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Thymic epithelial tumors (TETs) are rare thoracic tumors, often requiring multimodal approaches. Surgery represents the first step of the treatment, possibly followed by adjuvant radiotherapy (RT) and, less frequently, chemotherapy. For unresectable tumors, a combination of chemotherapy and RT is often used. Currently, the optimal dose for patients undergoing radiation is not clearly defined. Current guidelines on RT are based on studies with a low level of evidence, where 2D RT was widely used. We aim to shed light on the optimal radiation dose for patients with TETs undergoing RT through a systematic review of the recent literature, including reports using modern RT techniques such as 3D-CRT, IMRT/VMAT, or proton-therapy. A comprehensive literature search of four databases was conducted following the PRISMA guidelines. Two investigators independently screened and reviewed the retrieved references. Reports with < 20 patients, 2D-RT use only, median follow-up time < 5 years, and reviews were excluded. Two studies fulfilled all the criteria and therefore were included. Loosening the follow-up time criteria to > 3 years, three additional studies could be evaluated. A total of 193 patients were analyzed, stratified for prognostic factors (histology, stage, and completeness of resection), and synthesized according to the synthesis without meta-analysis (SWIM) method. The paucity and heterogeneity of eligible studies led to controversial results. The optimal RT dose neither for postoperative, nor primary RT in the era of modern RT univocally emerged. Conversely, this overview can spark new evidence to define the optimal RT dose for each TETs category.

Thymic epithelial tumors (TETs) are rare thoracic tumors, often requiring multimodal approaches. Surgery represents the first step of the treatment, possibly followed by adjuvant radiotherapy (RT) and, less frequently, chemotherapy. For unresectable tumors, a combination of chemotherapy and RT is often used. Currently, the optimal dose for patients undergoing radiation is not clearly defined. Current guidelines on RT are based on studies with a low level of evidence, where 2D RT was widely used. We aim to shed light on the optimal radiation dose for patients with TETs undergoing RT through a systematic review of the recent literature, including reports using modern RT techniques such as 3D-CRT, IMRT/VMAT, or proton-therapy. A comprehensive literature search of four databases was conducted following the PRISMA guidelines. Two investigators independently screened and reviewed the retrieved references. Reports with < 20 patients, 2D-RT use only, median follow-up time < 5 years, and reviews were excluded. Two studies fulfilled all the criteria and therefore were included. Loosening the follow-up time criteria to > 3 years, three additional studies could be evaluated. A total of 193 patients were analyzed, stratified for prognostic factors (histology, stage, and completeness of resection), and synthesized according to the synthesis without meta-analysis (SWIM) method. The paucity and heterogeneity of eligible studies led to controversial results. The optimal RT dose neither for postoperative, nor primary RT in the era of modern RT univocally emerged. Conversely, this overview can spark new evidence to define the optimal RT dose for each TETs category.

Introduction Immune checkpoint inhibitors (ICIs) have become an important part of the treatment of multiple cancers, especially for advanced melanoma and non-small cell lung cancer. Some tumors are capable of escaping immunosurveillance by stimulating checkpoints on T-cells. ICIs prevent activation of these checkpoints and thereby stimulate the immune system and indirectly the anti-tumor response. However, the use of ICIs is associated with various adverse events. Ocular side effects are rare but may have a major impact on the quality of life of the patient. Methods A comprehensive literature search of the medical databases Web of Science, Embase and PubMed was performed. Articles that provided a comprehensive description of a case report containing 1) cancer patient(s) treated with (a combination of) immune checkpoint inhibitors, and 2) assessed occurrence of ocular adverse events, were included. A total of 290 case reports were included. Results Melanoma (n = 179; 61.7%) and lung cancer (n = 56; 19.3%) were the most frequent reported malignancies. The primary used ICIs were nivolumab (n = 123; 42.5%) and ipilimumab (n = 116; 40.0%). Uveitis was most the common adverse event (n = 134; 46.2%) and mainly related to melanoma. Neuro-ophthalmic disorders, including myasthenia gravis and cranial nerve disorders, were the second most common adverse events (n = 71; 24.5%), mainly related to lung cancer. Adverse events affecting the orbit and the cornea were reported in 33 (11.4%) and 30 cases (10.3%) respectively. Adverse events concerning the retina were reported in 26 cases (9.0%). Conclusion The aim of this paper is to provide an overview of all reported ocular adverse events related to the use of ICIs. The insights retrieved from this review might contribute to a better understanding of the underlying mechanisms of these ocular adverse events. Particularly, the difference between actual immune-related adverse events and paraneoplastic syndromes might be relevant. These findings might be of great value in establishing guidelines on how to manage ocular adverse events related to ICIs.

Psychotic disorders are debilitating mental illnesses associated with abnormalities in various neurotransmitter systems. The development of disease-modifing therapies has been hampered by the mostly unknown etiologies and pathophysiologies.Autoantibodies against several neuronal antigens are responsible for autoimmune encephalitis. These auto antibodies disrupt neurotransmission within the brain, resulting in a wide range of psychiatric and neurologic manifestations, including psychosis. The overlap of symptoms of autoimmune encephalitis with psychotic disorders raised the question as to whether autoantibodies against a number of receptors, ion channel and associated proteins could ultimately be responsible for some forms of psychosis. Here we review our current knowledge, on antibody mediated autoimmunity in psychotic disorders, the different diagnostic methods and their limitations, as well as on varying therapeutic approaches targeting the immune system.

Psychotic disorders are debilitating mental illnesses associated with abnormalities in various neurotransmitter systems. The development of disease-modifing therapies has been hampered by the mostly unknown etiologies and pathophysiologies. Autoantibodies against several neuronal antigens are responsible for autoimmune encephalitis. These autoantibodies disrupt neurotransmission within the brain, resulting in a wide range of psychiatric and neurologic manifestations, including psychosis. The overlap of symptoms of autoimmune encephalitis with psychotic disorders raised the question as to whether autoantibodies against a number of receptors, ion channel and associated proteins could ultimately be responsible for some forms of psychosis. Here we review our current knowledge, on antibody mediated autoimmunity in psychotic disorders, the different diagnostic methods and their limitations, as well as on varying therapeutic approaches targeting the immune system.

Eculizumab is the first drug approved for the treatment of complement-mediated diseases, and current dosage schedules result in large interindividual drug concentrations. This review provides insight into the pharmacokinetic and pharmacodynamic properties of eculizumab, both for reported on-label (paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis) and off-label (hematopoietic stem cell transplantation-associated thrombotic microangiopathy) indications. Furthermore, we discuss the potential of therapeutic drug monitoring to individualize treatment and reduce costs. ispartof: CLINICAL PHARMACOKINETICS vol:58 issue:7 pages:859-874 ispartof: location:Switzerland status: published

BackgroundRheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management.MethodsFirst, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed.ResultsThe overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies.ConclusionThese statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.

The α7 acetylcholine receptor (AChR) has been linked with the onset of psychotic symptoms and we hypothesized therefore that it might also be an autoimmune target. Here, we describe a new radioimmunoassay (RIA) using iodine 125-labelled α-bungarotoxin and membrane extract from transfected HEK293 cells expressing human α7 AChR. This RIA was used to analyze sera pertaining to a cohort of 711 subjects, comprising 368 patients diagnosed with schizophrenia spectrum disorders, 140 with bipolar disorder, 58 individuals diagnosed of other mental disorders, and 118 healthy comparison subjects. We identified one patient whose serum tested positive although with very low levels (0.2 nM) for α7 AChR-specific antibodies by RIA. Three out of 711 sera contained antibodies against iodine 125-labelled α-bungarotoxin, because they precipitated with it in the absence of α7 AChR. This first evidence suggests that autoantibodies against α7 AChR are absent or very rare in these clinical groups. ispartof: PLOS ONE vol:13 issue:12 ispartof: location:United States status: published

Summary Background Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. Methods The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394. Findings Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0–464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0–470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0–288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. Interpretation Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC. Funding Bristol-Myers Squibb.

In jawed vertebrates, the crosstalk between immune and endocrine system as well as many fundamental mechanisms of T cell development are evolutionary conserved. Oestrogens affect mammalian thymic function and plasticity, but the mechanisms of action and the oestrogen receptors involved remain unclear. To corroborate the oestrogenic regulation of thymic function in teleosts and to identify the implicated oestrogen receptor subtypes, we examined the distribution of nuclear and membrane oestrogen receptors within the thymus of the European Sea bass, Dicentrarchus labrax, in relation to its morpho-functional organisation. Immunohistological analysis specified thymus histology and organisation in teleosts and described, for the first time, Hassall's corpuscle like structures in the medulla of sea bass. All oestrogen receptors were expressed at the transcript and protein level, both in T cells and in stromal cells belonging to specific functional areas. These observations suggest complex regulatory actions of oestrogen on thymic function, notably through the stromal microenvironment, comprising both, genomic and non-genomic pathways that are likely to affect T cell maturation and trafficking processes. Comparison with birds, rodents and humans supports the thymic localization of oestrogen receptors and suggests that oestrogens modulate T cell maturation in all gnathostomes. (C) 2017 Elsevier Ltd. All rights reserved. ANR [ANR-15-CE32-0014] FR CNRS 3730 SCALE info:eu-repo/semantics/publishedVersion

Autoimmune diseases are affecting around 7.6-9.4% of the general population. A number of central nervous system disorders, including encephalitis and severe psychiatric disorders have been demonstrated to associate with specific neuronal surface autoantibodies. It has become clear that specific autoantibodies targeting neuronal surface antigens and ion channels could cause severe mental disturbances. A number of studies have focused or are currently investigating the presence of autoantibodies in specific mental conditions such as schizophrenia and bipolar disorders. However, less is known about other conditions such as depression. Depression is a psychiatric disorder with complex etiology and pathogenesis. The diagnoses criteria of depression are largely based on symptoms but not on the origin of the disease. The question which arises is whether in a subgroup of patients with depression, the symptoms might be caused by autoantibodies targeting membrane associated antigens. Here, we describe how autoantibodies targeting membrane proteins and ion channels cause pathological effects. We discuss the physiology of these antigens and their pathogenicity in relation to depression. Finally, we summarize a number of studies detecting neuronal surface autoantibodies with a special focus on those that the cohorts include depression diagnosis and/ or show depressive symptoms.

Cervical dystonia is the most frequent form of focal dystonia. Symptoms often result in pain and functional disability. Local injections of botulinum neurotoxin are currently the treatment of choice for cervical dystonia. Although this treatment has proven effective and is widely applied worldwide, many issues still remain open in the clinical practice. We performed a systematic review of the literature on botulinum toxin treatment for cervical dystonia based on a question-oriented approach, with the aim to provide practical recommendations for the treating clinicians. Key-questions from the clinical practice were explored. Results suggest that while the beneficial effect of botulinum toxin treatment on different aspects of cervical dystonia is well established, robust evidence is still missing concerning some practical aspects, such as doseequivalence between different formulations, optimal treatment intervals, treatment approaches, and the use of supportive techniques including electromyography (EMG) or ultrasounds. Established strategies to prevent or manage common side effects (including excessive muscle weakness, pain at injection site, dysphagia) and potential contraindications to this treatment (pregnancy and lactation, use of anticoagulants, neurological comorbidities) should also be further explored.

Cervical dystonia (CD) is the most frequent form of focal dystonia. Symptoms often result in pain and functional disability. Local injections of botulinum neurotoxin are currently the treatment of choice for CD. Although this treatment has proven effective and is widely applied worldwide, many issues still remain open in the clinical practice. We performed a systematic review of the literature on botulinum toxin treatment for CD based on a question-oriented approach, with the aim to provide practical recommendations for the treating clinicians. Key questions from the clinical practice were explored. Results suggest that while the beneficial effect of botulinum toxin treatment on different aspects of CD is well established, robust evidence is still missing concerning some practical aspects, such as dose equivalence between different formulations, optimal treatment intervals, treatment approaches, and the use of supportive techniques including electromyography or ultrasounds. Established strategies to prevent or manage common side effects (including excessive muscle weakness, pain at injection site, dysphagia) and potential contraindications to this treatment (pregnancy and lactation, use of anticoagulants, neurological comorbidities) should also be further explored.

Item does not contain fulltext PURPOSE: Patients with a neuromuscular disease (NMD) can present with dysarthria and/or dysphagia. Literature regarding prevalence rates of dysarthria and dysphagia is scarce. The purpose of this study was to determine prevalence rates, severity and co-presence of dysarthria and dysphagia in adult patients with NMD. METHOD: Two groups of adult patients with NMD were included: 102 consecutive outpatients (the "unselected cohort") and 118 consecutive patients who were referred for multidisciplinary assessment (the "selected cohort"). An experienced speech-language pathologist examined each patient in detail. RESULTS: The pooled prevalence of dysarthria was 46% (95% CI: 36.5-55.9) and 62% (95% CI: 53.3-70.8) in the unselected and selected cohorts, respectively. The pooled prevalence of dysphagia was 36% (95% CI: 27.1-45.7) and 58% (95% CI: 49.4-67.2) in the unselected and selected cohorts, respectively. There was a modest but significant association between the presence of dysarthria and dysphagia (rs = 0.40; p < 0.01). Although the dysphagia was generally mild, dysarthria was moderate to severe in 15% of the dysarthric patients. CONCLUSION: The prevalence rates of dysarthria and dysphagia among patients with various types of NMD are high. Physicians should therefore be aware of this prevalence and consider referring NMD patients to a speech-language pathologist. IMPLICATONS OF REHABILITATION: Both dysarthria and dysphagia are highly prevalent among patients with neuromuscular diseases; moreover, although often mild, these disorders can occur relatively early in the course of the disease. Clinicians should routinely check for signs and symptoms related to dysarthria and/or dysphagia in patients who present with a neuromuscular disease, preferably using standardised instruments.

Background. Understanding of the consequences of a neuromuscular disease (NMD) can improve when a valid sample of disease-specific categories based on the International Classification of Functioning, Disabilities, and Health (ICF) is available. Objective. To examine the content validity of the initial ICF Core Set for neuromuscular diseases (NMDs). The initial ICF Core Set was developed for three chronic neurological diseases. Design. A qualitative method. Methods. To examine the content validity of the initial ICF Core Set for NMD, concepts in established disease-specific health-related Quality of Life Questionnaires (HRQOL) were compared with ICF categories. Next, the selected ICF categories were linked to the ICF categories in the initial ICF Core Set. Results. All concepts in the HRQOL questionnaires, except one body function concept, were covered by the initial ICF Core Set. However, the NMD Core Set reflects a broader scope concerning health problems than the concepts in the HRQOL questionnaires do, especially concerning the "Participation" and "Environmental Factors" components. Conclusion. The NMD Core Set, as well as a measurement based on this Core Set, can contribute to a better understanding of the consequences of NMDs and can also serve as a basis for clinical practice, research, social security systems, and educational programs. Clinical rehabilitation impact. The newly developed NMD Core Set can be a basis for enhancing the development of rehabilitation interventions and improving overall health care for patients with a NMD.

Earlier diagnosis and the availability of effective treatments have reduced the burden of high mortality and severe disability previously associated with myasthenia gravis (MG). Consequently, the prognosis of MG is now much improved. However, despite extensive knowledge of MG and its aetiology, diagnosing the disease remains problematic and can be delayed because of its nonspecific and fluctuating symptoms, and the management of MG is associated with considerable limitations. Current treatments based on immunomodulation are associated with adverse effects arising from prolonged immune suppression. There is a need for improved awareness among primary caregivers about this relatively rare, but treatable, disease.

The sleep disorder narcolepsy is linked to the HLA-DQB1*0602 haplotype and dysregulation of the hypocretin ligand-hypocretin receptor pathway. Narcolepsy was associated with Pandemrix vaccination (an adjuvanted, influenza pandemic vaccine) and also with infection by influenza virus during the 2009 A(H1N1) influenza pandemic. In contrast, very few cases were reported after Focetria vaccination (a differently manufactured adjuvanted influenza pandemic vaccine). We hypothesized that differences between these vaccines (which are derived from inactivated influenza viral proteins) explain the association of narcolepsy with Pandemrix-vaccinated subjects. A mimic peptide was identified from a surface-exposed region of influenza nucleoprotein A that shared protein residues in common with a fragment of the first extracellular domain of hypocretin receptor 2. A significant proportion of sera from HLA-DQB1*0602 haplotype-positive narcoleptic Finnish patients with a history of Pandemrix vaccination (vaccine-associated narcolepsy) contained antibodies to hypocretin receptor 2 compared to sera from nonnarcoleptic individuals with either 2009 A(H1N1) pandemic influenza infection or history of Focetria vaccination. Antibodies from vaccine-associated narcolepsy sera cross-reacted with both influenza nucleoprotein and hypocretin receptor 2, which was demonstrated by competitive binding using 21-mer peptide (containing the identified nucleoprotein mimic) and 55-mer recombinant peptide (first extracellular domain of hypocretin receptor 2) on cell lines expressing human hypocretin receptor 2. Mass spectrometry indicated that relative to Pandemrix, Focetria contained 72.7% less influenza nucleoprotein. In accord, no durable antibody responses to nucleoprotein were detected in sera from Focetria-vaccinated nonnarcoleptic subjects. Thus, differences in vaccine nucleoprotein content and respective immune response may explain the narcolepsy association with Pandemrix.

PROBLEM: Incipient ovarian failure (IOF) is characterized by regular menstrual cycles, infertility and a raised early-follicular FSH in women under 40. IOF might be a precursor or a mitigated form of premature ovarian failure (POF). Disturbances in the immune system may play a role in ovarian failure. METHOD OF STUDY: Autoantibodies and lymphocyte subsets were determined in 3 POF patients, 50 IOF patients, and 27 controls. RESULTS: The prevalence of autoantibodies did not differ between the groups. There was a statistically significant difference in lymphocyte subsets between the control group and the POF group, with the IOF group taking an intermediate position. We found a decrease in percentage of T-suppressor cells with a rise in T-helper/T-suppressor cell ratio, a decrease in natural killer cells, and an increase in B lymphocytes and HLA-DR positive T cells. CONCLUSIONS: These data support the concept that IOF is a mitigated form of POF. The question remains whether these changes are the cause or the consequence of the ovarian failure.

Laryngeal paralysis is the effect of an inability to abduct the arytenoid cartilages duringinspiration, resulting in respiratory signs consistent with partial airway obstruction. Theaetiology of the disease can be congenital (hereditary laryngeal paralysis or congenitalpolyneuropathy), or acquired (trauma, neoplasia, polyneuropathy, endocrinopathy). Themost common form of acquired laryngeal paralysis (LP) is typically seen in old, large breeddogs and is a clinical manifestation of a generalised peripheral polyneuropathy recentlyreferred to as geriatric onset laryngeal paralysis polyneuropathy. Diagnosing LP based onclinical signs, breed and history has a very high sensitivity (90%) and can be confirmed bylaryngeal inspection. Prognosis after surgical correction depends on the aetiology: traumaticcases have a good prognosis, whereas tumour-induced or polyneuropathy-induced LP has aguarded prognosis. Acquired idiopathic LP is a slow progressive disease, with dogs reachingmedian survival times of 3–5 years after surgical correction.

BACKGROUND: Understanding of the consequences of a neuromuscular disease (NMD) can improve when a valid sample of disease-specific categories based on the International Classification of Functioning, Disabilities, and Health (ICF) is available. OBJECTIVE: To examine the content validity of the initial ICF Core Set for neuromuscular diseases (NMDs). The initial ICF Core Set was developed for three chronic neurological diseases. DESIGN: A qualitative method. METHODS: To examine the content validity of the initial ICF Core Set for NMD, concepts in established disease-specific health-related Quality of Life Questionnaires (HRQOL) were compared with ICF categories. Next, the selected ICF categories were linked to the ICF categories in the initial ICF Core Set. RESULTS: All concepts in the HRQOL questionnaires, except one body function concept, were covered by the initial ICF Core Set. However, the NMD Core Set reflects a broader scope concerning health problems than the concepts in the HRQOL questionnaires do, especially concerning the "Participation" and "Environmental Factors" components. CONCLUSION: The NMD Core Set, as well as a measurement based on this Core Set, can contribute to a better understanding of the consequences of NMDs and can also serve as a basis for clinical practice, research, social security systems, and educational programs. CLINICAL REHABILITATION IMPACT: The newly developed NMD Core Set can be a basis for enhancing the development of rehabilitation interventions and improving overall health care for patients with a NMD.

An extended pharmacokinetic/pharmacodynamic (PK/PD) model is presented, in which the effect of binding of the drug to plasma proteins and to tissue binding sites in a peripheral compartment, and nonspecific and receptor binding in the effect compartment are taken into account. It represents an extension of the classical Sheiner model, and the model proposed by Donati and Meistelman. The present model is characterized by the following parameters: ku(e) (exit rate constant of unbound drug from the effect compartment), Pu-e (ratio of the unbound clearances to and from the effect compartment), fu(e) (fraction of drug in effect compartment that is not bound to nonspecific binding sites), K-d (equilibrium dissociation constant of drug-receptor binding), and R(tot) (concentration of receptor binding sites in effect compartment). The rate of association and dissociation of the drug-receptor complex can be incorporated in the model. The influence of the pharmacokinetic parameters (V-1, V-2, fu, fu(2), CLu10, CLu20, CLu12, CLu21) and the PK/PD model parameters (ku(e), Pu-e, fu(e), K-d, R(tot)) on various dynamic parameters is analyzed. These include potency (single dose needed to produce 90% effect, ED(90)), constant infusion dosing rate needed to maintain a constant effect of 90%, time to maximum effect (onset time), and duration to 90% recovery. The neuromuscular blocking agent vecuronium is used as an example. It is shown that both potency and time course of action are strongly dependent on the ratio V-1/fu, CLu10, ku(e), Pu-e (at equipotent doses the time course is not affected by Pu-e), fu(e), K-d, and R(tot) (only if R(tot) is high), whereas they are less affected by the ratio V-2/fu(2), CLu20, CLu12, and CLu21. In general, the model parameters affect the ED(90) and the time course of action in the same direction, e.g., an increase of V-1 results in an increase of ED(90) and an increase of onset time and duration. However, the unbound clearance CLu10, the intercompartmental unbound clearance CLu12 and the receptor affinity K-d have an opposite effect on ED(90) and the time course parameters, e.g., an increase of CLu10 results in an increase of ED(90) and a decrease of onset time and duration. This effect may be responsible for the inverse relationship between onset time and potency of neuromuscular blocking drugs observed in animal experiments and clinical studies. We demonstrate that PK/PD analysis using the traditional effect compartment model (Sheiner model) results in an apparent value of k(eO), which is a function of ku(e), fu(e), K-d, R(tot), as well as the unbound drug concentration in the effect compartment Cu-e. On the other hand, the model proposed by Donati and Meistelman gives correct values of k(eO) (equal to the product fu(e) . ku(e)), but the receptor affinity K-d and the receptor density R(tot) obtained by this method are apparent values, which depend on fu, fu(e), and Pu-e.

A 10-year-old male castrated European Shorthair was presented with signs of scaling, alopecia and pruritus. The dermatopathological examination demonstrated an interface dermatitis with a few apoptotic keratinocytes, a mural lymphocytic folliculitis and the absence of sebaceous glands. These skin changes are compatible with a paraneoplastic syndrome caused by a thymoma. A thoracic radiograph confirmed the presence of a mass in the cranial mediastinum. A sternal thoracotomy was performed. One large tumor and two smaller masses were removed. Histopathological examination of the masses revealed a lymphocyte-rich thymoma. Initially, the skin lesions improved significantly. A few weeks after surgery, there was a relapse of the exfoliative dermatitis, which regressed with a dexamethasone treatment. On the last follow-up consult, 6 months post-operatively, the cat was no longer administered any medication and only showed mild scaling and no pruritus.

The clinical symptoms and MRI characteristics of transverse myelopathy (TM) due to non-compressive causes are reviewed, with special emphasis on the differential diagnosis between inflammatory demyelinating lesions, and metabolic and vascular myelopathies. Inflammatory transverse myelopathies are the commonest and most difficult ones to identify. The differentiation between clinically isolated syndromes, multiple sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis and metabolic causes is based on both clinical symptoms and paraclinical signs including magnetic resonance imaging, cerebrospinal fluid analysis, and immunological and biochemical parameters. The most intriguing form of TM is that where there is clinical evidence of complete spinal cord transection, with normal findings in magnetic resonance imaging in the acute phase, but subsequent cord atrophy.

Corticosteroid-induced osteoporosis (CIOP) is currently undertreated. Systematic review of the literature revealed that the percentage of patients treated adequately is dependent on study quality. Therefore, it remains unknown whether adherence to the guidelines is really so poor. Five major quality criteria provide the standard for future studies on this scope.Introduction It has recently been stated that the degree of prophylaxis of corticosteroid-induced osteoporosis (CIOP) is low and effort should be put into determining reasons for non-prescribing of preventive agents. The aim of this study was to identify: how many studies adequately audit the prevalent guideline; the longitudinal trends in prevention of CIOP; which patient groups appear to be most undertreated; and which intervention strategies are effective.Methods We performed a comprehensive search of MEDLINE and systematically recorded the outcomes and quality of published studies, using five major criteria.Results Twenty-four studies were included in the analysis. The quality of the included studies was poor (31%) or moderate (37%). There was a longitudinal increase in quality of the studies and percentage of prevention. Multivariable linear regression showed that the quality of the study was the only independent predictor of the prevention rate reported in the study.Conclusions The results show undertreatment of CIOP might be due to insufficient quality of the studies rather than poor practice or failure to recognise the right patients. Future interventions should comply with five major quality criteria, and a multifaceted approach is required in order to make an impact on the underprescribing of CIOP prophylaxis.

Pemphigoid gestationis (PG) is a subepidermal autoimmune blistering disease characterized by self-reactive T and B cells specific for the transmembrane hemidesmosomal protein type XVII collagen/BP180. Major T and B cell epitopes are located within the immunodominant 16(th) non-collagenous domain A (NC16A) of type XVII collagen. The aim of the present study was to map the pathogenically relevant epitopes targeted by blister-inducing patients'autoantibodies. For this purpose, we used an in vitro model of autoantibody-induced leukocyte-dependent dermal-epidermal separation. Pre-adsorption against a recombinant form of the NC16A region abolished the blister-inducing potential of autoantibodies from all PG patients. Using overlapping synthetic peptides, we demonstrated that PG autoantibodies bind to two defined epitopes within the NC16A region (aa 500-514 and aa 511-523). Importantly, pre-adsorption using an affinity matrix containing these epitopes completely abolished dermal-epidermal separation induced by PG autoantibodies. This study identifies the epitopes relevant for blister induction in PG and should facilitate the development of an antigen-specific immunoadsorption therapy for this disease.

SummaryImmunotherapies against autoimmune diseases have been of limited success. Preventive vaccines could be developed on the basis to abrogate unwanted immune responses to defined autodeterminants. In this study it is shown that immunization of BALB/c mice with two linear T and B cell epitopes of the human La/SSB autoantigen (spanning the regions 289–308aa and 349–364aa) and their complementary forms specified by the complementary mRNA, results in characteristic B and T cell responses. Mice immunized with the 289–308aa epitope or its complementary peptide elicited specific antibodies against both epitopes. In contrast, mice immunized with the 349–364aa epitope or its complementary peptide mounted antibody titres against the immunizing peptide only. According to these data, the 289–308aa epitope and its complementary form were capable to generate an idiotypic–anti-idiotypic response, which were cross-regulated. Peptide-specific T cell proliferation and cytokine production in vitro revealed the induction of a two-stage T helper response (Th1→Th2 type) after immunization with either the epitope 289–308 or its complementary peptide. IgG1 was the predominant subclass after immunization with the two forms of epitopes 289–308 and 349–364, while a response of the IgG2b > IgG2a was obtained after the immunization with the complementary form of 349–364 epitope reflecting the TH2/TH1 polarization, respectively. Our data suggest that the complementary peptides of two immunodominant epitopes of human LaSSB can mimic the autoantibodies against these epitopes and establish an active idiotypic–anti-idiotypic network.

Application of complementary B and T cell epitopes in inducing anti-idiotypic and anticlonotypic antibodies capable of regulating or suppressing the autoimmune responses in experimental autoimmune myasthenia gravis (EAMG), allergic neuritis (EAN) and allergic encephalomyelitis (EAE) has been the stimulus of many research efforts. Studies on the idiotypic/anti-idiotypic network of anti-La/SSB positive sera from patients with Sjogren's Syndrome (SS) and Systemic Lupus Erythematous (SLE) and oil animals immunized with the complementary epitopes are presented. Protein Pept Lett

Background: Antibodies to La/SSB are usually found in sera of patients with Sjogren's Syndrome (SS) and Systemic Lupus Erythematosus (SLE). Recent work from our laboratory (Mol Med 2002;8:293-305) revealed that an active idiotypic network involving antibodies to epitopes of La/SSB and their anti-idiotypes exist in human sera. The anti-idiotypic antibodies were detected using complementary peptides to B-cell epitopes of the autoantigen. The principle of the complementary peptides is based on the molecular recognition' theory. According to this theory, translation of two complementary RNA strands (coding and non-coding strand) into protein, generate a pair of peptides, which bind each other with specificity and high affinity. Aim: To investigate antibody production and T-cell responses in non-autoimmune-susceptible animal strains which were immunized with the epitope 289-308aa of La/SSB as well as its complementary epitope. Materials and Methods: Balb/c mice were immunized with a peptide corresponding to epitope 289-308aa (pep) or its complementary (cpep) peptide (5 animals/group). The sera were tested for the presence of antibodies to pep and cpep as well as for epitope spreading to recombinant human La/SSB and a major B-cell epitope of La/SSB spanning the region 349-364aa. Another group of animals was sacrificed on day 10 and T-cell responses against pep and cpep were evaluated in cells from lymph nodes and spleen. Results: Immunizations with either pep or cpep led to the appearance of antibodies against the immunogen peptide by day 31 which subsequently was followed by antibody production to its complementary peptide by day 55. In two out of five animals immunized with the epitope 289-308aa, a spreading of the immune response to epitope 349-364aa was observed. In the remaining three animals, negative for antibodies to pep349-364, a specific treatment of sera, using cpep349-364 revealed that anti-idiotypic antibodies masked antibodies to pep349-364. In all immunization experiments high T-cell proliferative responses to both pep and cpep peptides were detected. Conclusions: Complementary peptides to epitopes of La/SSB can be utilized as probes to study the development of an idiotypic-anti-idiotypic network towards the major autoantigen. The ability of pep and cpep peptides to induce both B-cell and T-cell responses may provide useful insights into understanding further the initiation and maintenance of autoimmune response and create new tools for therapeutic intervention. (C) 2003 Elsevier Ltd. All rights reserved. J Autoimmun

PROBLEM: Incipient ovarian failure (IOF) is characterized by regular menstrual cycles, infertility and a raised early-follicular FSH in women under 40. IOF might be a precursor or a mitigated form of premature ovarian failure (POF). Disturbances in the immune system may play a role in ovarian failure. METHOD OF STUDY: Autoantibodies and lymphocyte subsets were determined in 3 POF patients, 50 IOF patients, and 27 controls. RESULTS: The prevalence of autoantibodies did not differ between the groups. There was a statistically significant difference in lymphocyte subsets between the control group and the POF group, with the IOF group taking an intermediate position. We found a decrease in percentage of T-suppressor cells with a rise in T-helper/T-suppressor cell ratio, a decrease in natural killer cells, and an increase in B lymphocytes and HLA-DR positive T cells. CONCLUSIONS: These data support the concept that IOF is a mitigated form of POF. The question remains whether these changes are the cause or the consequence of the ovarian failure.

The conformational properties of two [D-A70, A76] and [Aib70, A76] analogues of the alpha67-76 Torpedo acetylcholine receptor fragment, with low binding capacity for the anti main immunogenic region (MIR) antibodies, were studied in DMSO by two-dimensional nmr techniques and molecular dynamics simulations. The results were compared to the free and bound conformations of the [A76] analogue, which has twice more affinity for the anti-MIR monoclonal antibody 6 (mAb6), than the natural Torpedo sequence. It appeared that a single substitution of the A70, at a crucial position, by the D-A70 or Aib70 ,could modify completely the conformational behavior of the peptide and reduced its recognition by the anti-MIR antibody. The WNPADY rigid structure at the N-terminal part was essential for antibody recognition. The adjacent more flexible C-terminal sequence (GGIK) gives additional stability to the monoclonal antibody-peptide complex probably due to an adequate orientation of the peptide side chains in the complex, by setting them in close contact with the antibody. Biopolymers

Two-dimensional NMR experiments [correlated spectroscopy (COSY) and two-dimensional transferred nuclear Overhauser enhancement spectroscopy (TR-NOESY)] have been applied to study the interactions of a monoclonal antibody (mAb) directed to the main immunogenic region (MIR) of the acetylcholine receptor (AChR), and four synthetic decapeptides from the MIR. The decapeptides were the Torpedo AChR alpha-67-76 fragment (W67-N68-P69-A70-D71-Y72-G73-G74-I75-K76) and its three [A69], [A73], and [A76] analogues. The results led to the following conclusions: (1) the magnitude of the TR-NOE cross peaks does not depend only on the structuration of the peptide in the bound state, but also on restrictions of the mobility, i.e., on the correlation time tau-c, which can be different for every residue; (2) the binding capacity of the synthetic peptides to mAbs measured by radioimmunoassay is directly correlated to the NOE magnitude; and (3) the combined interpretation of the COSY and TR-NOESY experiments gives a qualitative information about the nature and the overall conformation of the sequence which is in contact with the mAb binding site. Biopolymers

Immune-checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are arguably the most important development in cancer therapy over the past decade. The indications for these agents continue to expand across malignancies and disease settings, thus reshaping many of the previous standard-of-care approaches and bringing new hope to patients. One of the costs of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs), which are often distinctly different from the classical chemotherapy-related toxicities. Owing to the growing use of ICIs in oncology, clinicians will increasingly be confronted with common but also rare irAEs; hence, awareness needs to be raised regarding the clinical presentation, diagnosis and management of these toxicities. In this Review, we provide an overview of the various types of irAEs that have emerged to date. We discuss the epidemiology of these events and their kinetics, risk factors, subtypes and pathophysiology, as well as new insights regarding screening and surveillance strategies. We also highlight the most important aspects of the management of irAEs.