Intermediate dose enoxaparin in hospitalized patients with moderate-severe COVID-19: a pilot phase II single-arm study, INHIXACOVID19.

BACKGROUND: Randomized clinical trials in non-critically ill COVID-19 patients showed that therapeutic-dose heparin increased survival with reduced organ support as compared with usual-care thromboprophylaxis, albeit with increased bleeding risk. The purpose of the study is to assess the safety of intermediate dose enoxaparin in hospitalized patients with moderate to severe COVID-19. METHODS: A phase II single-arm interventional prospective study including patients receiving intermediate dose enoxaparin once daily according to body weight: 60 mg for 45-60 kg, 80 mg for 61-100 kg or 100 mg for > 100 kg for 14 days, with dose adjustment according to anti-factor Xa activity (target range: 0.4-0.6 UI/ml); an observational cohort (OC) included patients receiving enoxaparin 40 mg day for comparison. Follow-up was 90 days. Primary outcome was major bleeding within 30 and 90 days after treatment onset. Secondary outcome was the composite of all-cause 30 and 90-day mortality rates, disease severity at the end of treatment, intensive care unit (ICU) admission and length of ICU stay, length of hospitalization. All outcomes were adjudicated by an independent committee and analyzed before and after propensity score matching (PSm). RESULTS: Major bleeding was similar in IC (1/98 1.02%) and in the OC (none), with only one event observed in a patient receiving concomitantly anti-platelet therapy. The composite outcome was observed in 53/98 patients (54%) in the IC and 132/203 (65%) patients in the OC (p = 0.07) before PSm, while it was observed in 50/90 patients (55.6%) in the IC and in 56/90 patients (62.2%) in the OC after PSm (p = 0.45). Length of hospitalization was lower in the IC than in OC [median 13 (IQR 8-16) vs 14 (11-21) days, p = 0.001], however it lost statistical significance after PSm (p = 0.08). At 30 days, two patients had venous thrombosis and two pulmonary embolism in the OC. Time to first negative RT-PCR were similar in the two groups. CONCLUSIONS: Weight adjusted intermediate dose heparin with anti-FXa monitoring is safe with potential positive impact on clinical course in COVID-19 non-critically ill patients. TRIAL REGISTRATION: The study INHIXACOVID19 was registred on ClinicalTrials.gov with the trial registration number (TRN) NCT04427098 on 11/06/2020.

Phenotyping congestion in patients with acutely decompensated heart failure with preserved and reduced ejection fraction: The Decongestion duRing therapY for acute decOmpensated heart failure in HFpEF vs HFrEF- DRY-OFF study.

AIMS: To evaluate pulmonary and intravascular congestion at admission and repeatedly during hospitalization for acute decompensated heart failure (ADHF) in HFrEF and HFpEF patients using lung (LUS) and inferior vena cava (IVC) ultrasound. METHODS AND RESULTS: Three-hundred-fourteen patients (82±9 years; HFpEF =172; HFrEF=142) admitted to Internal Medicine wards for ADHF were enrolled in a multi-center prospective study. At admission HFrEF presented higher indexes of pulmonary and intravascular congestion (LUS-score: 0.9 ±â€¯0.4 vs 0.7 ±â€¯0.4; p<0.01; IVC end-expiratory diameter: 21.6 ±â€¯5.1 mm vs 20±5.5 mm, p<0.01; IVC collapsibility index 24.4 ±â€¯17.4% vs 30.9 ±â€¯21.1% p<0.01) and higher Nt-proBNP values (8010 vs 3900 ng/l; p<0.001). At discharge, HFrEF still presented higher B-scores (0.4 ±â€¯4 vs 0.3 ±â€¯0.4; p = 0.023), while intravascular congestion improved to a greater extent, thus IVC measurements were similar in the two groups. No differences in diuretic doses, urine output, hemoconcentration, worsening renal function were found. At 90-days follow up HF readmission/death did not differ in HFpEF and HFrEF (28% vs 31%, p = 0,48). Residual congestion was associated with HF readmission/death considering the whole population; while intravascular congestion predicted readmission/death in the HFrEF, no association between sonographic indexes and the outcome was found in HFpEF. CONCLUSIONS: Serial assessment of pulmonary and intravascular congestion revealed a higher burden of fluid overload in HFrEF and, conversely, a greater reduction in intravascular venous congestion with diuretic treatment. Although other factors beyond EF could play a role in congestion/decongestion patterns, our data may be relevant for further phenotyping HF patients, considering the importance of decongestion optimization in the clinical approach.

Hyperuricemia and Risk of Cardiovascular Outcomes: The Experience of the URRAH (Uric Acid Right for Heart Health) Project.

The latest European Guidelines of Arterial Hypertension have officially introduced uric acid evaluation among the cardiovascular risk factors that should be evaluated in order to stratify patient's risk. In fact, it has been extensively evaluated and demonstrated to be an independent predictor not only of all-cause and cardiovascular mortality, but also of myocardial infraction, stroke and heart failure. Despite the large number of studies on this topic, an important open question that still need to be answered is the identification of a cardiovascular uric acid cut-off value. The actual hyperuricemia cut-off (> 6 mg/dL in women and 7 mg/dL in men) is principally based on the saturation point of uric acid but previous evidence suggests that the negative impact of cardiovascular system could occur also at lower levels. In this context, the Working Group on uric acid and CV risk of the Italian Society of Hypertension has designed the Uric acid Right for heArt Health project. The primary objective of this project is to define the level of uricemia above which the independent risk of CV disease may increase in a significantly manner. In this review we will summarize the first results obtained and describe the further planned analysis.

Disentangling the molecular mechanisms of multiple sclerosis: The contribution of twin studies.

Twin studies of disease concordance are useful to weight the relative contribution of genetic and environmental factors to the cause of common complex disorders. In multiple sclerosis (MS) different twinning rates from geographic areas at different prevalence suggested that heritable and non-heritable factors contribute in different proportions and ways to MS risk in diverse populations. This concept prompted genome-wide association studies, and the implementation of the co-twin control design, that allows stringent experimental approaches in MS-discordant identical pairs, controlling for genetic influences and many other known and unknown factors. The co-twin control design provided important clues on MS molecular model. These studies will be reviewed, focusing on those showing significant differences between affected and healthy co-twins. In some cases, differences that emerged in non-twin patients compared to matched controls were not confirmed in identical MS-discordant pairs, suggesting an 'MS subclinical trait'. Early patterns of magnetic resonance imaging and predictive biomarkers that characterize 'healthy' co-twins may be useful for the identification of a prodromal reversible phase of the disease.

Deer keds on wild ungulates in northern Italy, with a taxonomic key for the identification of Lipoptena spp. of Europe.

Deer keds (Lipoptena spp.) are blood-sucking ectoparasites of domestic and wild animals, and also accidentally of humans. In Europe, five Lipoptena spp. have been recorded, although the lack of specific taxonomic keys has often led to mistaken identification or to missing data. The present study aimed to develop an identification key of the European species and also to identify Lipoptena spp. found on wild ungulates in northern Italy. In total, 390 hippoboscids were collected from Rupicapra rupicapra, Capreolus capreolus, Cervus elaphus and Ovis aries musimon in an Alpine area of Italy. After morphological identification, 140 specimens were subjected to phylogenetic analysis based on mitochondrial (CO1) and nuclear (CAD) gene sequences. Despite the expected presence of slight morphological variations, all specimens examined were identified both microscopically and molecularly as Lipoptena cervi (100% identity for both CO1 and CAD genes). The massive increase in wild ungulate populations can favour the possibility of detecting other species of Lipoptena. The identification keys proposed in the present study may help with monitoring the presence of Lipoptena species, particularly in European countries where this ectoparasite is neglected and for which various data (from diffusion to control methods) are still missing.

Intestinal Permeability in Relapsing-Remitting Multiple Sclerosis.

Changes of intestinal permeability (IP) have been extensively investigated in inflammatory bowel diseases (IBD) and celiac disease (CD), underpinned by a known unbalance between microbiota, IP and immune responses in the gut. Recently the influence of IP on brain function has greatly been appreciated. Previous works showed an increased IP that preceded experimental autoimmune encephalomyelitis development and worsened during disease with disruption of TJ. Moreover, studying co-morbidity between Crohn's disease and MS, a report described increased IP in a minority of cases with MS. In a recent work we found that an alteration of IP is a relatively frequent event in relapsing-remitting MS, with a possible genetic influence on the determinants of IP changes (as inferable from data on twins); IP changes included a deficit of the active mechanism of absorption from intestinal lumen. The results led us to hypothesize that gut may contribute to the development of MS, as suggested by another previous work of our group: a population of CD8+CD161high T cells, belonging to the mucosal-associated invariant T (MAIT) cells, a gut- and liver-homing subset, proved to be of relevance for MS pathogenesis. We eventually suggest future lines of research on IP in MS: studies on IP changes in patients under first-line oral drugs may result useful to improve their therapeutic index; correlating IP and microbiota changes, or IP and blood-brain barrier changes may help clarify disease pathogenesis; exploiting the IP data to disclose co-morbidities in MS, especially with CD and IBD, may be important for patient care.

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials.

There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds' activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

Use of herbal remedies by multiple sclerosis patients: a nation-wide survey in Italy.

Though recent progress in multiple sclerosis (MS) treatment is remarkable, numerous unmet needs remain to be addressed often inducing patients to look for complementary and alternative medicines (CAM), especially herbal remedies (HR). HR use, scarcely investigated in MS, may cause adverse reactions (AR) and interfere with conventional treatment. We performed a survey aimed at evaluating use and attitudes towards HR and factor associated to HR use. Other CAM use and attitudes have been investigated as well. Multiple-choice questionnaires were distributed to MS out patients attending 14 Italian referral Centers. Multivariable logistic regression was used to identify HR use determinants. Present/past HR use for either MS or other diseases was reported in 35.6 % of 2419 cases (95 % CI 36.0-40.0 %). CAM use was reported in 42.5 % of cases. Independent predictors of HR use were represented by higher education, geographic area, dissatisfaction with conventional treatment of diseases other than MS and benefit perception from CAM use. Both HR and CAM use were not always disclosed to the healthcare professional. In conclusion, HR and other CAM appear to be popular among MS patients. The involvement of the healthcare professionals appears to be scarce with potential risk of AR or interference with conventional treatments.

IFN-ß and multiple sclerosis: from etiology to therapy and back.

Several immunomodulatory treatments are currently available for relapsing-remitting forms of multiple sclerosis (RRMS). Interferon beta (IFN) was the first therapeutic intervention able to modify the course of the disease and it is still the most used first-line treatment in RRMS. Though two decades have passed since IFN-ß was introduced in the management of MS, it remains a valid approach because of its good benefit/risk profile. This is witnessed by new efforts of pharmaceutical industry to improve this line: a PEGylated form of subcutaneous IFN-ß 1a, (Plegridy(®)) with a longer half-life, has been recently approved in RRMS. This review will survey the various stages of the use of type I IFN in MS, with special attention to the effect of the treatment on the supposed viral etiologic factors associated to the disease. The antiviral activities of IFN (that initially prompted its use as immunomodulatory agent in MS), and the mounting evidences in favor of a viral etiology in MS, allowed us to outline a re-appraisal from etiology to therapy and back.

Attitudes and preferences for the clinical management of hypertension and hypertension-related cardiac disease in general practice: results of the Italian Hypertension and Heart Survey.

The aim of this study was to evaluate attitudes and preferences for the clinical management of hypertensive patients with cardiac organ disease, including left ventricular hypertrophy (LVH) and coronary artery disease (CAD), in Italy. A predefined 15-item questionnaire was anonymously administered to a large community sample of general practitioners (GPs) and specialised physicians between November 2012 and June 2013. Estimated prevalence of hypertension-related clinical conditions was stratified into four groups (10-20%, 20-40%, 40-50%, >50%); preferences were reported as percentage among valid answers to the survey questionnaire. A total of 1319 physicians (672 males, age 55.0 ± 7.1 years, age of medical activity 27.1 ± 7.6 years), among whom 1264 GPs and 55 specialised physicians, was included. LVH was reported to be the most frequent marker of organ damage by the majority of physicians (73.5%). LV diastolic dysfunction was reported to be relatively frequent (>40%) by more than half of the specialised physicians (58.2%) and less frequent (10-20%) by GPs (49.8%); LV systolic dysfunction, atrial fibrillation and CAD were considered to be less frequent (10-20%) by the majority of physicians (61.3, 71.6 and 53.3%, respectively). Echocardiography was the preferred diagnostic tool used to estimate LVH (76.6%). Tight blood pressure control (130/80 mm Hg) was considered to be the most appropriate by the majority of physicians, both in hypertensive patients with LVH and in those with CAD. With the well-known limitations of a cross-sectional survey, this study provides information on attitudes and preferences for the clinical management of outpatients with hypertension and high CV risk profile in general practice in Italy.

TET2 gene expression and 5-hydroxymethylcytosine level in multiple sclerosis peripheral blood cells.

Aberrant DNA methylation can lead to genome destabilization and to deregulated gene expression. Recently, 5-hydroxymethylcytosine (5hmC), derived from oxidation of 5-methylcytosine (5mC) by the Ten-Eleven Translocation (TET) enzymes, has been detected. 5hmC is now considered as a new epigenetic DNA modification with relevant roles in cell homeostasis regulating DNA demethylation and transcription. Our aim was to investigate possible changes in the DNA methylation/demethylation machinery in MS. We assessed the expression of enzymes involved in DNA methylation/demethylation in peripheral blood mononuclear cells (PBMCs) from 40 subjects with MS and 40 matched healthy controls. We performed also, DNA methylation analysis of specific promoters and analysis of global levels of 5mC and 5hmC. We show that TET2 and DNMT1 expression is significantly down-regulated in MS PBMCs and it is associated with aberrant methylation of their promoters. Furthermore, 5hmC is decreased in MS PBMCs, probably as a result of the diminished TET2 level.

Results from a pilot study on amiodarone administration in monogenic frontotemporal dementia with granulin mutation.

Frontotemporal dementia (FTD) is one of the most important neurodegenerative conditions and Granulin (GRN) is one of the major genes associated to the disease. FTD-GRN patients are still orphan for any evidence-based target-therapy approach. Interestingly, it has been recently found that alkalizing agents rescued haploinsufficiency in cellular models expressing FTD-GRN mutations. We set up a pilot phase II clinical trial in five FTD patients with GRN Thr272s(g.1977_1980delCACT) mutation, to determine if amiodarone (200 mg/day) may (1) reverse progranulin deficiency and (2) delay disease progression. Each patient was scheduled for 7 study visits over 12 months period. We assessed GRN levels at baseline and after amiodarone administration during the treatment course. Somatic and neurologic examinations, along with cognitive and behavioral assessment were recorded as well. No significant effect on peripheral GRN levels was observed. In treated FTD, disease course did not differ when compared with a group of untreated FTD-GRN patients. This is the first trial targeting progranulin rescue in FTD-GRN patients using amiodarone. Despite the negative findings, it may be interesting to extend this attempt to a larger sample of subjects and to other alkalizing agents to restore granulin haploinsufficiency.

Observational case-control study of the prevalence of chronic cerebrospinal venous insufficiency in multiple sclerosis: results from the CoSMo study.

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) has been proposed as a possible cause of multiple sclerosis (MS). OBJECTIVES: The CoSMo study evaluated the association between CCSVI and MS. METHODS: The primary end-point of this multicentric, case-control study was to compare the prevalence of CCSVI between patients with MS, patients with other neurodegenerative diseases (ONDs) and healthy controls (HCs). Color-coded duplex sonography was performed by a sonologist and the images were sent to one of three central sonologists for a second reading. Agreement between local and central sonologists or, in case of disagreement, the predominant judgment among the three central readers, was required for a diagnosis of CCSVI. All readings, data collection and analysis were blinded. RESULTS: The study involved 35 MS centers across Italy and included 1874 subjects aged 18-55. 1767 (94%) were evaluable: 1165 MS patients, 226 patients with ONDs and 376 HCs. CCSVI prevalence was 3.26%, 3.10% and 2.13% for the MS, OND and HC groups, respectively. No significant difference in CCSVI prevalence was found amongst the three cohorts (MS versus HC, OR = 1.55, 95%CI = 0.72-3.36, p = 0.30; OND versus HC, OR = 1.47, 95%CI = 0.53-4.11, p = 0.46; MS versus OND, OR = 1.05, 95%CI = 0.47-2.39, p = 0.99). High negative and low positive agreement was found between the local and centralized readers. CONCLUSIONS: CCSVI is not associated with MS.

Identification of the hemodynamic modulators and hemodynamic status in uncontrolled hypertensive patients.

Only 20-30% out of the treated hypertensive patients in Europe are achieving blood pressure (BP) control. Among other recognized factors, these poor results could be attributable to the fact that for many doctors it is very difficult to detect which is the predominant hemodynamic cause of the hypertension (hypervolemia, hyperinotropy or vasoconstriction). The aim of the study was to use non-invasive thoracic electrical bioimpedance (TEB) to evaluate hemodynamic modulators and subsequent hemodynamic status in uncontrolled hypertensive patients, receiving at least two antihypertensive drugs. A number of 134 uncontrolled hypertensive patients with essential hypertension were evaluated in nine European Hypertension Excellence centers by means of TEB (the HOTMAN(®) System). Baseline office systolic and diastolic BP averaged 156/92 mmHg. Hemodynamic measurements show that almost all patients (98.5%) presented at least one altered hemodynamic modulator: intravascular hypervolemia (96.4%) and/or hypoinotropy (42.5%) and/or vasoconstriction (49.3%). Eleven combinations of hemodynamic modulators were present in the study population, the most common being concomitant hypervolemia, hypoinotropy and vasoconstriction in 51(38%) patients. Six different hemodynamic states (pairs of mean arterial pressure and stroke index) were found. Data suggest that there is a strong relation between hypertension and abnormal hemodynamic modulators. This method might be helpful for treatment individualization of hypertensive patients.

Effect of glatiramer acetate on disease reactivation in MS patients discontinuing natalizumab.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients discontinuing natalizumab are at risk of rebound of disease activity. METHODS: In the present multi-center, open-label, non-randomized, prospective, pilot study, we tested whether treatment with glatiramer acetate (GA) is safe and effective after natalizumab in MS patients. The study was performed at academic tertiary medical centers. Forty active relapsing-remitting MS patients who never failed GA therapy and who discontinued natalizumab after 12-18 months of therapy were enrolled. GA was initiated 4 weeks after the last dose of natalizumab. RESULTS: 62.5% of patients were relapse-free 12 months after GA initiation. Annualized relapse rate and time to relapse were significantly lower than before natalizumab. Notably, the frequency of relapses was significantly lower amongst those patients who had experienced ≤2 relapses the year before initiation of natalizumab therapy, compared with patients who had had three or more relapses. No evidence of rebound was observed in magnetic resonance imaging scans. Furthermore, Expanded Disability Status Scale and Multiple Sclerosis Functional Composite were stable in our patients, again suggesting that 12 months of post-natalizumab-GA therapy is not associated with clinical deterioration. CONCLUSIONS: Following discontinuation of natalizumab, 12 months of therapy with GA is safe and well tolerated in MS patients. GA can reduce the risk of early reactivation/rebound of disease activity in this setting.

Valoración del grado de coagulación y del factor anti-Xa al introducir el dializador AN69ST® con heparina impregnada / Evaluation of coagulation and anti-Xa factor using a heparin-coated AN69ST® dialyser

Introducción: Los sistemas de hemodiálisis tienen capacidad trombogénica, por lo que se utiliza de forma rutinaria la anticoagulación. Su prescripción no se encuentra exenta de riesgos, a pesar de lo cual las recomendaciones respecto a la dosis pautada siguen basándose en criterios muy diversos. Métodos: Se realizó un estudio experimental aleatorizado y cruzado. Seis pacientes realizaron seis sesiones de hemodiafiltración posdilución con el dializador de polisulfona HF80® y anticoagulación habitual con nadroparina, y seis sesiones con el dializador AN69ST® de poliacrilonitrilo con una cubierta de heparina sin el uso de anticoagulación sistémica. Evaluamos cada hora el grado de coagulación del dializador y del circuito extracorpóreo mediante una escala visual y las variaciones en los parámetros de coagulación, entre los que se incluyó el factor anti-Xa. Nuestro objetivo primario fue valorar las variaciones en la actividad del factor anti-Xa en ausencia de diferencias en la tasa de coagulación masiva entre los dos grupos. Resultados: No se coaguló el dializador de forma completa o grado 4 en ninguna de las 36 sesiones realizadas con cada dializador. Se produjo una coagulación parcial del dializador inferior del 25% (grado 1-2) en 32 (88,9%) sesiones con AN69ST® y 35 (97,2%) con el dializador habitual, y superior del 25% (grado 3-4) en 4 (11,1%) sesiones con AN69ST® y en 1 (2,8%) sesión con el dializador con heparina. La coagulación del atrapaburbujas arterial no fue superior al 25% (grados 3 y 4) en ninguna de las sesiones estudiadas, y la cámara venosa en sólo 1 (2,8%) sesión con el dializador habitual y 3 (8,4%) con AN69ST® sin diferencias entre los dos dializadores. El (..) (AU)

Background: Haemodialysis systems are potentially thrombogenic, so anticoagulation is routinely used. Its prescription involves certain risks, despite which the recommendations regarding dosage are still based on very disparate criteria. Methods: We performed a randomised, crossed pilot study. Six patients underwent six sessions of post-dilution haemodiafiltration with a polysulfone HF80® dialyser and standard anticoagulation with nadroparin, and six sessions with heparincoated poliacrylonitrile AN69ST® membrane without the administration of systemic anticoagulation therapy. The coagulation level of the dialyser and extracorporeal circuit was evaluated every hour using a visual scale along with variation in clotting parameters such as anti-Xa factor. Our primary objective was to assess anti-Xa activity in the absence of differences in the rate of massive coagulation between the two groups. Results: No complete or grade 4 dialyser clotting occurred in any of the 36 sessions with either dialyser. Partial clotting of the dialyser occurred below 25% (grade 1-2) in 32 (88.9%) AN69ST® sessions and 35 (97.2%) sessions using the standard dialyser, and partial clotting surpassed 25% (grade 3-4) in 4 (11.1%) AN69ST® sessions and 1 (2.8%) dialysis session with heparin. Arterial chamber blood clotting did not surpass 25% (grade 3 and 4) in any of the studied sessions, and venous chamber coagulation occurred in only 1 (2.8%) session with the usual dialyser and in 3 (8.4%) sessions with the AN69ST®, with no significant differences between the two (..) (AU)

Evaluation of coagulation and anti-Xa factor when using a heparin-coated AN69ST® dialyser.

BACKGROUND: Hemodialysis systems are potentially thrombogenic, so it is routinely used anticoagulation. Its prescription is with risks though which the recommendations regarding the scheduled dose are still based on very different criteria. METHODS: We performed a randomized, crossover pilot study. Six patients underwent six sessions of post-dilution hemodiafiltration with polysulfone HF80® dialyzer and standard anticoagulation with nadroparin, and six sessions with heparin-coated poliacrylonitrile AN69ST® membrane without using systemic anticoagulation. Dialyser and the extracorporeal circuit clotting grade was evaluated through visual scale every hour and coagulation parameters like anti-Xa factor. Our endpoint was to assess anti-Xa activity without differences in the rate of massive clotting between the two groups. RESULTS: No complete or grade 4 dialyzer clotting occurred in any of 36 sessions with each dialyzer. A partial lower 25% (grade 1-2) dialyzer clotting was in 32 (89.7%) AN69ST® sessions and 35 (97.2%) with the usual dialyzer and upper 25% (grade 3-4) in 4 (11.1%) AN69ST® sessions and 1 (2.8%) dialysis session with heparin. Arterial chamber blood coagulation was not greater than 25% (grade 3 and 4) in any of the studied sessions and the venous chamber in only 1 (2.8%) session with the usual dialyzer and 3 (8.4%) with no differences AN69ST® between the two dialyzers. The activated partial thromboplastin time at two hours showed differences between techniques related to administration of low molecular weight heparin (33.3 ± 2.7s with polysulfone and 27.5 ± 2.3s in AN69ST®; P < 0.05) which remained significant at the end of the session (29.8 ± 2.1s with polysulfone and 27.2 ± 1.8s with AN69ST®; P < 0.05). Anti-Xa factor activity was maximal two hours after administration of nadroparin, with differences between the two dialyzers (0.46 ± 0.13 IU / ml in dialysis with polysulfone and 0.04 ± 0.04 IU / ml with AN69ST®p<0.005) and went down after 4 hours (0.17 ± 0.12 IU / ml in dialysis with polysulfone and 0.02 ± 0.03 IU / ml in AN69ST®; p<0.05). One patient in dialysis AN69ST®; had an adverse reaction characterized by generalized pruritus and was excluded from the study, by withdrawing the consent in the first session. CONCLUSION: We demonstrate the low thrombogenicity of the AN69ST®; dialyzer that allows post-dilution hemodiafiltration sessions without systemic anticoagulation, and without increasing the frequency of severe clotting events compared to HF80®; dialyzer with nadroparin and with less risk of bleeding by not modifying the anti-Xa factor activity.

Neuromyelitis optica spectrum disorders in patients with myasthenia gravis: ten new aquaporin-4 antibody positive cases and a review of the literature.

BACKGROUND: Neuromyelitis optica (NMO, Devic syndrome) and myasthenia gravis (MG) are rare antibody-mediated autoimmune disorders. Concurrent incidence has been reported in only few patients, mostly non-Caucasians. OBJECTIVE: To report on ten Caucasian patients with NMO spectrum disorders (NMOSD) and MG and to provide a comprehensive review of the literature. METHOD: Retrospective study. RESULTS: In total, 26 patients (m:f = 1:12; Caucasian in 12) with MG (generalized in 17) and NMOSD (NMO in 21, longitudinally extensive transverse myelitis in five) were identified from the authors' own files (n = 10) and the previous literature (n = 16). MG preceded NMOSD in 24/25 cases (96%). AQP4-Ab were tested in 20 patients and were positive in 17 (85%). Twenty out of 25 patients (80%) had been treated with thymectomy or thymic irradiation, which preceded NMOSD in all cases (median latency, 12 years; range, 0.3-32). At last follow-up, complete remission of MG was reported in 15/22 (68%), and MG was well controlled with pyridostigmine in three. Co-existing autoimmune disorders or autoimmune antibodies were reported in 17 patients. CONCLUSION: Our study demonstrates that i) AQP4-Ab-positive NMOSD are more commonly associated with MG in Caucasians than previously thought; ii) MG precedes NMOSD in most cases, often by more than a decade; iii) NMOSD almost exclusively occur in females with juvenile or early-onset MG; and iv) MG frequently takes an unusually mild course in patients with NMOSD. A history of thymectomy could be a possible risk factor for the later development of NMOSD. We recommend testing for AQP4-Ab in MG patients presenting with atypical motor or optic symptoms.

Epstein-Barr virus nuclear antigen-1 B-cell epitopes in multiple sclerosis twins.

BACKGROUND: Compared with quantitative observations, the search for qualitative changes that may characterize the immune response to Epstein-Barr virus (EBV) in multiple sclerosis (MS) has been less intense. OBJECTIVE: To examine the B-cell epitopes of antibodies against the Epstein-Barr nuclear antigen-1 (EBNA-1) and their relevance for MS, through a study in disease-discordant identical twins. METHODS: We evaluated the antibodies to all unique, maximally overlapping octapeptides of EBNA-1 in 12 pairs of monozygotic (MZ) twins (9 MS-discordant, 3 healthy), 3 non-twin patients and 2 healthy subjects. All except one of the patients were untreated. The EBV serology of these individuals had been assessed in advance using commercially available and in-house enzyme-linked immunosorbent assay (ELISA) kits, including assays for antibodies against select peptides of EBNA-1: EBNA-72 (GAGGGAGAGG) and EBNA-206 (EADYFEYHQEGGPDGE). RESULTS: The glycine-alanine rich domain of EBNA-1 was immunodominant in all subjects. Compared with healthy individuals, and similarly to what has been described in infectious mononucleosis (IM) patients, affected co-twins and non-twin patients had a significantly increased response to another EBNA-1 epitope (aa. 401-411). CONCLUSION: In a study that controls for confounders, our data focus an EBNA-1 specificity that may be associated with MS pathogenesis.