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This paper presents an explorative study on microservices monitoring. The study paves the way for MetroFunnel, our novel application-transparent and zeroconf monitoring tool, which aims to cope with the flexibility of microservices systems. MetroFunnel generates a tracelog of microservices' invocations based on the REST request-response communication model. We present an overview of MetroFunnel and its assessment within the well-consolidated Clearwater IMS.

Introduction: Parinaud syndrome, caused by midbrain infarction, usually manifests as an ocular conjugate upgaze palsy. However, this sign should not point out straightforwardly to Parinaud syndrome, as other lesions in the central nervous system could cause it. Case description: The case of a 47-year-old woman showing acute onset of diplopia with bilateral upward gaze palsy is described. Parinaud syndrome was suspected on clinical grounds. However, brain magnetic resonance imaging displayed an acute ischemic lesion in the right anteromedial thalamus. Conclusions: Bilateral upward gaze palsy may be caused by unilateral thalamic infarction. The mechanism by which a unilateral thalamic lesion causes bilateral gaze palsy is discussed.

Background: The observations of neuromyelitis optica spectrum disorders (NMOSD) occurring in the setting of cancer suggest that aquaporin-4 (AQP4) autoimmunity may in some cases be paraneoplastic. Results: We describe a 72-year-old patient who developed a longitudinally extensive transverse myelitis associated with AQP4 autoantibodies in the setting of a lung adenocarcinoma recurrence. AQP4 expression was demonstrated in tumor cells. IgG in patient’s cerebrospinal fluid bound to tumor cells co-localizing with AQP4 immunoreactivity. Conclusions and relevance: This case expands the spectrum of paraneoplastic AQP4 autoimmunity highlighting the importance of considering an oncological screening in patients with late-onset NMOSD.

Myasthenia gravis (MG) is characterized by fatigable weakness of voluntary muscles caused by immunoglobulin G autoantibodies binding to post-synaptic proteins at the neuromuscular junction. Antibodies specific for the acetylcholine receptor are detected in the great majority (85%) of MG patients. Serum immunoglobulin G binding to the muscle-specific kinase (MuSK) are found in approximately 40% of anti-acetylcholine receptor-negative patients. Recently, the low-density lipoprotein receptor-related protein 4 (Lrp4), which is the MuSK co-receptor for agrin, has been recognized as a new antigen in MG. Specific antibodies bind to the extracellular domains of MuSK and Lrp4 and, as experimental models have shown, interfere with the protein function. The present review describes the MuSK-Lrp4 complex, and summarizes the effects of MuSK and Lrp4 antibodies at the neuromuscular junction. Furthermore, the epidemiological and clinical characteristics, the response to therapy and the controversies in management of the specific diseases are discussed.

Following the current epidemic of obesity, the worldwide prevalence of nonalcoholic fatty liver disease (NAFLD) has increased with potential serious health implications. While it is established that in adults NAFLD can progress to end-stage liver disease in many cases, the risk of progression during childhood is less well defined. Since most obese children are not adherent to lifestyle modifications and hypocaloric diets, there is a growing number of studies on pharmacological interventions with the risk of disease mongering, the practice of widening the boundaries of illness in order to expand the markets for treatment. Here, we propose a critical appraisal of the best available evidence about long-term course of pediatric NAFLD and efficacy of treatments other than hypocaloric diet and physical exercise. As a result, the number of NAFLD children with a poor outcome is small in spite of the alarming tones used in some papers; large-scale longitudinal studies with long-term follow-up of pediatric NAFLD patients are lacking; the studies on ancillary pharmacological interventions have been performed in few patients with inconclusive and conflicting results.

No study has previously investigated the side, duration or number of audible cavitation sounds during high-velocity low-amplitude (HVLA) thrust manipulation to the cervicothoracic spine.The primary purpose was to determine which side of the spine cavitates during cervicothoracic junction (CTJ) HVLA thrust manipulation. Secondary aims were to calculate the average number of cavitations, the duration of cervicothoracic thrust manipulation, and the duration of a single cavitation.Quasi-experimental study.Thirty-two patients with upper trapezius myalgia received two cervicothoracic HVLA thrust manipulations targeting the right and left T1-2 articulation, respectively. Two high sampling rate accelerometers were secured bilaterally 25 mm lateral to midline of the T1-2 interspace. For each manipulation, two audio signals were extracted using Short-Time Fourier Transformation (STFT) and singularly processed via spectrogram calculation in order to evaluate the frequency content and number of instantaneous energy bursts of both signals over time for each side of the CTJ.Unilateral cavitation sounds were detected in 53 (91.4%) of 58 cervicothoracic HVLA thrust manipulations and bilateral cavitation sounds were detected in just five (8.6%) of the 58 thrust manipulations; that is, cavitation was significantly (p0.001) more likely to occur unilaterally than bilaterally. In addition, cavitation was significantly (p0.0001) more likely to occur on the side contralateral to the clinician's short-lever applicator. The mean number of audible cavitations per manipulation was 4.35 (95% CI 2.88, 5.76). The mean duration of a single manipulation was 60.77 ms (95% CI 28.25, 97.42) and the mean duration of a single audible cavitation was 4.13 ms (95% CI 0.82, 7.46). In addition to single-peak and multi-peak energy bursts, spectrogram analysis also demonstrated high frequency sounds, low frequency sounds, and sounds of multiple frequencies for all 58 manipulations.Cavitation was significantly more likely to occur unilaterally, and on the side contralateral to the short-lever applicator contact, during cervicothoracic HVLA thrust manipulation. Clinicians should expect multiple cavitation sounds when performing HVLA thrust manipulation to the CTJ. Due to the presence of multi-peak energy bursts and sounds of multiple frequencies, the cavitation hypothesis (i.e. intra-articular gas bubble collapse) alone appears unable to explain all of the audible sounds during HVLA thrust manipulation, and the possibility remains that several phenomena may be occurring simultaneously.2b.

Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism, caused by mutations in the ATP7B gene. A clear demand for novel WD treatment strategies has emerged. Although therapies using zinc salts and copper chelators can effectively cure WD, these drugs exhibit limitations in a substantial pool of WD patients who develop intolerance and/or severe side effects. Several lines of research have indicated intriguing potential for novel strategies and targets for development of new therapies. Here, we review these new approaches, which comprise correction of ATP7B mutants and discovery of new compounds that circumvent ATP7B-deficiency, as well as cell and gene therapies. We also discuss whether and when these new therapeutic strategies will be translated into clinical use, according to the key requirements for clinical trials that remain to be met. Finally, we discuss the hope for the current rapidly developing research on molecular mechanisms underlying WD pathogenesis and for the related potential therapeutic targets to provide a solid foundation for the next generation of WD therapies that may lead to an effective, tolerable and safe cure.

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long-term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long-term outcome. We identified 781 patients, median age 12 years, with 4,277 person-years of follow-up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event-free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC–inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5-0.9, and 0.7, 95% confidence interval 0.5-0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long-term outcome. Conclusion: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC–inflammatory bowel disease are more favorable disease phenotypes. (Hepatology 2017;66:518–527).

This document presents the guidelines for testing antibodies against neuronal surface antigens that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on autoimmune encephalitis associated with antibodies against neuronal surface antigens, indications and limits of testing for such antibodies, instructions for result interpretation, and an agreed laboratory protocol (Appendix A) are reported for the communicative community of neurologists and clinical pathologists.

BACKGROUND A transient dysfunction of the endocrine growth axis has been reported in celiac disease (CD). This apparent growth hormone deficiency (GHD) generally normalizes with the institution of a gluten-free diet (GFD). However, in few cases, the dysfunction of the GH axis persists despite a good adherence to the GFD. Aims of this study were to investigate pediatric patients with concurrent CD and GHD and to compare them with patients with isolated CD. METHODS Data regarding CD patients with and without associated GHD were retrospectively collected. Inclusion criteria were availability of anthropometric and laboratory data at baseline and regularly at the reference center up to a 2-year follow-up. In case of poor catch-up growth despite a good adherence to the GFD, endocrinological investigation was carried on. RESULTS Fifty-three patients with CD were included. Four (7.5%) out of 53 CD patients had a concurrent GHD. In two cases, firstly diagnosed with CD, GHD was suspected because of a poor catch-up growth despite a good adherence to the GFD. In two other cases, firstly diagnosed with GHD, gastrointestinal symptoms revealed the diagnosis of CD. Normalization of height velocity was achieved by GH treatment in all cases. No statistical significant difference between the two groups of patients was found as regard laboratory and histological features of CD. It is to note that 2 out of 4 patients with concomitant CD and GHD had thyroiditis compared to 6% of patients with isolated CD (P=0.004). CONCLUSIONS A high prevalence of CD and GHD association was found. CD patients with poor catch-up growth despite a good adherence to the GFD should be carefully investigated for endocrine disorders.

Myasthenia gravis is an autoimmune disorder of the neuromuscular junction caused by circulating antibodies specific for the post-synaptic acetylcholine receptor or, in a minority of cases, for the muscle-specific tyrosine-kinase and the low-density lipoprotein receptor-related protein 4. A wide range of symptomatic and immunosuppressive treatments is currently available for MG patients with variable outcome. However, most immunosuppressive treatments are characterized by delayed onset of action and in some cases are not sufficient to induce stable remission of the disease. Rituximab (RTX) is a chimaeric monoclonal antibody specific for the CD20 B-cell surface antigen. Recent studies have provided evidence that RTX may be an effective treatment for patients with myasthenia gravis (MG) who are refractory to standardized immunosuppressive therapy. We performed a systematic review and a meta-analysis of the efficacy and safety of RTX in myasthenia gravis considering the potential predictive factors related to patients' response to RTX in this disease.

The accelerometer-based system is a portable surgical navigation system for TKA that does not require the use of a large computer console for registration and alignment feedback as required in computer-assisted surgery (CAS). The purpose of this prospective study was to determine the accuracy of the accelerometer-based system in the tibial component positioning and also to evaluate clinical outcomes.Between December 2011 and July 2012, a total of 53 consecutive patients with primary gonarthrosis were prospectively enrolled for unilateral TKA using a handheld surgical navigation system to perform the tibial resection. Pre-operatively and postoperatively, patients were asked to fill out a visual analogue scale for pain (VAS) and a knee injury and osteoarthritis outcome score (KOOS). Standing antero-posterior (AP) hip-knee-ankle (HKA) and lateral knee-to-ankle radiographs were performed to determine the varus/valgus alignment and the posterior slope of the tibial components relative to the mechanical axis.The mean duration of follow-up was 23 months. Average preoperative VAS was 8.3 ± 0.67, which significantly improved to a mean 1.2 ± 0.57 at final follow up (P 0.001). All scores significantly increased compared with pre-operative scores, except for the KOOS sport component (P = 0.075) and quality of life (P = 0.19). Intra-operatively, the average reading provided by the system with regard to varus/valgus alignment before performing the tibial resection was 0.55° ± 0.43. The average postoperative radiographic alignment of the tibial component in the coronal plane was 0.65° ± 0.59 of deviation by the ideal alignment (P 0.05).This study demonstrates that the OrthAlign navigation system combines the accuracy of the computer-assisted surgery systems with the ease of use and familiarity of the traditional instruments while avoiding the drawbacks of the CAS technique and disadvantages of conventional IM femoral alignment systems. The system could demonstrate an improvement in the incidence of outliers in final coronal alignment, as compared with a patient-specific cutting guide.

Water channels are a recognized “novel” target for central nervous system, inflammatory, autoimmune, demyelinating diseases, and represent an evolving spectrum of disorders termed neuromyelitis optica (NMO) spectrum disorders (SD). These disorders should now be considered under the umbrella term “autoimmune aquaporin-4 channelopathy”. NMOSD represent the first multiple sclerosis (MS)-like disease for which a specific antigen has been identified – the astrocytic water channel aquaporin-4 (AQP4). MS lacks a distinguishing biomarker. This discovery represents a seismic shift from historic emphasis on the oligodendrocyte and myelin to the astrocyte. The NMO of today represents a relapsing spectrum of disease, not necessarily restricted to the optic nerves and spinal cord, that is different from the monophasic disorder in which near simultaneous bilateral optic neuritis and transverse myelitis occur, as was originally described by Devic. Recent clinical, radiological and pathological findings have documented brain involvement in NMO spectrum disorders, particularly in children. Most patients with NMOSD have brain abnormalities on magnetic resonance imaging, and these are consistent with MS in up to 10% of patients. Others have lesions in areas that highly express AQP4 including the circumventricular organs accounting for intractable nausea and vomiting, and the syndrome of inappropriate antidiuresis as presenting symptoms or heralds of relapse. Diencephalic involvement might explain recently recognized sleep disorders and endocrinopathies. Continued progress in our understanding of the immunobiology of AQP4 autoimmunity necessitates continuing revision of the clinical diagnostic criteria for NMO spectrum disorders. As the clinical spectrum broadens, the importance of highly specific assays that detect pathogenic AQP4-immunoglobulin G targeting extracellular epitopes of AQP4 cannot be overemphasized.

In recent years, patient-specific instruments (PSI) has been introduced with the aim of reducing the overall costs of the implants, minimising the size and number of instruments required, and also reducing surgery time. The purpose of this study was to perform a review of the current literature, as well as to report about our personal experience, to assess reliability of patient specific instrument system in total knee arthroplasty (TKA).A literature review was conducted of PSI system reviewing articles related to coronal alignment, clinical knee and function scores, cost, patient satisfaction and complications.Studies have reported incidences of coronal alignment ≥3° from neutral in TKAs performed with patient-specific cutting guides ranging from 6% to 31%.PSI seem not to be able to result in the same degree of accuracy as the CAS system, while comparing well with standard manual technique with respect to component positioning and overall lower axis, in particular in the sagittal plane. In cases in which custom-made cutting jigs were used, we recommend performing an accurate control of the alignment before and after any cuts and in any further step of the procedure, in order to avoid possible outliers.

The article "Eculizumab improves fatigue in refractory generalized myasthenia gravis", written by "Henning Andersen, Renato Mantegazza, Jing Jing Wang, Fanny O'Brien, Kaushik Patra, James F. Howard Jr. and The REGAIN Study Group" was originally published electronically on the publisher's internet portal (currently SpringerLink) on 23 March 2019 without open access.

Introduction The hypothesis of this study is that computer-aided navigation experience could improve the ability to better place components in the coronal plane and to improve visual/spatial awareness based on the ability of navigation to provide instant feedback. The purpose of this study is to demonstrate the educational role of the navigation system to obtain a better alignment of the prosthetic components with standard instrumentation after a computer-aided navigation experience. Materials and methods One hundred fifty patients were operated by the same surgeon, with more than 5years experience with TKA. They were equally divided in three groups: group A (operated with non-navigated technique by surgeon without computer-assisted experience); group B (operated with computer-assisted surgery by the same surgeon); group C (operated with non-navigated technique by the same surgeon after the computer-navigated experience). We evaluated by full-length weight-bearing radiographs the overall alignment of the lower limb in the coronal plane. The optimum placement of the components was considered when the angle was within the limits of ±3° varus/valgus on the coronal x-rays. Comparison between groups was done using one-way ANOVA followed by post hoc Bonferroni test and Pearson chi-square statistics for proportions of optimum placement ( P Results In the group A 34 patients (68%) had the optimum placement on the coronal x-rays; in the group B they were 46 (92%) and in the group 41 (82%). The difference is statistically significant in comparing group A and Group B ( 0.001), group A and group C ( P =0.04), but not for group B and C ( P =0.2). Conclusion We believe that the navigation system has an educational role to improve the ability of surgeon of positioning prosthetic components precisely in the coronal plane.

Longitudinally extensive transverse myelitis (LETM) is a characteristic feature of Neuromyelitis Optica (NMO), but it can also occur in several other inflammatory diseases of the central nervous system (CNS). An IgG autoantibody that binds to aquaporin-4 (AQP4), the predominant water channel of the CNS, is a reliable biomarker of the NMO spectrum disorders, and if detected predicts the recurrence of the myelitis. In this study, we compared the clinical and neuroimaging characteristics of AQP4-IgG+ and AQP4-IgG- LETM patients. Thirty-seven first-ever LETM patients were retrospectively evaluated and divided into two groups according to the presence of AQP4 autoantibodies. AQP4-IgG was detected in the serum and in the cerebrospinal fluid of sixteen patients. The female to male ratio was higher in AQP4-IgG+ patients. Intractable nausea and vomiting and paroxysmal tonic spasms often accompanied the LETM in AQP4-IgG+ patients. T2-weighted spinal cord MRI revealed that inflammatory lesions extending into the brainstem and involving the central grey matter occurred more frequently in AQP4-IgG+ LETM patients. Hypointense lesions on T1-weighted spinal cord MRI were detected more frequently in the seropositive group, and their presence correlated with attack severity. In conclusion, this study provides clinical and spinal cord neuroimaging clues that can help distinguishing AQP4-IgG+ LETM patients.

The principal central nervous system (CNS) water channel, aquaporin-4 (AQP4), is confined to astrocytic and ependymal membranes and is the target of a pathogenic autoantibody, neuromyelitis optica (NMO)-IgG. This disease-specific autoantibody unifies a spectrum of relapsing CNS autoimmune inflammatory disorders of which NMO exemplifies the classic phenotype. Multiple sclerosis and other immune-mediated demyelinating disorders of the CNS lack a distinctive biomarker. Two AQP4 isoforms, M1 and M23, exist as homotetrameric and heterotetrameric intramembranous particles (IMPs). Orthogonal arrays of predominantly M23 particles (OAPs) are an ultrastructural characteristic of astrocytic membranes. We used high-titered serum from 32 AQP4-IgG-seropositive patients and 85 controls to investigate the nature and molecular location of AQP4 epitopes that bind NMO-IgG, and the influence of supramolecular structure. NMO-IgG bound to denatured AQP4 monomers (68% of cases), to native tetramers and high order arrays (90% of cases), and to AQP4 in live cell membranes (100% of cases). Disease-specific epitopes reside in extracellular loop C more than in loops A or E. IgG binding to intracellular epitopes lacks disease specificity. These observations predict greater disease specificity and sensitivity for tissue-based and cell-based serological assays employing “native” AQP4 than assays employing denatured AQP4 and fragments. NMO-IgG binds most avidly to plasma membrane surface AQP4 epitopes formed by loop interactions within tetramers and by intermolecular interactions within high order structures. The relative abundance and localization of AQP4 high order arrays in distinct CNS regions may explain the variability in clinical phenotype of NMO spectrum disorders.

Subacute cerebellar degeneration associated with metabotropic glutamate receptor type 1 (mGluR1) autoantibodies is an uncommon syndrome known to be part of the spectrum of paraneoplastic cerebellar degenerations associated with neuronal autoantibodies. We describe a patient with prostate adenocarcinoma who developed a subacute cerebellar ataxia. Autoantibodies specific to mGluR1 were detected in patient's serum and cerebrospinal fluid (CSF). Immunohistochemistry analyses of patient's prostate adenocarcinoma revealed abundant mGluR1 expression in luminal acinar epithelial cells and binding of patient's IgGs to tumoral mGluR1. These findings suggest that cerebellar degeneration associated with mGluR1 antibodies can be a paraneoplastic accompaniment of prostate adenocarcinoma. (C) 2013 Elsevier B.V. All rights reserved.

Background Several studies have recently shown better restoration of normal knee kinematics and improvement of rotator knee stability after reconstruction with higher femoral tunnel obliquity. The aim of this study is to evaluate tunnel obliquity, length, and posterior wall blowout in single-bundle anterior cruciate ligament (ACL) reconstruction, comparing the transtibial (TT) technique and the out–in (OI) technique. Materials and methods Forty consecutive patients operated on for ACL reconstruction with hamstrings were randomly divided into two groups: group A underwent a TT technique, while group B underwent an OI technique. At mean follow-up of 10 months, clinical results and obliquity, length, and posterior wall blowout of femoral tunnels in sagittal and coronal planes using computed tomography (CT) scan were assessed. Results In sagittal plane, femoral tunnel obliquity was 38.6 ± 10.2° in group A and 36.6 ± 11.8° in group B (p = 0.63). In coronal plane, femoral tunnel obliquity was 57.8 ± 5.8° in group A and 35.8 ± 8.2° in group B (p = 0.009). Mean tunnel length was 40.3 ± 1.2 mm in group A and 32.9 ± 2.3 mm in group B (p = 0.01). No cases of posterior wall compromise were observed in any patient of either group. Clinical results were not significantly different between the two groups. Conclusions The OI technique provides greater obliquity of the femoral tunnel in coronal plane, along with satisfactory length of the tunnel and lack of posterior wall compromise. Level of evidence II, prospective study.

Paraneoplastic neurological syndromes (PNS) are an extensive group of neurologic disorders that occur in patients with cancer and can affect any part of the nervous system.

In recent years, the discovery of new autoantigens and the use of sensitive assays have expanded the clinical spectrum of myasthenia gravis (MG). In particular, antibodies binding to clustered acetylcholine receptors and to the low-density lipoprotein receptor-related protein 4 have not only bridged a significant gap in diagnosis but also have relevant clinical implications. MG management includes different therapeutic options, from symptomatic agents as the only therapy in mildly affected cases to combined long-term immunosuppression and thymectomy in patients with severe disabling disease. MG biological diversity can influence the response to therapies and should be taken into account when planning treatment. Biologic agents are promising, though their use is currently limited to patients with refractory disease.

High tibial osteotomy (HTO) is an established technique for the treatment of symptomatic varus malaligned knees. The results of our study seem to show greater accuracy of mechanical axis correction and smaller increases in tibial slope when a navigation system is used in open-wedge HTO.

The purpose of our study was to compare clinical and radiological results of two groups of patients treated for medial compartment osteoarthritis of the knee with either conventional or computer-assisted open-wedge high tibial osteotomy (HTO). Goals of surgical treatment were a correction of the mechanical axis between 2° and 6° of valgus and a modification of posterior tibial slope between −2° and +2°. Twenty-four patients (27 knees) affected by varus knee deformity and operated with HTO were prospectively followed-up. They were randomly divided in two groups, A (11 patients, conventional treatment) and B (13 patients, navigated treatment). The American Knee Society Score and the Modified Cincinnati Rating System Questionnaire were used for clinical assessment. All patients were radiologically evaluated with a comparative lower limb weight-bearing digital radiograph, a standard digital anteroposterior, a latero-lateral radiograph of the knee, and a Rosenberg view. Patients were followed-up at a mean of 39 months. Clinical evaluation showed no statistical difference (n.s.) between the two groups. Radiological results showed an 86% reproducibility in achieving a mechanical axis of 182°–186° in group B compared to a 23% in group A (p = 0.0392); furthermore, in group B, we achieved a modification of posterior tibial slope between −2° and +2° in 100% of patients, while in group A, this goal was achieved only in 24% of cases (p = 0.0021). High tibial osteotomy with navigator is more accurate and reproducible in the correction of the deformity compared to standard technique. Therapeutic study, Level II.

A 27-year-old professional martial arts athlete experienced recurrent right knee patellar tendon rupture on three occasions. He underwent two operations for complete patellar tendon rupture: an end-to-end tenorrhaphy the first time, and revision with a bone-patellar-tendon (BPT) allograft. After the third episode, he was referred to our department, where we performed a surgical reconstruction with the use of hamstring pro-patellar tendon, in a figure-of-eight configuration, followed by a careful rehabilitation protocol. Clinical and radiological follow-ups were realized at 1, 3, and 6 months and 1 and 2 years postop, with an accurate physical examination, the use of recognized international outcome scores, and radiograph and MRI studies. As far as we know, this is the first paper to report a re-revision of a patellar tendon rupture.

Open-wedge high tibial osteotomy (HTO) is an established technique for the treatment of symptomatic varus malaligned knees. In this study, we prospectively followed up 13 patients (14 knees) who underwent navigation system–supported HTO for varus knee deformity. Preoperatively all patients underwent a physical examination, and anteroposterior and laterolateral lower limb weight-bearing digital radiographs were obtained. The following parameters were examined: (1) Insall-Salvati index; (2) posterior tibial slope angle; (3) mechanical femorotibial angle; (4) inferior limb length. At a mean follow-up of 12.6 months, clinical examination showed satisfactory results in all patients. The mean Modified Cincinnati Rating System Questionnaire rating increased significantly from 46.5±7.2 to 84.6±8, while the mean Knee Society Score increased significantly from 51.4±9.9 to 85.1±7.3. The mean Insall-Salvati index changed from 1.11 preoperatively to 1.10 postoperatively ( P =.742). According to the navigation system data, the femorotibial mechanical axis was corrected from a varus of 6.3°±1.9° to a valgus of 2.1°±1.6°. These data matched postoperative radiographic lower limb weight-bearing data. In the group of patients in whom we evaluated the posterior tibial slope with the navigation system, we detected an increase of 0.3°±0.4° compared with the preoperative radiographic examination evaluations; the comparison between the postoperative and the preoperative radiograhic examination results showed an increase of 0.5°±0.7° ( P =.87). The results of our study seem to show greater accuracy of mechanical axis correction and smaller increase in tibial slope when a navigation system is used in open-wedge HTO.

Background: Increased femoral tunnel widening and weakness of the hamstring muscles postoperatively have been described as potential adverse events after anterior cruciate ligament (ACL) reconstruction (ACLR) with a hamstring graft. Meniscectomy and cartilage lesions are important factors for the development of degenerative osteoarthritis. Purpose: To compare 15-year follow-up data with 5-year follow-up data from the same cohort of patients after ACLR with a hamstring autograft using an outside-in technique. Study Design: Case series; Level of evidence, 4. Methods: A total of 72 patients who underwent anatomic ACLR with a quadruple hamstring graft and an outside-in technique were selected for this prospective study. Patients were reviewed at a minimum follow-up of 15 years. Results were compared with the same series of patients previously reviewed at 5 years after surgery. Lysholm, International Knee Documentation Committee (IKDC), and Tegner scores as well as KT-1000 arthrometer measurements were obtained at final follow-up. Comparative weightbearing radiographs were obtained and analyzed according to the Fairbank, Kellgren-Lawrence, and IKDC classifications and used for the tunnel evaluation. Results: No significant difference was detected on the subjective evaluation. Objectively, patients categorized as A or B according to the IKDC score were not significantly different at 5 and 15 years ( P < .01). A KT-1000 arthrometer side-to-side manual maximum difference >5 mm, a pivot shift >2+, any giving-way episode, and ACL revision surgery were considered as failures, and these were noted in 6 patients at 5 years and 6 patients at 15 years. The radiological evaluation at 15 years showed a higher rate of osteoarthritis in 2 of 3 radiological scales used in the study compared with results at 5-year follow-up ( P < .01). At 15-year follow-up, there was a statistically significant reduction in the mean tibial tunnel diameter ( P < .01). Conclusion: Endoscopic single-bundle ACLR using hamstring grafts and an outside-in technique demonstrated good results at 15-year follow-up in terms of subjective, objective, and radiographic evaluations. As compared with 5-year follow-up, clinical results remained stable both subjectively and objectively. However, a progression of osteoarthritis changes was observed, especially in patients in whom meniscectomy had been performed.

Septic arthritis after arthroscopic anterior cruciate ligament (ACL) reconstruction is a rare complication. In the literature, several treatments have been proposed. The aim of the study was to report our results using ambulatory irrigation of the knee and parenteral and oral antibiotics.From January 2001 to December 2008, a total of 12 patients were treated for postoperative septic arthritis of the knee after ACL reconstruction in our hospital. The average age at trauma was 24 years (range 16-43 years). The treatment protocol included irrigation of the knee (for 2 days) and parenteral antibiotics and oral antibiotics subsequently. Repetitive irrigation was performed if necessary. The average duration of follow-up for our series was 38 months (range 6-54 months). Follow-up included International Knee Documentation Committee (IKDC) forms, radiography, Tegner and Lysholm scores, and KT-1000 arthrometric evaluation.In all cases treatment of infection was successful. Neither graft nor hardware removal was needed in any of the cases. At final examination, the pivot shift was negative in 10 of 12 patients, and it was 1+ in the other 2 patients; the Lachman was negative in all cases. The mean postoperative Tegner score was 7.2, and the mean Lysholm score was 98.3. In all, 10 of the 12 patients were graded as group A and the other 2 as group B using the IKDC form. The mean postoperative manual maximum KT-1000 side-to-side difference was 2.3. No significant bone tunnel enlargement was found at radiographic evaluation.The described treatment regimen gives reliable results for this complication. There were no recurrences of septic arthritis or bone infection. No further surgeries were required, and the graft was retained during the treatment of septic arthritis.

ObjectiveTo report the clinical and immunological characteristics of 22 new patients with glial fibrillar acidic protein (GFAP) autoantibodies.MethodsFrom January 2012 to March 2017, we recruited 451 patients with suspected neurological autoimmune disease at the Catholic University of Rome. Patients’ serum and cerebrospinal fluid (CSF) samples were tested for neural autoantibodies by immunohistochemistry on mouse and rat brain sections, by cell-based assays (CBA) and immunoblot. GFAP autoantibodies were detected by immunohistochemistry and their specificity confirmed by CBA using cells expressing human GFAPα and GFAPδ proteins, by immunoblot and immunohistochemistry on GFAP-/- mouse brain sections.ResultsSerum and/or CSF IgG of 22/451 (5%) patients bound to human GFAP, of which 22/22 bound to GFAPα, 14/22 to both GFAPα and GFAPδ and none to the GFAPδ isoform only. The neurological presentation was: meningoencephalomyelitis or encephalitis in 10, movement disorder (choreoathetosis or myoclonus) in 3, anti-epileptic drugs (AED)-resistant epilepsy in 3, cerebellar ataxia in 3, myelitis in 2, optic neuritis in 1 patient. Coexisting neural autoantibodies were detected in five patients. Six patients had other autoimmune diseases. Tumours were found in 3/22 patients (breast carcinoma, 1; ovarian carcinoma, 1; thymoma, 1). Nineteen patients were treated with immunotherapy and 16 patients (84%) improved. Histopathology analysis of the leptomeningeal biopsy specimen from one patient revealed a mononuclear infiltrate with macrophages and CD8+ T cells.ConclusionsGFAP autoimmunity is not rare. The clinical spectrum encompasses meningoencephalitis, myelitis, movement disorders, epilepsy and cerebellar ataxia. Coexisting neurological and systemic autoimmunity are relatively common. Immunotherapy is beneficial in most cases.

Regulatory CD4+ CD25+Foxp3+ T cells are involved in the regulation of immune response and inhibit protective antitumor immunity. Celiac disease (CD), a food gluten-sensitive enteropathy, is considered a T-cell-mediated autoimmune disease and is generally associated with an overall increased risk of cancer in CD patients. We observed a higher percentage of circulating CD4+CD25+Foxp3+ T cells and an increased Foxp3 expression in CD4+CD25+ T cells from untreated than from treated CD patients. In co-culture, CD4+CD25+ T cells from both treated and untreated CD patients significantly suppressed the proliferation of autologous CD4+CD25(-) T cells similarly to values in healthy subjects. Our study suggests that Treg proportion and Foxp3 expression in circulating CD4+CD25+ T cells could justify the increased global risk of malignancy in CD population and support the efficacy of lifelong gluten-free diet in the reduction of the cancer risk.

article i nfo STAT1 STAT3 T-bet IFNγ IL17 Not all patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) develop clinically defined MS (CDMS). At first clinical event we observed increased production of IL17, IFNγ and IL10 by peripheral blood mononuclear cells from patients with CIS that remained high in remission. In CD4+ T cells pSTAT3 expression was higher in patients who subsequently converted to CDMS than in patients who did not and controls. The persistency of high levels of pSTAT3 in circulating CD4+ T cells from CIS patients after the first clinical event may favor the early conversion to CDMS.

Despite the relatively frequent involvement of the basal ganglia and subthalamic nucleus by multiple sclerosis (MS) plaques, movement disorders (MD), other than tremor secondary to cerebellar or brainstem lesions, are uncommon clinical manifestations of MS. MD were present in 12 of 733 patients with MS (1.6%): three patients had parkinsonism, two blepharospasm, five hemifacial spasm, one hemidystonia, and one tourettism. MD in patients with MS are often secondary to demyelinating disease. Also in cases without response to steroid treatment and demyelinating lesions in critical regions, it is not possible to exclude that MD and MS are causally related.

Neonatal hemochromatosis is a rare congenital disorder of the liver associated to a poor prognosis. Liver transplantation is often required, since no effective medical treatment has been found. Despite mounting evidence of an alloimmune etiology of this condition, exchange transfusion has never been proposed as a specific treatment for neonatal hemochromatosis. Here we describe two siblings affected by neonatal hemochromatosis. The first, a female, died at 18 days of severe coagulopathy and acute renal failure, diagnosed as affected by neonatal hemochromatosis only when the second sibling was suspected as being affected by the same disease. The second child showed a rapidly worsening coagulopathy which was treated with two exchange transfusions, followed by rapid clinical and laboratory improvement, before reaching a definite diagnosis of neonatal hemochromatosis. He is healthy at present after a follow-up of 12 months. Although exchange transfusion has never been considered as treatment for neonatal hemochromatosis, this case suggests that it could be a feasible treatment option for children affected by this disease, as for other alloimmune conditions.

High dose glucocorticoid (GC) treatment has been demonstrated to have a short-term beneficial effect on functional recovery in relapsing multiple sclerosis (MS) patients but the exact mechanism of action of GCs in MS is unclear. We found that high dose intravenous GCs strongly reduced T-bet and pSTAT1 expression in CD4+, CD8+, CD14+ circulating cells in RRMS patients in relapse. pSTAT1and T-bet reduction was associated with the decline of IFNgamma production by PBMCs. A significant increase of AV-positive CD4+ and CD8+ T cells was detectable after GC treatment without any variation in the percentage of annexin V-positive monocytes. By in vitro analysis, patients during relapse, either before or after GC treatment, exhibited a lower proportion of apoptotic lymphocytes than remitting patients and controls. Our study suggests that GCs can modulate T-bet and STAT1 expression and that IFNgamma signalling inhibition contributes to anti-inflammatory action of GCs in the treatment of relapses of MS patients.

Herein we report the results of mutation analysis of the ATP7B gene in a group of 134 Wilson disease (WD) families (268 chromosomes) prevalently of Italian origin. Using the SSCP and sequencing methods we identified 71 disease-causing mutations. Twenty-four were novel, while 19 more mutations already described, were identified in new populations in this study. A known mutation G591D showed a regional distribution, since it was only detected in 38.5% of the analyzed chromosomes in WD patients originating from Apulia, a region of South Italy. Detection of new mutations in the ATP7B gene increases our capability of molecular analysis that is essential for early diagnosis and treatment of WD.

Minimally invasive surgery has become a trend over the last few years in all aspects of orthopaedic surgery, including total hip arthroplasty So-called “mini-incision” techniques involve limiting the length of the skin incision to ≤ 10 cm with use of either an anterior, lateral or posterior approach. Between March 2004 and December 2005 one hundred consecutive unilateral total hip replacements were performed by the same senior surgeon in our institute. All patients were randomly assigned to study group (group A) or control group (group B). In group A (50 patients) the skin incision was ≤ 8 cm; in group B (50 patients) the skin incision was standard (about 12–14 cm). Patient demographic data, including sex, age, height, weight, BMI, diagnosis and preoperative Harris hip score were recorded. Other criteria evaluated included the perioperative and postoperative complications, the surgical time, the blood loss, the length of the incision, the acetabular and stem positions, the length of hospital stay, Harris Hip Score (HHS) and the WOMAC osteoarthritis index at six months. No significant differences were found between the groups with respect to the average surgical time, the acetabular and stem position, the length of hospital stay and the Harris Hip Score (HHS) and the WOMAC osteoarthritis index at six months. A significant lower blood loss was found in the mini-incision group. A higher percentage of peri-operative complications was recorded in Group A (two stupor of sciatic nerve and one fracture of the greater trochanter). On the basis of our experience we could speculate that minimally invasive surgery should be directed to the new surgical approach with muscle sparing, instead of a shorter skin incision using standard approaches.

Background & aims Wilson's disease (WD) is a genetic disorder of copper metabolism causing dysfunctions of various organs, mostly the liver and brain. If untreated, WD is fatal, but early treatment results in a good prognosis, although the long-term neurological outcome has not yet been clarified. To address this issue, we evaluated the neurological status of early-treated WD patients without overt nervous system impairment using neurophysiological, neuropsychological and neuroimaging procedures at least 10 years after treatment onset. Methods Thirty-eight WD patients (18 females, aged 24.47 ± 7.50 years), who received an early diagnosis (in presymptomatic or mild/moderate liver disease stages without neurological involvement) and prompt treatment, were clinically evaluated with the Global Assessment Scale. Presentation was hepatic in 36 subjects (95%), while 2 patients (5%) were presymptomatic. A neurophysiological study was performed to explore the central motor conduction time of the upper and lower limbs, and motor cortex excitability using single pulses and paired-pulse transcranial magnetic stimulation. Neuroimages were obtained with brain magnetic resonance scans. Cognitive abilities, and psychiatric and behavioral disturbances were evaluated with neuropsychological tests. Results Patients were undergoing treatment with penicillamine (7 patients) or zinc salts (31 patients) with good adherence. They did not present any neurological signs at clinical evaluation or at specific scale of impairment, the mean Global Assessment Scale score was 0.3 ± 0.7. Magnetic resonance imaging, transcranial magnetic stimulation studies and neuropsychological/neuropsychiatric assessment ruled out subclinical involvement. Conclusions This study suggests that early diagnosis and treatment of WD may prevent the onset of neurologic damage, even at subclinical level.

Serological markers of Nuromyelitis Optica (NMO), an autoimmune disorder of the central nervous system, are autoantibodies targeting the astrocytic water channel aquaporin-4 (AQP4). We have previously demonstrated that the main epitopes for these autoantibodies (AQP4-IgG) are generated by the supramolecular arrangement of AQP4 tetramers into an Orthogonal Array of Particles (OAPs). Many tests have been developed to detect AQP4-IgG in patient sera but several procedural issues affect OAP assembly and consequently test sensitivity. To date, the protein based ELISA test shows the lowest sensitivity while representing a valid alternative to the more sensitive cell based assay (CBA), which, however, shows economic, technical and interpretation problems. Here we have developed a high perfomance ELISA in which native OAPs are used as the molecular target. To this aim a native size exclusion chromatography method has been developed to isolate integral, highly pure and AQP4-IgG-recognized OAPs from rat brain. These OAPs were immobilized and oriented on a plastic plate by a sandwich approach and 139 human sera were tested, including 67 sera from NMO patients. The OAP-ELISA showed a 99% specificity and a higher sensitivity (91%) compared to the CBA test. A comparative analysis revealed an end-point titer three orders of magnitude higher than the commercial ELISA and six times higher than our in-house CBA test. We show that CNS-extracted OAPs are crucial elements in order to perform an efficient AQP4-IgG test and the OAP-ELISA developed represents a valid alternative to the CBA currently used.

Myasthenia gravis (MG) with antibodies to the muscle-specific tyrosine kinase receptor (MuSK) is characterized by prominent cranial and bulbar weakness. The disease course is often severe and some patients develop permanent, disabling symptoms despite long-term immunosuppression.1 In patients with MuSK MG, the administration of acetylcholinesterase inhibitors (AChE-I) is poorly effective and often associated with clinical and electrophysiologic signs of cholinergic hypersensitivity.2 3,4-Diaminopyridine (3,4-DAP) improves neuromuscular transmission (NMT) by increasing quantal release. We report the case of an adult patient with MuSK MG who was responsive to and tolerant of 3,4-DAP.

Neuromyelitis optica (NMO) (and NMO spectrum disorder) is an autoimmune inflammatory disease of the CNS primarily affecting spinal cord and optic nerves. Reliable and sensitive biomarkers for onset, relapse, and progression in NMO are urgently needed because of the heterogeneous clinical presentation, severity of neurologic disability following relapses, and variability of therapeutic response. Detecting aquaporin-4 (AQP4) antibodies (AQP4-IgG or NMO-IgG) in serum supports the diagnosis of seropositive NMO. However, whether AQP4-IgG levels correlate with disease activity, severity, response to therapy, or long-term outcomes is unclear. Moreover, biomarkers for patients with seronegative NMO have yet to be defined and validated. Collaborative international studies hold great promise for establishing and validating biomarkers that are useful in therapeutic trials and clinical management. In this review, we discuss known and potential biomarkers for NMO.

Autoimmune neurology is a rapidly emerging subspecialty that encompasses the diagnosis and treatment of neurological disorders with an autoimmune (paraneoplastic or non-cancer associated) basis. There has been a dramatic rise in discoveries of neural-specific autoantibodies and their target antigens. Laboratory testing is now available for most of these neural-specific autoantibodies, which serve as diagnostic markers directing the physician towards specific cancer types and assisting in therapeutic decision making. Autoimmune neurology intersects with many traditional neurological subspecialties including cognitive behavioral neurology, movement disorders, epilepsy, neuro-oncology, neuromuscular disorders, autonomic neurology, and demyelinating disorders. Antibodies targeting intracellular proteins (nuclear and intracytoplasmic enzymes, transcription factors, RNA binding proteins) serve as markers of neural peptide-specific cytotoxic effector T-cell mediated injury and are generally poorly responsive to immunotherapy. In contrast, antibodies targeting plasma membrane proteins (neurotransmitter receptors, ion channels, water channels, channel complex proteins) may act as pathogenic effectors and imply immunotherapy responsiveness.

We describe a case of Wilson's disease (WD) diagnosed at 5 years after routine biochemical test showed increased aminotransferases. Mutation analysis of the ATP7B gene revealed a 3039-bp deletion in the homozygous state spanning from the terminal part of intron 1 to nt position 368 of exon 2. This deletion results in the activation of 3 cryptic splice sites: an AG acceptor splice site in nt positions 578-579 producing a different breakpoint and removing the first 577 nts of exon 2, an acceptor and a donor splice site in nt positions 20363-4 and 20456-7, respectively, in intron 1, resulting in the activation of a 94-bp cryptic Alu exon being incorporated into the mature transcript. The resulting alternative transcript contains a TAG stop codon in the first amino acid position of the cryptic exon, likely producing a truncated, non-functional protein. This study shows that intron exonization can also occur in humans through naturally occurring gross deletions. The results suggest that the combination of DNA and RNA analyses can be used for molecular characterization of gross ATP7B deletions, thus improving genetic counseling and diagnosis of WD. Moreover these studies help to better establish new molecular mechanisms producing Wilson's disease.