Abstract

Lambert-Eaton Myasthenic Syndrome:
UAB (University of Alabama at Birmingham) Experience

Shin J. Oh

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease clinically characterized by easy fatigability, proximal leg weakness, paucity of oculobulbar symptoms, and hyporeflexia. LEMS is a presynaptic disorder induced by the antibodies against voltage-gated calcium channels. This antibody was found in 70% of UAB LEMS patients. LEMS is often associated with small cell lung cancer, seen in 60% of our cases. The classic clinical triad of LEMS includes proximal leg weakness, hyporeflexia or areflexia, and cholinergic dysautonomia. A transient improvement in muscle strength and reflexes immediately after brief exercise, the pathognomonic finding of LEMS, was found in 43% of cases according to our experience. LEMS is a disease of the elderly, with the most common age of onset of symptoms being about 60 years of age. The diagnosis of LEMS can only be confirmed by the repetitive nerve stimulation (RNS) test. It is characterized by the classical triad: (a) low compound muscle action potential, (b) decremental response at low rate stimulation, (c) marked incremental response at high rate stimulation or after brief exercise. Our study showed that 10 seconds exercise should be the standard test and a more than 60% increment in post-exercise facilitation and at high rate stimulation is sufficient for the diagnosis of LEMS. Our study also showed that the RNS test is more typical of LEMS and more abnormal in the seropositive LEMS group. Our studies showed that 3,4-diaminopyridine is the drug of choice for symptomatic treatment. Guanidine HCl is an alternative choice of drug, usually with pyridostigmine.

The History of Research into Heart Failure

Shigetake Sasayama

The first clear description of the circulation by William Harvey in 1628 put medical science on a new footing and made it possible to recognize the causal link between blood flow abnormalities in the heart and cardiac enlargement. Subsequently, two patterns of cardiac enlargement were identified. Lancisi first distinguished between enlarged hearts with increased cavity size (eccentric hypertrophy, dilatation), and with increased wall thickness (concentric hypertrophy, hypertrophy). Corvisart wrote an even more detailed description of these two types of cardiac enlargement and noted that dilatation has a worse prognosis. Early in 20th century, Starling demonstrated the major principles of cardiac function that increasing end-diastolic volume enhances cardiac performance. This view contradicted the above mentioned 18th century view that dilatation weakens the heart. Starling’s law is based on the myocardial length-active tension relation and its ascending and descending limbs were explained by the relation between sarcomere length and ventricular performance in the intact ejecting heart. Ventricular function was measured during the ejecting phase of contraction in terms of the appropriateness of the matching between afterload and the level of inotropic state as modulated by the preload. Then, the concept of afterload mismatch was illustrated and used as a basis for characterizing response to afterload changes. William Osler described three stages in the development of hypertrophy from adaptive to maladaptive. The latter half of the 20th century was devoted to elucidate the mechanisms responsible for progression in heart failure caused by maladaptive hypertrophy in the perspective of modern concept. Looking back at the history of the research in heart failure, the evolving concepts of heart failure encourage us to challenge the future trend of the study incorporating new information from molecular biology.

Tumor-induced Dysfunctions in Adaptive and Innate Immunity:A Novel Therapeutic Target for Melanoma Patients?

Licia Rivoltini

Several molecular mechanisms are deemed responsible for the inability of the immune system to efficiently control tumor growth in primary or metastatic lesions, and for the reduced immunological and clinical responses to cancer vaccines. We recently characterized in cancer patients the phenotypic and functional features of myeloid-derived suppressor cells (MDSC), a key player in tumor-related immunsoppression. A major involvement of monocyte-like MDSC (moMDSC) expressing low level of HLA-DR and secreting TGF-beta along with a large panel of pro-angiogenic and pro-tumorigenic cytokines and chemokines, has been identified in melanoma patients. Interestingly, moMDSC accumulation can be detected in primary melanoma lesions and in peripheral blood of early stage melanoma patients, suggesting a crucial involvement of this pathway in disease progression. In contrast, we could not identify any sign of altered function in peripheral blood neutrophils, implying a limited impact of granulocyte-MDSC in melanoma. We are recently studing whether altered metabolic condition affecting tumor site might also have relevant drawbacks on tumor immunity. Our data, obtained both in murine models and in cancer patients, clearly show that low pH, an hallmark feature of tumor microenvironment, enhances MDSC-mediated immunosuppression, while tumor pH buffering by the administration of proton pump inhibitors such as esomeprazole, readily reduces MDSC activity and allows T cell function recovery. Therefore, acidity of tumor microenvironment represents a further mechanism of immune escape that can be overcome by drugs like PPI for recovering effective tumor immunity in cancer patients.

Lineage Diversification of the Multipotent Cardiac Progenitors

Atsushi Nakano

While great progress has been made during the past 10 years in the analyses of the diversity of the cardiovascular lineages, our understanding of the cellular basis for the lineage diversification is still at its primitive stage. Recent studies have uncovered a diverse group of Isl1-positive cardiac progenitors derived from the second heart field that are central in controlling and coordinating the complex steps of cardiogenesis. Understanding the pathways that control their formation, renewal, and subsequent conversion to specific differentiated progeny forms the underpinning for unraveling the pathways for congenital heart diseases and has direct relevance to cardiovascular regenerative medicine. Lineage tracing using Isl1-Cre mice revealed that Isl1-positive cardiac progenitors contribute to three major cardiovascular cell types; cardiac, smooth muscle and endothelial cells in vivo. To investigate the multipotency of the cardiac progenitors, we used cardiac mesenchymal feeder layer and demonstrated that the early cardiac progenitors expressing Flk1/Isl1/Nkx2.5 give rise to three major cardiovascular cell types. While endothelial competency is lost early during cardiogenesis, the cardiac and smooth muscle lineages stay closely related until later stages. Even until midgestational stages, a subset of late Isl1-progenitors maintain their bipotency to give rise to smooth muscle cells in vivo and in vitro. This cardiac-smooth muscle differentiation potential seems to be required for the formation of the boundary between the heart and great vessels that facilitate the dynamism of the central circulatory system. Together, Isl1-progenitors play an essential role during the formation of the cardiovascular system at multiple steps.