Advances in the diagnosis, immunopathogenesis and therapies of IgM-anti-MAG antibody-mediated neuropathies.

Polyneuropathy with immunoglobulin M (IgM) monoclonal gammopathy is the most common paraproteinemic neuropathy, comprising a clinicopathologically and immunologically distinct entity. The clinical spectrum spans from distal paresthesias and mild gait imbalance to more severe sensory ataxia, with falls and a varying degree of distal sensorimotor deficits. In approximately 75% of patients, the monoclonal IgM immunoreacts with myelin-associated glycoprotein (MAG) and sulfoglucuronyl glycosphingolipid (SGPG), or other peripheral nerve glycolipids that serve as antigens. These antibodies are considered pathogenic because IgM and complement are deposited on the myelin sheath, splitting the myelin lamellae, while adoptive transfer of patients\u27 IgM into susceptible host animals causes sensory ataxia and reproduces the human pathology. In spite of the apparently convincing pathogenicity of these antibodies, the response to immunotherapies remains suboptimal. Clorambuscil, cladibrine, cyclophospamide and intravenous immunoglobulin may help some patients but the benefits are minimal and transient. Open-label studies in \u3e200 patients indicate that rituximab is helpful in 30-50% of these patients, even with long-term benefits, probably by suppressing IgM anti-MAG antibodies or inducing immunoregulatory T cells. Two controlled studies with rituximab did not however meet the primary endpoint, mostly because of the poor sensitivity of the scales used; they did however show statistical improvement in secondary endpoints and improved clinical functions in several patients. This review provides an overview of the clinical phenotypes and immunoreactivity of IgM to glycolipids or glycoproteins of peripheral nerve myelin, summarizes the progress on treatment with rituximab as a promising therapy, discusses the pitfalls of scales used, identifies possible biomarkers of response to therapy and highlights the promising new anti-B cell or target-specific immunotherapies

Neurological complications of immune checkpoint inhibitors: what happens when you \u27take the brakes off\u27 the immune system.

Patients with advanced malignancies treated with immune checkpoint inhibitors are at increased risk for developing immune-related neurological complications. It is a phenomenon of immunological twist when immunotherapy against co-stimulatory molecules activates previously normal T cells to kill tumor cells but, in so doing, the T cells become unrestrained, triggering other autoimmune diseases for which conventional immunotherapy is needed. The most common autoimmune neurological diseases, usually occurring within 2-12 weeks after immune checkpoint inhibitor initiation, include: inflammatory myopathies, myasthenia gravis, acute and chronic demyelinating polyradiculoneuropathies, vasculitic neuropathies, isolated cranial neuropathies, aseptic meningitis, autoimmune encephalitis, multiple sclerosis and hypophysitis. The neurological events can evolve rapidly, necessitating the need for vigilance at all stages of treatment, even after completion, because early immunotherapeutic interventions are effective. The review addresses these complications and the applied therapies, discusses immune pathomechanisms including triggering preexisting autoimmunity, highlights the distinction between paraneoplastic and autoimmune etiologies, and identifies uncertainties regarding risk factors, use of immune checkpoint inhibitors in patients with known immune diseases or restarting therapy after a neurological event. Although the autoimmune neurological complications are not very common, their incidence will likely increase as the use of immune checkpoint inhibitors in metastatic cancer is growing rapidly

Agricultural situation report of Cyprus and the market and trade policies for fruit/vegetable and olive oil

During the last decade the Cypriot agricultural sector has been declining in terms of most indices in the economy, mainly due to the spiraling growth of tourism, as crucial investment outlays were diverted from agriculture to tourism; the most important factors of production being land and labor due to substantially higher yields accruing to both. The Domestic Resource Cost (DRC) revealed that the three products studied for the period 1997 to 2000, i.e. tomatoes, oranges and olive oil had a comparative advantage. However, the opening of the European market with EU accession led to the substantive undermining of competitiveness of agricultural products and to the reduction of the value of exports. It is believed that DRC ratios would be higher today that the ones reported, due to unchanged /decreased border prices and increased costs of tradable inputs. It is suggested that the tomato, orange and olive oil sectors will become more competitive in the European market if factors that are affecting their marketing, like differentiation of production and quality, are improved. New concepts like organic farming and products of origin are very important and may provide profitable outlets in the new globalized economy. Additionally, favorable climatic conditions are vastly for and conducive to the production of early season Mediterranean products with obvious premium attached in the market place.Domestic Resource Cost, Competitiveness, Tomatoes, Oranges, Olive Oil, International Relations/Trade,

TESTING DYNAMIC MODELS OF THE FARM FIRM

In this paper two models of dynamic firm behavior are fitted to a data set developed from business records of Indiana dairy farms. The parametric restrictions implied by a cost-of-adjustment model are rejected. A less restrictive, disequilibrium model is accepted; this is a model of partial and interrelated adjustment among inputs and outputs. The results suggest that adjustment in quasi-fixed inputs is slow affecting the adjustment in variable inputs and outputs.Agricultural Finance, Livestock Production/Industries,

Rockfall hazard and risk assessment: an example from a high promontory at the historical site of Monemvasia, Greece

The paper presents the kinematics of rock instability of a high limestone promontory, where the Monemvasia historical site is situated, in Peloponnese in Southern Greece. The instability phenomena poses a significant threat to the town located at the base of the slope. Rockfall episodes occurred in the past due to the relaxation of the high cliff, whereas significant undermining of the castle frontiers has been observed at the slope crest. <br><br> The predominant types of instability are of planar, wedge and toppling failure of medium to large blocks. In order to investigate the existing stability conditions and decide upon the protection measures, stability and rockfall analyses were carried out for numerous slope sections under different loading conditions and protection measures were suggested. <br><br> A rock-fall risk rating system is proposed, which is based on morphological and structural criteria of the rock mass and on vulnerability and consequences. The rating system is applied for individual sections along the slope and a risk map was produced, which depicted areas having different degree of risk against rockfall occurrences

Law and compassion: between ethics and economy, philosophical speculation and archeology

This paper examines the relationship between law and compassion from the perspective of two diverse scholars. For philosopher Emmanuel Levinas, rejecting the idea homo homini lupus, there can simply be no organized society but for a primordial, unauthorized, human vocation for compassion (egoism and violence, for him, are nothing but attempts to repress this). Levinas, however, must be understood, as speaking of compassion not in the usual sense, that is as involving a human capacity for, and cultures of, empathy; he defines it, rather, in phenomenological terms, as an irreducible excess of affectivity for the ultimately meaningless suffering of another, beyond all theodicy and causality, whom one is ethically commanded to offer succour to as if s/he is a ‘higher’ and absolutely unique Other, prior to any comparison and judgement. General legal principles and rigorous rules, Natural Justice and positive law are equally ‘born’ of such an-archic, individuated, compassion for which one can only retroactively account. Justice is ‘born’ as one attempts to justify to third parties why one’s care benefits some but not others; the paper argues that this perspective is preferable to prioritizing empathic compassion over law for it binds compassion with responsibility. Turning to Giorgio Agamben, the role of compassion takes on a darker character; his historicized investigations of the ‘western-Christian’ paradigm shows how the Greek and Roman legal principles of epieikeia, and aequitas merged with the Christian postulates of God-dictated philanthropy and ‘divine economy’ (Gr: oikonomia), leading –instead of ethical anarchy followed by with infinite responsibility (Levinas) – to anomie, legal exceptionalism and social control via patronage and other bio-political practices to spectacles of compassion. This suggests that what Levinas calls ‘ethical anarchy’ has been captured by economic rationality and endless processes of anomic management that are equally free of ethical constraints as they are from legal and political decision. With reference to contemporary examples from the ‘law and emotion’ debates, medical laws and humanitarianism, the paper asks the reader to ponder upon the importance, if any, of Levinas’ thesis in a world where the expediency of managerial rationality, the secular heir of divine oikonomia, prevails over moral, legal and political principle

Inflammatory Muscle Diseases.

INFLAMMATORY MYOPATHIES ARE THE LARGEST GROUP OF POTENTIALLY treatable myopathies in children and adults. They constitute a heterogeneous group of disorders that are best classified, on the basis of distinct clinicopathologic features, in four subtypes: dermatomyositis, polymyositis, necrotizing autoimmune myositis, and inclusion-body myositis (throughout this review, I use this term to refer specifically to sporadic inclusion-body myositis). 1-6 A fifth subtype, termed overlap myositis, is also beginning to be recognized. The identification of the correct subtype and the distinction of these conditions from other diseases that have characteristics that mimic these conditions is fundamental, because each subtype has a different prognosis and response to therapies. This review reflects the current knowledge of these conditions, highlights how best to avoid erroneous diagnoses, describes the main clinicopathologic and immunologic features, and provides practical guidelines regarding therapies

Obinutuzumab, a potent anti-B-cell agent, for rituximab-unresponsive IgM anti-MAG neuropathy.

Anti-MAG demyelinating neuropathy is difficult to treat. All immunotherapies have failed except for rituximab, a chimeric B-cell–depleting monoclonal antibody against CD20, that helps up to 40% of patients based on 2 controlled and several uncontrolled series.1,–,3 Because the majority of these patients are left disabled, stronger anti–B-cell agents might be promising. We describe clinical response and autoantibody changes after treatment with obinutuzumab (Gazyva), a new generation of humanized anti-CD20 monoclonal antibodies, in 2 patients with anti-MAG neuropathy who continued to worsen despite multiple courses of rituximab. Obinutuzumab, approved for chronic lymphocytic leukemia (CLL), exerts greater peripheral and lymphoid B-cell depletion4 and might be more effective in rituximab-refractory patients. © Rakocevic et al