.08–2.35). There was no change from baseline in MFR at week 13 in either the empagliflozin: 0.01 (95% CI, −0.18 to 0.21) or placebo groups: 0.06 (95% CI, −0.15 to 0.27), with no treatment effect −0.05 (95% CI, −0.33 to 0.23). No effects on the secondary outcome parameters by Rubidium‐82 positron emission tomography/computed tomography was observed. Treatment with empagliflozin reduced hemoglobin A 1c by 0.76% (95% CI, 1.0–0.5; P P Conclusions Empagliflozin did not improve MFR among patients with type 2 diabetes mellitus and high cardiovascular disease risk. The present study does not support that short‐term improvement in MFR explains the reduction in cardiovascular events observed in the outcome trials. Registration URL: https://clinicaltrialsregister.eu/ ; Unique identifier: 2016‐003743‐10.

Purpose Recovery from aphasia after stroke has a decelerating trajectory, with the greatest gains taking place early and the slope of change decreasing over time. Despite its importance, little is known regarding evolution of language function in the early postonset period. The goal of this study was to characterize the dynamics and nature of recovery of language function in the acute and early subacute phases of stroke. Method Twenty-one patients with aphasia were evaluated every 2–3 days for the first 15 days after onset of acute ischemic or hemorrhagic stroke. Language function was assessed at each time point with the Quick Aphasia Battery (Wilson, Eriksson, Schneck, & Lucanie, 2018), which yields an overall summary score and a multidimensional profile of 7 different language domains. Results On a 10-point scale, overall language function improved by a mean of 1.07 points per week, confidence interval [0.46, 1.71], with 19 of 21 patients showing positive changes. The trajectory of recovery was approximately linear over this time period. There was significant variability across patients, and patients with more impaired language function at Day 2 poststroke experienced greater improvements over the subsequent 2 weeks. Patterns of recovery differed across language domains, with consistent improvements in word finding, grammatical construction, repetition, and reading, but less consistent improvements in word comprehension and sentence comprehension. Conclusion Overall language function typically improves substantially and steadily during the first 2 weeks after stroke, driven mostly by recovery of expressive language. Information on the trajectory of early recovery will increase the accuracy of prognoses and establish baseline expectations against which to evaluate the efficacy of interventions. Supplemental Material https://doi.org/10.23641/asha.7811876

INTRODUCTION Disseminated tumor cells (DTCs) are a subset of circulating tumor cells that migrate to the bone marrow. Colorectal cancer is a heterogeneous disease depending on the site of the primary tumor. OBJECTIVES We aimed to assess the association between the presence of DTCs in the bone marrow and tumor characteristics as well as long‑term treatment outcomes in patients with left‑sided colorectal cancer. PATIENTS AND METHODS This prospective study included 91 patients with left‑sided colorectal cancer (37 with colon cancer and 54 with rectal cancer) treated between 2007 and 2012 in a single tertiary center. Fifteen patients had stage I cancer; 26, stage II; 26, stage III; and 24, stage IV. Overall survival and cancer relapse rates were compared between patients with different cancer stages and DTC status. RESULTS Bone marrow DTCs were identified in 42 patients (46.1%). The prevalence of DTCs was not related to tumor infiltration depth, nodal involvement, distant metastasis, tumor stage, or primary tumor site. The 5‑year overall survival rates were 59.5% and 53% in the DTC‑positive and DTC‑negative groups, respectively (P = 0.19). There was a notable trend favoring survival in patients with DTCs with stage II and III disease (both separately and when combined). The number of metachronous distant metastases was significantly lower in DTC‑positive patients. CONCLUSIONS The presence of DTCs in the bone marrow is not associated with primary tumor characteristics and seems to reduce metastasis formation in left‑sided colorectal cancer. There is also a trend for improved overall survival in DTC‑positive patients. These results are intriguing and warrant further confirmation.

Key Clinical Message Hepatosplenic gamma‐delta T‐cell lymphoma with concurrent hemophogocytic lymphohistiocytosis is a rare but well‐recognized clinical scenario, associated with a grim prognosis. Clinicians must be aware of this aggressive type of lymphoma so that a prompt diagnosis can be made with timely initiation of systemic therapy and referral for bone marrow transplant.

As mineralocorticoid receptor antagonists (MRAs) may possess renoprotective effects in type 2 diabetes (T2D), it was decided to investigate the impact of high-dose MRA on prespecified secondary endpoints-namely, change in urinary albumin-creatinine ratio (UACR) and 24-h ambulatory blood pressure-in the MIRAD trial.This was a double-blind clinical trial in which T2D patients at high risk of or with established cardiovascular disease (CVD) were randomized to either high-dose (100-200 mg) eplerenone or a dose-matched placebo as an add-on to background antihypertensive treatment for 26 weeks. Safety was evaluated by the incidence of hyperkalaemia and kidney-related adverse events.A total of 140 patients were enrolled (70 in each group). Baseline UACR was 17 mg/g (geometric mean; 95% CI: 13-22); this decreased by 34% in the eplerenone group compared with the placebo group at week 26 (95% CI: -51% to -12%; P = 0.005). There was no significant decrease in 24-h systolic blood pressure (SBP) due to treatment (-3 mmHg; 95% CI: -6 to 1; P = 0.150). However, the observed change in 24-h SBP correlated with the relative change in UACR in the eplerenone group (r = 0.568, P 0.001). Mean baseline (± SD) estimated glomerular filtration rate (eGFR) was 85 (± 18.6) mL/min/1.73 mThe addition of high-dose eplerenone to T2D patients at high risk of CVD can markedly reduce UACR with an acceptable safety profile.

Key Clinical Message Vincristine‐induced vocal cord palsy (VCP) is a rare but critical complication. Prompt recognition of VCP is imperative. Vincristine‐induced VCP is reversible, and a complete remission of a lymphoma is still feasible upon withdrawal of vincristine from the chemotherapeutic regimen early in the course of treatment., Vincristine‐induced vocal cord palsy (VCP) is a rare but critical complication. Prompt recognition of VCP is imperative. Vincristine‐induced VCP is reversible, and a complete remission of a lymphoma is still feasible upon withdrawal of vincristine from the chemotherapeutic regimen early in the course of treatment.

Background:We have developed a model of stratified exercise therapy, in which three knee osteoarthritis (OA) subgroups (i.e., ‘high muscle strength subgroup’, ‘low muscle strength subgroup’ and ‘obesity subgroup’) can be distinguished and provided a subgroup-specific intervention. Currently, the (cost-)effectiveness of this model compared to usual exercise therapy is tested in a large-scaled randomized controlled trial (OCTOPuS-study [1]). Alongside this trial, we performed a qualitative study to explore perceived barriers and facilitators of the application of this model in primary care.Objectives:To explore barriers and facilitators of the application of this model in primary care, as perceived by patients, physiotherapists and dieticians.Methods:Qualitative data were collected through semi-structured interviews in a random sample of 15 patients (5 from each subgroup), 11 physiotherapists and 5 dieticians, from the experimental arm of the OCTUPuS trial. A thematic analysis of the data was performed.Results:We identified 14 themes in 5 categories. In general, patients and therapists were positive about the added value and applicability of the model, although some physiotherapists would prefer more flexibility. Regarding the ‘high muscle strength subgroup’, both patients and physiotherapists reported mixed feelings on the low number of supervised sessions, with some perceiving this low number as advantageous for stimulating the patient’s own responsibility, whereas others as hindering an optimally guided treatment. Regarding the ‘obesity subgroup’, dieticians and physiotherapists acknowledged the added value of the combined intervention, but both were disappointed by the lack of interdisciplinary collaboration. Moreover, those patients in this subgroup already following a diet restriction, therefore not perceiving any added value of the diet intervention.Conclusion:This qualitative study revealed relevant barriers and facilitators of our new model of stratified exercise therapy, which will help us interpreting the upcoming results on its (cost-) effectiveness [1]. If proven to be (cost-)effective, implementation strategies should specifically focus on guidance of patients from the ‘high muscle strength subgroup’ within only a few sessions, collaboration between physiotherapist and dietician in the ‘obesity subgroup’, and adequate use of booster sessions after the supervised period to optimize treatment adherence.References:[1]Knoop J, Dekker J, van der Leeden M, de Rooij M, Peter WFH, van Bodegom-Vos L, van Dongen JM, Lopuhäa N, Bennell KL, Lems WF, van der Esch M, Vliet Vlieland TPM, Ostelo RWJG. Stratified exercise therapy compared with usual care by physical therapists in patients with knee osteoarthritis: A randomized controlled trial protocol (OCTOPuS study). Physiother Res Int. 2020 Apr;25(2):e1819. doi: 10.1002/pri.1819. Epub 2019 Nov 28.Disclosure of Interests:None declared

Background:According to international recommendations, the Ankylosing Spondylitis Disease Activity Score (ASDAS) is the preferred score for assessing disease activity in axial spondyloarthritis (axSpA) [1]. However, routine determination of C-reactive protein (CRP) to calculate ASDAS values takes hours to days. This limits the use of ASDAS in clinical routine and clinical trials and hinders the implementation of treat-to-target approaches in axSpA. Whereas quick quantitative CRP (qCRP) tests allow CRP assessment within a few minutes. In a pilot project the performance of qCRP-based ASDAS assessment (ASDAS-qCRP) was already investigated in a single center study of 50 newly diagnosed, bDMARD-naïve axSpA patients with promising results [2].Objectives:To validate the ASDAS-qCRP in a prospective, multicenter study of axSpA patients in a typical axSpA cohort with an appropriate sample size.Methods:The study was conducted in five centers in Germany. Consecutive adult (≥ 18 years) axSpA patients were included. In addition to a rheumatological assessment, including patient reported outcomes (PROs), routine CRP and erythrocyte sedimentation rate (ESR) were measured in the local labs. Additionally, a qCRP testing with the „QuikRead go instrument“ (Aidian Oy, Finland) was performed at the study center (measurement range 0.5 - 200 mg/l for hematocrit concentrations of 40 – 45%). Statistical analysis included descriptive statistics, cross tabulation and weighted Cohen´s kappa comparing disease activity categories, Bland-Altman plots and intraclass correlation coefficient (ICC) for ASDAS-CRP and ASDAS-qCRP.Results:In this study 251 axSpA patients were included between January and September 2020 (mean age: 38.4 years; mean disease duration: 6.2 years, 159 patients (63.3%) were male, 211 (84.1%) HLA-B27 positive and 195 (77.7%) were classified as radiographic axSpA). 143 patients (57.0%) were treated with bDMARDs. CRP and qCRP showed mean values of 2.12 and 2.17 mg/l, respectively. With the ASDAS-qCRP, 242 patients (96.4%) were assigned to the same disease activity category as compared to the ASDAS based on the conventional lab CRP measurement (Table 1). Weighted Cohen´s kappa was 0.966 (95%CI: 0.943; 0.988). ICC for ASDAS-CRP- and ASDAS-qCRP-values was 0.997 (95%CI: 0.994; 0.999). The agreement of ASDAS-qCRP and ASDAS-CRP is shown in a Bland-Altman plot (Figure 1).Table 1.Disease activity categories by ASDAS-qCRP vs. ASDAS-CRPASDAS-qCRP (n = 251)Inactive Disease(< 1.3)Low Disease Activity (1.3 - < 2.1)High Disease Activity (2.1 - 3.5)Very high Disease Activity (> 3.5)ASDAS-CRPInactive Disease(< 1.3)56 (22.3%)2 (0.8%)Low Disease Activity (1.3 - < 2.1)62 (24.7%)7 (2.8%)High Disease Activity (2.1 - 3.5)97 (38.6%)Very high Disease Activity (> 3.5)27 (10.8%)The fields highlighted in red indicate that disease activity categories do not match.ASDAS = Ankylosing Spondylitis Disease Activity Score, CRP = C-reactive protein, qCRP = quick quantitative CRPConclusion:The ASDAS-qCRP and ASDAS-CRP showed an almost perfect agreement on the assignment to disease activity categories (96%) with the important advantage of time. With ASDAS-qCRP, rheumatologists could base their clinical decision-making on a disease activity measurement by using a composite score immediately. ASDAS-qCRP, therefore, can be integrated in clinical routine and clinical trials in the future and may facilitate implementation of the treat-to-target concept in axial SpA.References:[1]Smolen JS, et al. Ann Rheum Dis. 2018 Jan; 77(1):3-17.[2]Proft F, et al. Joint Bone Spine. 2019 Jul 29.Figure 1.Bland-Altman plot for ASDAS-qCRP and ASDAS-CRPAcknowledgements:The authors would like to deeply thank Braun T, Doerwald C, Deter N, Höppner C, Lackinger J, Lorenz C, Lunkwitz K, Mandt B, Sron S and Zernicke J for their practical support and coordinating the study.Funding statement: The AQUA study was supported by an unrestricted research grant from Novartis. Testing kits were provided free of charge from Aidian Oy, Finland.Disclosure of Interests:None declared

AIMS: The DANPACE trial randomized patients with sick sinus syndrome (SSS) to single lead atrial (AAIR) or dual chamber (DDDR) pacemaker (PM). After 5 years follow-up, no difference in overall survival, stroke or heart failure (HF) was observed, whereas risk of atrial fibrillation (AF) and PM reoperation were increased in the AAIR group. The present study aimed to investigate very long term risk of death, AF hospitalization, stroke, HF and rate of change in pacing mode using national register-based data.METHODS AND RESULTS: The study population consisted of all 1384 patients included at Danish PM centres in the DANPACE trial randomized to AAIR (n = 696) or DDDR (n = 688). Long-term follow-up data was obtained from Danish national registers. Analysis was intention-to-treat.RESULTS: During mean follow-up of 8.9 years, 413 patients (59.3%) died in the AAIR-group compared to 367 (53.3%) in the DDDR-group (adjusted hazard ratio 1.03; 95% confidence interval 0.90-1.19; P = 0.65). We observed no difference in risk of AF hospitalization, stroke or HF. During extended follow-up, annual rate of pacing mode change to DDDR in the AAIR group was 4.5%, and higher than the 2.3% observed during trial conduct.CONCLUSION: This register-based long-term follow-up study indicates that there is no difference in mortality among patients with SSS randomized to AAIR or DDDR pacing, even with very long follow-up. Nor is there any difference in risk of AF hospitalization, stroke or HF. The higher rate of pacing mode-change to DDDR in the AAIR group suggests a different management of patients with an AAIR PM after the DANPACE trial.

Objectives: Primary myelofibrosis is rare in pediatrics, often manifesting as persistent idiopathic thrombocytosis.Transitions from pediatric to adult medical care can be complicated by workup requiring invasive procedures. J.M., an 18-year-old healthy male, presented for excessive gingival bleeding after wisdom tooth extraction. Workup revealed persistent thrombocytosis to 1,165K, prompting a referral to hematology-oncology. A peripheral smear was notable for many platelets but normal RBC morphology. He had splenomegaly on abdominal ultrasound and a decreased von-Willebrand's activity to antigen ratio, suggesting acquired vWD. A bone marrow biopsy was advised; however, J.M. became lost to follow up for over 9 months owing to self-reported anxiety about the procedure. He remained asymptomatic in this interim until he re-presented to clinic for easy bruising, with no other evidence of bleeding at the time. The biopsy was pursued, revealing hypercellular marrow for age with left shifted granulocytic and erythroid maturation, abnormal megakaryocytes, and 3% blasts. This was consistent with primary early myelofibrosis (PMF), positive for MF-1, CALR, and TP53 mutations and negative for JAK2 and BCR-ABL. He was transitioned to adult hematology, maintained on baby aspirin, and referred for potential allogeneic hematopoietic stem cell transplant (HSCT). PMF is characterized by marrow fibrosis due to secretion of fibroblast growth factor by clonally proliferative megakaryocytes. It is a disease of adulthood, with 67 years being the median age at diagnosis. Only 100 cases have been reported in children, most of which are secondary to AML, ALL or other malignancies.1 Most patients present with complications of extramedullary hematopoiesis or bleeding.2 Diagnosis is suggested by a leukoerythroblastic picture on peripheral smear and confirmed with a bone marrow biopsy "dry tap" revealing marrow fibrosis.3 Prognosis in pediatric PMF is difficult to predict but outcomes tend to be worse;4 TP53 mutation is rare and based on limited adult studies may portend a poorer prognosis.5 Our young patient with this rare mutation was therefore referred for HSCT evaluation. Further complicating this case was J.M.'s anxiety, which delayed definitive diagnosis by biopsy. He only agreed to it when, at the med-peds clinic, the concept of local pain management was discussed. Anticipation of upcoming procedures by primary care physicians and close follow-up is especially important for patients transitioning from pediatric to adult providers. Disclosures No relevant conflicts of interest to declare.

This study was aimed at investigating the frequencies of non-radiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) diagnoses and their ratios in relation to symptom duration in patients referred because of chronic back pain and suspicion of axial SpA.In this monocentre study, orthopaedists and primary care physicians were requested to refer patients with chronic low back pain (duration3 months) and onset of back pain before 45 years of age to a SpA-specialised rheumatology outpatient clinic for further diagnostic investigation, if proposed screening parameters were present. The ratio of nr-axSpA to AS was analysed in relation to the duration of symptoms.A diagnosis of definite axial SpA was made in 43.7% of the referred patients (n=522). Axial SpA was diagnosed in a similar percentage of about 50% if back pain duration was9 years but decreased to 36% if symptom duration was9 years. Nr-axSpA represented the majority of patients (67.3%) only if duration of back pain was 1 year and less at the time of referral. Between 1 and 6 years of back pain duration the probability of nr-axSpA and AS was nearly equal (1-3 years: 52.5% and 47.5%, respectively; 3-6 years: 53.7% and 46.3%, respectively). In patients with back pain duration of 6-9 years, AS was more likely (61.1%) to be diagnosed than nr-axSpA (38.9%), and this increased further over time.Non-radiographic axial SpA represents an important differential diagnosis of back pain, especially in patients with recent symptom onset.

Ankylosing spondylitis (AS) and its early form account for up to 5% of all patients with chronic back pain. Interest has recently focused on shortening the delay of 5-10 years between the appearance of first symptoms and the diagnosis of AS, particularly because effective treatments have now become available. Referral parameters that are easy for doctors in primary care to apply to patients presenting with possible AS could contribute to earlier diagnosis.Orthopaedists and primary-care doctors were requested to refer patients with (1) chronic low back pain (duration3 months) and (2) onset of back pain before45 years of age to a specialist rheumatology outpatient clinic for further diagnostic investigation if at least one of the following screening parameters was present: (1) inflammatory back pain, (2) positive human leucocyte antigen B27, and (3) sacroiliitis detected by imaging. The final diagnosis was made according to expert opinion.In total, 350 referred cases were analysed. A diagnosis of definite axial spondyloarthritis (axial SpA), comprising established AS and pre-radiographic axial SpA, could be made in 45.4% of all referred patients (of which 50.3% were classified as AS and 49.7% as preradiographic axial SpA), whereas 45.4% were classified as non-SpA and 9.1% as possible SpA. A diagnosis of definite axial SpA could be made in 34.2% if only one referral parameter was positive, and in 62.6% if there was1 positive referral parameter.The proposed referral parameters have proven useful when applied in primary care in identifying patients with AS/pre-radiographic axial SpA among young to middle-aged patients with chronic low back pain.

Introduction Chemokines are cytokines with chemotactic functions in the initiation and maintenance of immune reactions. They have also been shown to regulate other processes such as cancer progression and cancer cell migration. Objectives The aim of this study was to determine the prognostic role of serum levels of chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-C motif) ligand 5 (CCL5) in patients with colorectal cancer. Patients and methods The study included a group of 45 patients with colorectal cancer. The serum concentrations of CCL2 and CCL5 were measured preoperatively. Peripheral blood mononuclear cells (PBMC) from patients' blood were isolated and cultured alone or with cancer cells. The concentrations of chemokines in serum and culture supernatants were measured using the cytometric bead array method. The cut-off points for serum chemokine levels were set based on the receiver-operating characteristic curve analysis at a level of 103.6 pg/ml for CCL2 and of 11933.2 pg/ml for CCL5. The survival analysis and multivariate analysis of prognostic factors were performed. Results The 5-year survival was 57.5% for the group with low CCL2 levels and 23.87% for the group with high CCL2 levels. For the groups with low and high CCL5 levels, the survival was 18.3% and 49.3%, respectively. For CCL2, the survival of the low-level group was significantly better than that of the highlevel group (P = 0.0028). In the Cox proportional hazard model, radicality of resection (P = 0.001) and CCL2 levels (P = 0.029) were independent prognostic factors. Conclusions The serum level of CCL2 in patients with colorectal cancer may have prognostic value. One of the possible mechanisms of CCL2 production is the interaction of PBMC with cancer cells.

Zusammenfassung: Polyposis und chronisch inflammatorische Darmerkrankungen, die bereits im Alter von 2 bis 5 Jahren beginnen konnen, pradisponieren fur kolorektale Karzinome in der 4. und 5. Lebensdekade. Bei der Polyposis wird eine Mutation in dem Tumorsuppressorgen (TSG) APC (adenomatous polyposis coli gene) in der Lymphozyten-DNA gefunden. Bei der ulcerativen Kolitis tritt meistens eine Mutation im TSG p53 als erster Hinweis auf die Krebsentstehung auf. Das hereditare nicht-polypose Kolonkarzinom (HNPCC), das 5 % aller kolorektalen Karzinome umfasst, wird durch die Inaktivierung in DNA-Reperaturgenen (MMR) hervorgerufen, welche durch eine Instabilitat von polymorphen einfachen repetitiven Sequenzen in der DNA nachweisbar ist. Zur Karzinomentstehung mussen zu den Keimbahnmutationen weitere Mutationen in Genen wie ras, DCC, MCC und p53 hinzukommen. Es wurden Labormethoden etabliert, die den Nachweis von Mutationen in TSG und MMR ermoglichen. Man muss dabei die direkte Bestimmung einer Mutation mittels Sequenzierung mit fluoreszenz-markierten Didesoxy-Nukleotiden von indirekten Methoden wie dem Protein Truncation Assay oder der denaturierenden HPLC unterscheiden. Positive Ergebnisse mit den indirekten Methoden mussen stets durch Sequenzierung bestatigt werden. Alle Methoden sind auf Lymphozyten-DNA und DNA aus Gewebe von Polypen, Adenomen und Karzinomen anwendbar. Patienten mit einer nachgewiesenen Mutation in TSG oder MMR tragen ein hohes Karzinomrisiko, sollten engmaschig kontrolliert werden und eine konsequente Behandlung der Primarerkrankung ist notwendig. Bei Patienten mit einer APC-Mutation wird eine grose Variabilitat der Zeitspanne bis zum Ausbruch des Karzinoms beobachtet. Aufgrund von Ergebnissen an Mausmodellen, die eine Mutation im APC-analogen Gen der Maus tragen, kann man auf die Existenz von Tumor-modifier Genen auch beim Menschen schliesen, die mit den TSG und MMR kooperieren. Uber sie konnte in Zukunft eine individuellere Bestimmung des Karzinomrisikos und auch der Progredienz von bestehenden Karzinomen moglich werden. Summary: Polyposis and chronic inflammatory large bowel diseases with its earliest onset at age 2 to 5 are prone for cancer development in the thirties or forties. In polyposis, one allele of the tumor-suppressor gene (TSG) adenomatous polyposis coli gene (APC) is already inactivated in the germ line, whereas in ulcerative colitis the p53 TSG is affected in the inflammatory tissue. Hereditary non-polyposis colorectal cancer, comprising 5 % of all cancer cases, is caused by mutations in mismatch repair genes (MMR) which is detectable by a genetic instability of simple sequence polymorphic DNA stretches. Subsequent mutations have to follow accidentally to develop the complete malignant phenotype: ras, DCC (deleted in colon cancer, Chr. 18q), MCC (mutated in colon cancer, Chr. 5q), and p53 mutations are required for full malignant transformation. Laboratory methods have been established to determine the TSG and MMR mutations. Using direct sequencing methods such as the didesoxy-nucleotides and indirect methods such as the protein truncation assay or denaturating HPLC most of the mutations are detectable. The methods are applicable to DNA from lymphocytes, tissue from polyps, adenomas, and cancer. Patients indicated to harbor TSG or MMR mutations are at high risk, and as a consequence, short-term follow-up and, if detectable, consequent treatment of the primary disease is necessary. In respect to individuals inheriting an APC mutation predisposing to colorectal cancer different outcomes are observed, ranging from early aggressive cancer to disease-free survival. This might be explained by the cooperation of TSGs and MMRs with tumor-modifier genes. Tumor-modifier genes were identified from investigations of the genetic background effects on phenotypic expression in mice carrying a point mutation in the mouse equivalent of the APC gene (APCMIN) and could provide us with genetic markers with which individuals could be tested for disease susceptibility or tumor progression.

Inflectional morphology lies at the intersection of phonology, syntax and the lexicon, three language domains that are differentially impacted in the three main variants of primary progressive aphasia (PPA). To characterize spared and impaired aspects of inflectional morphology in PPA, we elicited inflectional morphemes in 48 individuals with PPA and 13 healthy age-matched controls. We varied the factors of regularity, frequency, word class, and lexicality, and used voxel-based morphometry to identify brain regions where atrophy was predictive of deficits on particular conditions. All three PPA variants showed deficits in inflectional morphology, with the specific nature of the deficits dependent on the anatomical and linguistic features of each variant. Deficits in inflecting low-frequency irregular words were associated with semantic PPA, with lexical/semantic deficits, and with left temporal atrophy. Deficits in inflecting pseudowords were associated with non-fluent/agrammatic and logopenic variants, with phonological deficits, and with left frontal and parietal atrophy.

Objective.To assess the diagnostic value for axial spondyloarthritis (SpA) of unilateral sacroiliitis in scintigraphy in daily clinical practice.Methods.In 207 patients with chronic back pain, the diagnostic value of scintigraphy was assessed retrospectively. The diagnosis made by the rheumatologist (axial SpA vs no axial SpA) was the standard.Results.Sensitivities of scintigraphy for any (unilateral or bilateral), bilateral, and isolated unilateral sacroiliitis were 64.9%, 40.2%, and 24.7%, respectively. Respective specificities were 50.5%, 57.7%, and 92.8%, resulting in likelihood ratios of 1.3, 1.0, and 3.4.Conclusion.Scintigraphy of the sacroiliac joints is of limited value for the diagnosis of axial SpA. Unilateral compared to bilateral sacroiliitis is slightly superior, but is associated with a low sensitivity.

This multicentre, double-blind, randomized study compared the pharmacokinetics of itraconazole given at 200 mg once daily for 3 months and intermittently at 200 mg twice daily for 1 week per month followed by a 3-week drug-free period for 3 months in the treatment of onychomycosis. Patients were followed for 9 months after treatment. Itraconazole and hydroxy-itraconazole plasma concentrations and itraconazole nail tip concentrations were determined at regular intervals. With intermittent therapy (n = 64), increases of consistent magnitude were seen in the mean itraconazole and hydroxy-itraconazole plasma concentrations at the end of each 1-week treatment phase; values returned towards baseline during each subsequent 3-week drug-free period. The mean concentration of itraconazole in fingernail tips increased steadily from week 4, reached a maximum value at week 24 (213 ng/g), declined sharply between weeks 24 and 36 and returned to baseline by week 48; the mean concentration profile was similar for toenail tips (maximum value 305 ng/g at week 24) but decreased at a slower rate. With continuous therapy (n = 65), steady-state mean plasma concentrations of itraconazole and hydroxy-itraconazole were obtained within 4-5 weeks of the start of treatment and remained reasonably constant between weeks 4 and 12. The mean concentration of itraconazole in fingernail tips reached a maximum value at week 12 (524 ng/g) and returned towards baseline by week 48; in contrast, the maximum mean concentration of itraconazole in toenail tips was 698 ng/g at week 36 and did not return to baseline by week 48. No clear relationship was observed between response to treatment and concentration of itraconazole or hydroxy-itraconazole in plasma or itraconazole in nails, suggesting that concentrations exceeded therapeutic levels. In conclusion, intermittent therapy resulted in higher maximum itraconazole plasma concentrations but lower total drug exposure, and hence lower itraconazole nail concentrations, than continuous therapy. However, the intermittent schedule was not associated with a lower cure rate, which indicates that itraconazole nail concentrations remained within the therapeutic range.

In this multicentre, double-blind, parallel group study, we evaluated the efficacy and safety of continuous treatment with itraconazole, 200 mg daily for 3 months, in comparison with itraconazole pulse therapy, 400 mg daily 1 week per month for 3 months, in the treatment of toe-nail onychomycosis. The study included 129 patients with distal subungual onychomycosis of the toe-nails, confirmed by microscopy and positive for dermatophyte culture; 65 received continuous treatment and 64 received pulse therapy. Patients were followed up for 9 months after treatment. After 12 months, there were 62 evaluable patients in the continuous group and 59 evaluable patients in the pulse group. The clinical response (i.e. the size of the affected area and the progress of the infection) and mycological cure (i.e. negative results on microscopy and culture) were the main outcome measures. A clinical response was defined as a cure or a marked improvement. Clinical response rates were 69%, in the continuous group, and 81% in the pulse group at month 12; the corresponding mycological cure rates were 66 and 69%. A better improvement in signs and symptoms was noted in the pulse group. Six patients were withdrawn from treatment because of adverse events, not all of which were thought to be drug-related. There were no clinically relevant laboratory abnormalities. We conclude that both regimens are effective, safe and well tolerated. The superiority of one treatment over the other was not established, but the results tended to favour pulse therapy. Equivalence testing confirmed that pulse therapy was at least equivalent to continuous treatment.

BackgroundAnorexia nervosa (AN) is associated with behavioral traits that predate the onset of AN and persist after recovery. We identified patterns of behavioral traits in AN trios (proband plus two biological parents).MethodA total of 433 complete trios were collected in the Price Foundation Genetic Study of AN using standardized instruments for eating disorder (ED) symptoms, anxiety, perfectionism, and temperament. We used latent profile analysis and ANOVA to identify and validate patterns of behavioral traits.ResultsWe distinguished three classes with medium to large effect sizes by mothers' and probands' drive for thinness, body dissatisfaction, perfectionism, neuroticism, trait anxiety, and harm avoidance. Fathers did not differ significantly across classes. Classes were distinguished by degree of symptomatology rather than qualitative differences. Class 1 (~33%) comprised low symptom probands and mothers with scores in the healthy range. Class 2 (~43%) included probands with marked elevations in drive for thinness, body dissatisfaction, neuroticism, trait anxiety, and harm avoidance and mothers with mild anxious/perfectionistic traits. Class 3 (~24%) included probands and mothers with elevations on ED and anxious/perfectionistic traits. Mother–daughter symptom severity was related in classes 1 and 3 only. Trio profiles did not differ significantly by proband clinical status or subtype.ConclusionsA key finding is the importance of mother and daughter traits in the identification of temperament and personality patterns in families affected by AN. Mother–daughter pairs with severe ED and anxious/perfectionistic traits may represent a more homogeneous and familial variant of AN that could be of value in genetic studies.

Objective: To examine the potential therapeutic effect of methotrexate 20 mg given weekly as subcutaneous injections to 20 patients with ankylosing spondylitis refractory to non-steriodal antirheumatic drugs. Patients and methods: 20 patients with ankylosing spondylitis, a mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 5.6 (range 4–9.3) and predominantly axial manifestations were treated with weekly 15 mg methotrexate subcutaneously for 4 weeks, which was then increased to 20 mg subcutaneously for the next 12 weeks. Clinical outcome assessments included, among others, BASDAI score physical function, spinal mobility, patients’ and physicians’ global assessment (visual analogue scale), peripheral joint assessment, quality of life (Short Form 36) and C reactive protein. The primary end point of the study was a 20% improvement on the ASsessments in Ankylosing Spondylitis (ASAS 20) scale. Results: Using an intention-to-treat analysis, ASAS 20 was achieved in only 25% of patients. An ASAS 40 response was achieved in 10% of patients, and no patient reached an ASAS 70 response or the ASAS criteria for partial remission. For the mean BASDAI score, no change was observed between baseline and week 16 (baseline 5.6 v week 16, 5.6). No improvement was observed in any of the clinical parameters or C reactive protein, except a small but non-significant decrease in the number of swollen joints. Conclusions: In this open study, methotrexate did not show any benefit for axial manifestations in patients with active ankylosing spondylitis beyond the expected placebo response.

Moderate to severe papulopustular acne requires systemic and long-term treatment, the first choice therapy most often being tetracycline. In this double-blind randomized parallel-group study a new erythromycin derivative, erythromycin acistrate (EA), a 2′-acetyl ester prodrug of erythromycin, was compared with routine tetracycline treatment. The study group comprised 60 patients with moderate or severe acne who were treated for up to 6 months. One patient in each treatment group was completely cured within the first 3 months. After 6 months' treatment a further patient in the tetracycline group was completely cured. There were no significant changes in laboratory test values. Both drugs were well tolerated: one patient in each treatment group discontinued treatment due to diarrhoea during the first week. EA is a safe and well-tolerated alternative to tetracycline for the systemic treatment of acne.

Background Between first symptoms and making a diagnosis of axial spondyloarthritis (SpA) there is still a delay of 5-7 years. Effective treatments for active disease have become available. Several strategies for making an earlier diagnosis have been proposed (1), focusing on primary care physicians and orthopaedists and having proven effectiveness in daily clinical practice (2, 3). Objectives To evaluate the performance of a patient-based online-questionnaire in identifying patients with axial SpA. Methods Patients suffering from chronic low back pain without diagnosis were asked to complete an online-questionnaire offered on the homepage of our rheumatologic clinic asking, among other parameters, for onset and duration of back pain, type of back pain, presence of other SpA-typical manifestations, elevated ESR or CRP, HLA-B27-positivity, and results of imaging (if available). Following a recent published diagnostic algorithm, the likelihood ratios of these features and the post test probability (PTP) were automatically calculated (1). Patients achieving a PTP of ≥50 received an identification number and were recommended to present to our clinic for further work-up. Results To date 97 cases were collected and diagnosed. Of these, 14 were diagnosed as axial SpA (n=14/97: 14.4%); 7 fulfilling the modified New York Criteria and 7 being diagnosed as early axial SpA. In 79 of 97 patients an axial SpA was excluded and 4 of 89 patients were diagnosed as possible axial SpA. Of the diagnosed axial SpA patients, 10 of 14 (71.4%) had reached a calculated PTP of ≥90; but also 3 out of 4 (75%) with possible axial SpA and 36 of 79 (45.6%) patients with a diagnosis of non-SpA presented with a PTO of ≥90. If only focussing on those patients presenting with a PTP of ≥90 (n=49), a diagnosis of axial SpA was made in 20,4% (n=10/49) Thus, the rheumatologist would have to see 5 referred patients to identify one axial SpA patient. The sensitivity of such an approach would be 71.4% (10 out of 14). In the patients with a PTP of ≥90 and excluded diagnosis of axial SpA (n=36) other inflammatory diagnoses like psoriatic arthropathy/arthritis (n=7) or peripheral SpA (n=2) were made, partly explaining the high PTP. Conclusions A patient-based online-questionnaire to identify patients with axial spondyloarthritis (SpA) in patients with chronic low back pain seems to be of limited value resulting in relatively low percentage of diagnosed axial SpA patients, in comparison to referral programmes in collaboration with primary care physicians (2,3). References Rudwaleit M. et al. Ann Rheum Dis. 2004 May;63(5):535-43. Brandt H et al. Ann Rheum Dis. 2007 Nov;66(11):1479-84. Poddubnyy D, et al. J Rheumatol. 2011 Nov;38(11):2452-60. Disclosure of Interest None Declared

Background Non-radiographic axial spondyloarthritis (nr-axSpA) and radiographic axial SpA (=ankylosing spondylitis – AS) are considered currently as two stages of axial SpA. We reported recently that about 12% of the patients with non-radiographic axial SpA progress in AS over 2 years [1]. Although it can be expected that in the first years after back pain onset non-radiographic (without definite sacroiliitis on the x-ray) SpA is more likely to see than established AS, their frequencies and their ratio in relation to back pain duration at the referral time point is not known. Objectives To estimate the ratio of nr-axSpA and AS diagnoses in relation to the symptom duration in patients referred to a rheumatologist because of chronic back pain and suspicion of axial SpA. Methods In this monocenter study performed in Berlin [2] orthopaedists and primary care physicians were requested to refer patients with chronic low back pain (duration >3 months) and onset of back pain before Results In total, 522 patients were referred. A diagnosis of definite axial SpA was made in 43.7% of the cases. Among patients who were referred with chronic back pain axial SpA was diagnosed in a similar percentage of about 50% if symptom (back pain) duration was 9 years. The ratios of nr-axSpA to AS among patients with definite axial SpA in relation to the duration of back pain at the time-point of referral are presented in figure. Nr-axSpA represented the majority of patient (67.3%) only if duration of back pain was 1 year and less at the time of referral. Between 1 and 6 years of back pain duration the probability of nr-axSpA and AS was nearly equal. In patients with back pain duration of more than 6 years, AS was more likely to be diagnosed than nr-axSpA, and this increased further over time. Conclusions Non-radiographic axial SpA is a relevant diagnosis in patients with axial SpA at any time point, however, the probability of non-radiographic form of axial SpA is highest if symptom duration is short. References Poddubnyy D, et al. Ann Rheum Dis 2011;70:1369-74. Brandt HC, et al. Ann Rheum Dis 2007;66:1479-84. Disclosure of Interest None Declared

The influence of intestinal bacteria on acute graft vs host disease (GvHD) after human marrow transplantation currently remains controversial. Clinical trials on the role of intestinal bacterial decontamination in human marrow transplant recipients led to inconsistent results as a consequence of non-uniform definitions of decontamination efficacy, varying microbiological techniques for isolation, quantification and differentiation of the intestinal flora, small patient numbers and differing patient populations [1–4]. In addition, most of these analyses did not take other potential factors influencing the pathogenesis of acute GvHD into account.

A 43 year-old, white man presented with a four month-history of six plaques well-circumscribed. Laboratory results, includingseveral serological tests, as well as a radiological investigation, were either negative or normal. The Mitsuda reaction was po sitive (9mm). He was put on prednisone therapy and multi-drug therapy (MDT) with subsequent healing of the cutaneous lesions andimprovement of the neuritis in about six months. The diagnostic hypothesis was reactional tuberculoid leprosy (Figure 1).

Albendazole chemotherapy of larval Echinococcus multilocularis was studied in the Mongolian jird by administration of medicated feed at various concentrations and durations. The effects were evaluated by comparison of treated and control groups in terms of host mortality, larval metastases to the lungs, and final weight and histologic appearance of larval tissue. Viability of larval tissue at necropsy of each animal was tested by inoculation into two noninfected jirds. Albendazole-medicated feed (0.05%-0.10%) significantly inhibited larval growth. Other effects of the drug included larval degeneration and necrosis, inhibition of protoscolex formation, decreased pulmonary metastases, and reduced mortality of hosts. Adverse effects on the parasite correlated significantly with serum albendazole metabolite levels and duration of therapy. However, serum albendazole levels in jirds equal to or exceeding concentrations achieved in humans receiving daily doses of 10 mg/kg of body weight did not kill the parasite.

Groups of ferrets inoculated with Dracunculus insignis were treated with various anthelminthic compounds to evaluate the potential use of drugs in controlling the human parasite D. medinensis. The three primary compounds tested were diethylcarbamazine (DEC), albendazole (ALBZ), and ivermectin (IVER); they were administered in dosages of 60 mg/kg, 10 mg/kg, and 1 mg/kg, respectively. Groups of animals received treatment either once at 60 days after inoculation, once at 60 and 90 days, or for 3 days at either 60 or 90 days postinoculation. The most marked decrease occurred in the animals that received treatment once at 60 and at 90 days after inoculation. This was observed for all three drugs tested. Increased dosages, i.e., 3 days of treatment at 60 or 90 days did not result in decreased worm burdens. In no group was there a statistically significant reduction in worm burden when compared with controls. Two other compounds, metrifonate and CGP 6140, were tested in a more limited manner, but again the worm recovery rates were comparable with those in control groups. It would appear that existing drugs commonly used to treat helminthic infections are poor candidates for use in the campaign to eradicate guinea worm disease.

Involvement of the sacroiliac joints is a hallmark of the spondyloarthropathies, especially in ankylosing spondylitis. The conventional diagnostic imaging of sacroiliitis in early stages might cause problems, because sensitivity of conventional radiographic methods is known to be too low in early stages of the disease. Magnetic resonance imaging of the sacroiliac joints certainly enables one to detect acute as well as chronic inflammatory changes in all stages of the disease. The potential disadvantages of this method are the dependency on the examiner, the lack of standardization, and the relatively high costs. Therefore, the "Workgroup of Diagnostic Imaging in Rheumatology of the Regional Center of Rheumatology of Berlin" including experienced rheumatologists, skeletal radiologists, and orthopedists acquired an imaging graduation for detection of sacroiliitis in consideration of the clinical background, the technical details of the methods, questions of ionizing radiation exposure, and cost effectiveness.

Infection with Dracunculus insignis was established in 7 of 10 ferrets experimentally inoculated intraperitoneally with 10 third-stage larvae (L3's). Worm recovery and infection rate were comparable to animals inoculated with 50 L3's. This study demonstrates that once infective larvae traverse the gut and pass into the peritoneal cavity, very few larvae are required to establish infection.

From 106 ferrets experimentally infected with Dracunculus insignis, 273 female worms and 42 male worms were recovered. The percentage of female worms that mated, the location of all worms, and the rate of emergence of gravid females were recorded. Of 174 mature female worms recovered, only 11% had emerged before necropsy. Eighty-one percent of the male worms and 87% of all unmated (immature) females were found on the trunk of the animal or on the skin overlying it. Gravid female worms were found on the extremities (legs) 88% of the time. Almost one-third of gravid female worms were found on the left front leg. On 4 occasions, females were found in unusual locations: the tail, the cheek, the lumbar region of the spinal cord, and the peritoneal cavity associated with the omentum. The results showed that only a small percentage of mature female worms emerge, which suggests that infected persons harbor many more gravid female worms than indicated by reports of emergent worms. More than one-third of female worms were not mated, but it is likely that these immature females would be capable of further development. Furthermore, male worms have been observed to survive for up to 330 days, suggesting that male or unmated female worms may carry over from one transmission season to the next.

A family study was prompted by the presence of benign recurrent intrahepatic cholestasis in three members and probably in a fourth. Pruritus and/or jaundice occurred during pregnancy in nine members. Two additional members suffered from pruritus while using oral contraceptives. The literature on benign recurrent intrahepatic cholestasis since 1959 describes at least 57 cases. A familial form of this condition proved to be fairly common. There seems to be a relation to the intrahepatic cholestasis sometimes seen during pregnancy and during oral contraceptive use. The data of the family study are suggestive for an interrelation of the three types of intrahepatic cholestasis, although a common denominator remains obscure.

DNA distribution patterns and the fractions of the cell cycle phases were determined by means of flow-through cytometry in 87 samples of normal, atrophic, hyperplastic and carcinomatous human endometrium. The S-phase fractions vary during the normal menstrual cycle between 1 and 3% and reach a periovulatory maximum between 4.4 and 4.7%. Atrophic endometrium and regressive glandular cystic hyperplasia have little DNA synthesis (1.01% and 1.68% S-phase fractions respectively). Proliferating glandular cystic hyperplasia reveals 3.38% S-phase fraction, whereas adenomatous hyperplasia has an increased number of DNA-synthesizing cells (4.81%). The well-differentiated endometrial carcinoma shows no cytophotometrically detectable differences in comparison to adenomatous hyperplasia. All endometrial samples except for poorly differentiated endometrial carcinoma showed a diploid to tetraploid DNA distribution pattern. The poorly differentiated endometrial carcinoma displays two different types: one rapidly growing diploid-tetraploid tumor with 8.0 to 9.6% S-phase fractions, and another type with stemline deviations, polyploid nuclei and less pronounced synthetic activity.

Two strains of amoebae, one (CDC:0180:1) from the lung tissue of a patient who died of granulomatous amoebic encephalitis and the other (CDC:0179:1) from the debrided tissue of a mandibular autograft, were isolated and identified as Acanthamoeba castellanii based on the morphological and immunofluorescent staining characteristics of the trophozoites and cysts. Both strains of amoebae caused cytopathic effects in mammalian cell cultures and destroyed the cell sheet. However, only the CDC:0180:1 strain, on intranasal instillation into mice, produced the disease manifested by ruffled fur and aimless wandering, followed by coma and death within 30 days. The CDC:0180:1 strain also differed consistently from CDC:0179:1 and another nonpathogenic A. castellanii strain (ATCC 30,011) in isoenzyme makeup, a dissimilarity which probably reflects its pathogenic potential.

Monoclonal antibodies (MAbs) to Naegleria fowleri, the etiologic agent of primary amebic meningoencephalitis (PAM), have been produced and used as probes to identify N. fowleri amebae in brain sections of patients who died of that disease. These MAbs were characterized for their specificity by the indirect immunofluorescence assay (IIF), dot immunobinding assay (DIBA), and enzyme-linked immunotransfer blot technique (EITB). The MAbs reacted intensely with all strains of N. fowleri tested originating from different geographic areas in the IIF and DIBA tests, but showed no reactivity with four other species of Naegleria, N. gruberi, N. jadini, N. lovaniensis, and N. australiensis, or a strain of Acanthamoeba castellanii. In the EITB assay the MAbs reacted with the antigens of N. fowleri and produced intensely staining bands at the 160-, 104-, 93-, and 66-kilodalton (kDa) regions and several minor bands at the 30- and 50-kDa regions. The MAbs also reacted with the antigens of N. lovaniensis and produced a darkly staining band at 160 kDa and a diffusely staining band at 116 kDa, indicating that these antigens were shared by the two species. The MAbs, however, showed no reactivity with N. jadini and N. gruberi in the EITB assay.

Samples of serum, bile, and urine were collected simultaneously from patients with cholestasis of varying aetiology and from patients with cirrhosis; their bile acid composition was determined by gas/liquid chromatography and mass spectrometry. In cholestasis, the patterns in all three body fluids differed consistently and strikingly. In serum, cholic acid was the major bile acid and most bile acids (greater than 93%) were unsulphated, whereas, in urine, chenodeoxycholic was the major bile acid, and the majority of bile acids (greater than 60%) were sulphated. Secondary bile acids were virtually absent in bile, serum, and urine. The total amount of bile acids excreted for 24 hours correlated highly with the concentration of serum bile acids; in patients with complete obstruction, urinary excretion averaged 71-6 mg/24 h. In cirrhotic patients, serum bile acids were less raised, and chenodeoxycholic acid was the predominant acid. In healthy controls, serum bile acids were consistently richer in chenodeoxycholic acid than biliary bile acids, and no bile acids were present in urine. No unusual monohydroxy bile acids were present in patients with primary biliary cirrhosis, but, in several patients, there was a considerable amount of hyocholic acid present in the urinary bile acids. The analyses of individual bile acids in serum and urine did not appear to provide helpful information in the differential diagnosis of cholestasis. Thus, in cholestasis, conjugation of chenodeoxycholic acid with sulphate becomes a major biochemical pathway, urine becomes a major route of bile acid excretion, and abnormal bile acids are formed.

Die vorliegende Arbeit geht kurz auf die Atiologie und Pathogenese der Gicht ein. Auserdem wird die Lokalisation dieser Erkrankung in den Gelenken untersucht. An Hand von 9 Patienten wird darauf hingewiesen, das die Gicht im Huftgelenk als Huftkopfnekrose auftreten kann. Der Nachweis dieser Erkrankung erfolgt durch das Auffinden von Uratkristallen in der Gelenkkapsel. Es wird auserdem geschildert, das die Luxation der Gicht im Huftgelenk oft atypisch verlaft.

Serum and urinary bile-acids were measured during three episodes of cholestasis in an 8-year-old girl with benign recurrent intrahepatic cholestasis. In the very early phase of cholestasis, serum bile-acid levels were extremely high, while the serum-bilirubin level was still normal. The early phase was accompanied by very severe pruritus. The discrepancy between serum-bile-acids and serum-bilirubin suggests an acute interruption of the enterohepatic circulation of bile-acids; it also indicates that a deficiency of an enzyme involved in the transport of bile-acids by the liver cell might possibly be the primary cause of the cholestasis.

The efficacy and tolerability of a novel stiff dithranol stick (Ditrastick®, Orion, Espoo, Finland) were evaluated in an open multicenter trial comprising 121 outpatients with limited psoriasis of the plaque type. Daily treatment was startet with 1.5% dithranol sticks and continued in most patients with 3% sticks after 2 weeks. An excellent or good result was obtained in over half of the patients. Early irritation of a rather narrow rim of the skin surrounding the lesions was common, but only about 10% of the patients discontinued the trial due to this side effect. Paraffin-based dithranol sticks thus enable ambulatory treatment of chronic plaque psoriasis in the areas of predilection. Dithranol is stable in this novel preparation for at least 3 years.

Acanthamoeba keratitis is a chronic infection of the human cornea. Many people who have this infection wear soft contact lenses. Usually lens wearers clean and maintain their lenses with various ophthalmic solutions including homemade saline. Recently it has been shown that homemade saline solutions play a role in lens contamination and thus in Acanthamoeba keratitis. We therefore evaluated the viability of cysts of three species of Acanthamoeba by exposing them for various time periods to saline, cleaning, and disinfectant solutions generally used to care for these lenses. We found that the viability of the cysts in saline solutions ranged from a minimum of 14 days to 90 days of exposure. In cleaning solutions, the survival times ranged from a minimum of 1 day to 90 days of exposure. Disinfectants, as expected, were the most effective of all tested solutions in killing Acanthamoeba cysts. The survival times ranged from 6 h to 14 days. None of these products were effective in destroying Acanthamoeba cysts in less than 6 h of exposure, which exceeds the suggested time that any given solution should be used for lens care.

It is well known that diphtheria may be transmitted by domestic animals by way of fur, particularly by animals coming in close contact with people during attacks of diphtheria. Having traced the source of infection to the throat of a dog, I am prompted to report the following cases: Case 1.—History. —Jan. 14, 1908, I was called to attend a girl, aged 11, who complained of having pain in the neck and right arm. Examination. —Temperature and pulse were normal; the throat showed some congestion, with two very small blisters on the left anterior pillar, but no other deposit. The next day the temperature was 99.5 F. and pulse 110, somewhat irregular. Throat inspection showed two white spots where the blisters had been the day before, and four other spots on the left tonsil. The glands at the angle of the jaw were enlarged, more so on the left

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