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Mercuri E.,Catholic University | Mercuri E.,University College London | Muntoni F.,University College London
The Lancet | Year: 2013

Muscular dystrophies are a heterogeneous group of inherited disorders that share similar clinical features and dystrophic changes on muscle biopsy. An improved understanding of their molecular bases has led to more accurate definitions of the clinical features associated with known subtypes. Knowledge of disease-specific complications, implementation of anticipatory care, and medical advances have changed the standard of care, with an overall improvement in the clinical course, survival, and quality of life of affected people. A better understanding of the mechanisms underlying the molecular pathogenesis of several disorders and the availability of preclinical models are leading to several new experimental approaches, some of which are already in clinical trials. In this Seminar, we provide a comprehensive review that integrates clinical manifestations, molecular pathogenesis, diagnostic strategy, and therapeutic developments.

Mercuri E.,Catholic University | Bertini E.,Bambino Gesu Hospital | Iannaccone S.T.,University of Texas Southwestern Medical Center
The Lancet Neurology | Year: 2012

Spinal muscular atrophy is an autosomal recessive disorder characterised by degeneration of motor neurons in the spinal cord and is caused by mutations of the survival of motor neuron 1 gene SMN1. The severity of spinal muscular atrophy is highly variable and no cure is available at present. Consensus has been reached on several aspects of care, the availability of which can have a substantial effect on prognosis, but controversies remain. The development of standards of care for children with the disorder and the identification of promising treatment strategies have changed the natural history of spinal muscular atrophy, and the prospects are good for further improvements in function, quality of life, and survival. A long-term benefit for patients will be the development of effective interventions (such as antisense oligonucleotides), some of which are in clinical trials. The need to be prepared for clinical trials has been the impetus for a remarkable and unprecedented cooperation between clinicians, scientists, industry, government, and volunteer organisations on an international scale. © 2012 Elsevier Ltd.

Patrono C.,Catholic University
Journal of the American College of Cardiology | Year: 2015

Inactivation of platelet cyclooxygenase (COX)-1 by low-dose aspirin leads to long-lasting suppression of thromboxane (TX) A2 production and TXA2-mediated platelet activation and aggregation. This effect is necessary and sufficient to explain aspirin's unique (among other COX-1 inhibitors) effectiveness in preventing atherothrombosis, as well as its shared (with other antiplatelet agents) bleeding liability. However, different mechanisms of action have been suggested to explain other beneficial effects of aspirin, such as prevention of venous thromboembolism, chemoprevention of colorectal (and other) cancers, and reduced risk of dementia. These mechanisms include acetylation of other proteins in blood coagulation, inhibition of COX-2 activity, and other COX-independent mechanisms. The intent of this review is to develop the concept that the multifaceted therapeutic effects of low-dose aspirin may reflect pleiotropic consequences of platelet inhibition on pathophysiological tissue repair processes. Furthermore, the clinical implications of this concept will be discussed in terms of current clinical practice and future research. © 2015 American College of Cardiology Foundation.

Evoli A.,Catholic University
Current Opinion in Neurology | Year: 2010

Purpose of review: This review discusses recent studies on myasthenia gravis with onset in childhood (juvenile myasthenia gravis) and neonatal myasthenia gravis. Recent findings: The occurrence of myasthenia gravis in childhood is strongly influenced by genetic and environmental factors. Juvenile myasthenia gravis is associated with antibodies to the acetylcholine receptor (AChR) in most patients. Thymoma is rare, but often malignant in children. The frequency of juvenile myasthenia gravis with antibodies to the muscle-specific kinase (MuSK) varies markedly in different countries; some distinct features have been described. Management of juvenile myasthenia gravis does not differ, on the whole, from that of adult myasthenia gravis. Timing of thymectomy in young children is still controversial.Maternal antifetal type AChR antibodies can cause persistent focal weakness in the offspring, while neonatal myasthenia gravis associated with MuSK antibodies is often a severe and protracted albeit transient disease. Summary: Juvenile myasthenia gravis, like its adult-onset counterpart, is a heterogeneous disease. Clinical presentation is influenced by antibody status, ethnicity and age of onset. Treatment is very effective, but guidelines and controlled trials are needed.The risk for neonatal myasthenia gravis appears to be markedly influenced by maternal antibody subclass and antigen specificity. Adequate treatment in mothers can reduce both frequency and severity of neonatal disease. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Scatena R.,Catholic University
Advances in Experimental Medicine and Biology | Year: 2012

At the beginning of the twentieth century, Otto Warburg demonstrated that cancer cells have a peculiar metabolism. These cells preferentially utilise glycolysis for energetic and anabolic purposes, producing large quantities of lactic acid. He defined this unusual metabolism "aerobic glycolysis". At the same time, Warburg hypothesised that a disruption of mitochondrial activities played a precise pathogenic role in cancer. Because of this so-called "Warburg effect", mitochondrial physiology and cellular respiration in particular have been overlooked in pathophysiological studies of cancer. Over time, however, many studies have shown that mitochondria play a fundamental role in cell death by apoptosis or necrosis. Moreover, metabolic enzymes of the Krebs cycle have also recently been recognised as oncosuppressors. Recently, a series of studies were undertaken to re-evaluate the role of oxidative mitochondrial metabolism in cancer cell growth and progression. Some of these data indicate that modulation of mitochondrial respiration may induce an arrest of cancer cell proliferation and differentiation (pseudodifferentiation) and/or or death, suggesting that iatrogenic manipulation of some mitochondrial activities may induce anticancer effects. Moreover, studying the role of mitochondria in cancer cell dedifferentiation/differentiation processes may allow further insight into the pathophysiology and therapy of so-called cancer stem cells. © 2012 Springer Science+Business Media B.V.

Crea F.,Catholic University | Liuzzo G.,Catholic University
Journal of the American College of Cardiology | Year: 2013

Experimental models of atherogenesis have provided a growing body of information about molecular mechanisms of plaque growth; however, transition from coronary stability to instability is less well understood due to the lack of animal models reflective of human disease. The abrupt clinical presentation of acute coronary syndromes gives a strong signal of discontinuity in the natural history of atherothrombosis. The causes of such discontinuity are complex, probably multiple, and still largely unknown. A better knowledge of the causes of coronary instability might allow identification of new therapeutic targets aimed at the preservation of plaque stability in those subjects in whom primary prevention fails to prevent plaque growth. The goal of this review was to propose a pathogenetic classification of acute coronary syndromes that might help in the search of new diagnostic algorithms and therapeutic targets. © 2013 American College of Cardiology Foundation.

Ratto C.,Catholic University
Techniques in Coloproctology | Year: 2014

Transanal hemorrhoidal dearterialization (THD) is an effective treatment for hemorrhoidal disease. The ligation of hemorrhoidal arteries (called "dearterialization") can provide a significant reduction of the arterial overflow to the hemorrhoidal piles. Plication of the redundant rectal mucosa/submucosa (called "mucopexy") can provide a repositioning of prolapsing tissue to the anatomical site. In this paper, the surgical technique and perioperative patient management are illustrated. Following adequate clinical assessment, patients undergo THD under general or spinal anesthesia, in either the lithotomy or the prone position. In all patients, distal Doppler-guided dearterialization is performed, providing the selective ligation of hemorrhoidal arteries identified by Doppler. In patients with hemorrhoidal/muco-hemorrhoidal prolapse, the mucopexy is performed with a continuous suture including the redundant and prolapsing mucosa and submucosa. The description of the surgical procedure is complemented by an accompanying video (see supplementary material). In long-term follow-up, there is resolution of symptoms in the vast majority of patients. The most common complication is transient tenesmus, which sometimes can result in rectal discomfort or pain. Rectal bleeding occurs in a very limited number of patients. Neither fecal incontinence nor chronic pain should occur. Anorectal physiology parameters should be unaltered, and anal sphincters should not be injured by following this procedure. When accurately performed and for the correct indications, THD is a safe procedure and one of the most effective treatments for hemorrhoidal disease. © 2013 Springer-Verlag Italia.

Iorio R.,Catholic University | Lennon V.A.,Mayo Medical School
Immunological Reviews | Year: 2012

Neural-specific autoantibodies have been documented and their diagnostic utility validated in diseases affecting the neuraxis from cerebral cortex to the somatic, autonomic, and enteric nervous system and skeletal muscle. These neurological disorders occur both idiopathically and in a paraneoplastic context. Molecular identification of the antigens has expedited development of confirmatory and high-throughput tests for serum and cerebrospinal fluid, which permit early diagnosis and reveal the underlying molecular pathogenic mechanisms. The autoantibodies are classifiable on the basis of antigen location: intracellular (nuclear or cytoplasmic) or plasma membrane. Immunohistopathological studies of patients' biopsied and autopsied tissues suggest that effector T cells mediate the autoimmune neurological disorders for which defining autoantibodies recognize intracellular antigens. Antigens within intact cells are inaccessible to circulating antibody, and the associated neurological deficits rarely improve with antibody-depleting therapies. Tumoricidal therapies may arrest neurological progression, but symptom reversal is rare. In contrast, autoantibodies specific for plasma membrane antigens have pathogenic potential, and the associated neurological deficits are often amenable to antibody-depleting immunotherapy, such as plasma exchange and anti-B-cell monoclonal antibody therapy. These reversible neurological disorders are frequently misdiagnosed as neurodegenerative. The focus of this review is the immunobiology, pathophysiology, and clinical spectrum of autoimmune neurological disorders accompanied by neural-specific IgGs. © 2012 John Wiley & Sons A/S.

De Stefano V.,Catholic University | Rossi E.,Catholic University
Thrombosis and Haemostasis | Year: 2013

The clinical penetrance of venous thromboembolism (VTE) susceptibility genes is variable, being lower in heterozygous carriers of factor V Leiden and prothrombin 20210A (mild thrombophilia), and higher in the rare carriers of deficiencies of antithrombin, protein C or S, and those with multiple or homozygous abnormalities (high-risk throm-bophilia). The absolute risk of VTE is low, and the utility of laboratory investigation for inherited thrombophilia in patients with VTE and their asymptomatic relatives has been largely debated, leading to the production of several Guidelines from Scientific Societies and Working Groups. The risk for VTE largely depends on the family history of VTE. Therefore, indiscriminate search for carriers is of no utility, and targeted screening is potentially more fruitful. In patients with VTE inherited thrombophilia is not scored as a determinant of recurrence, playing a minor role in the decision of prolonging anticoagulation; indeed, a few guidelines consider testing worthwhile to identify carriers of high-risk thrombophilia, particularly those with a family history of VTE. The identification of the asymptomatic carrier relatives of the probands with VTE and thrombophilia could reduce cases of provoked VTE, offering them primary antithrombotic prophylaxis during risk situations. In most guidelines, this is considered justified only for relatives of probands with a deficiency of natural anticoagulants or multiple abnormalities. Counselling the asymptomatic female relatives of individuals with VTE and/or thrombophilia before pregnancy or the prescription of hormonal treatments should be administered with consideration of the risk driven by the type of thrombophilia and the family history of VTE. © Schattauer 2013.

Scatena R.,Catholic University
Advances in Experimental Medicine and Biology | Year: 2012

Mitochondria play a central role in the life and death of cells. They are not merely the centre for energy metabolism, but are also the headquarters for different catabolic and anabolic processes, calcium fluxes, and various signalling pathways. Mitochondria maintain homeostasis in the cell by interacting with reactive oxygen-nitrogen species and responding adequately to different stimuli. In this context, the interaction of pharmacological agents with mitochondria is an aspect of molecular biology that is too often disregarded, not only in terms of toxicology but also from a therapeutic point of view, especially considering the potential therapeutic applications related to the modulation of mitochondrial activity. At the mitochondrial level, there are several potential drug targets that can lead to toxicity, but only for few of them, a real clinical counterpart has been demonstrated. Recently, antiviral nucleoside analogues have shown mitochondrial toxicity through the inhibition of DNA polymerase-gamma. Other drugs targeted to different components of the mitochondrial channels can disrupt ion homeostasis or affect the mitochondrial permeability transition pore. Many molecules are known inhibitors of the mitochondrial electron transport chain, interfering with one or more of the complexes in the respiratory chain. Some drugs, including non-steroidal anti-inflammatory drugs (NSAIDs), may lead to uncoupling of oxidative phosphorylation, while the mitochondrial toxicity of other drugs seems to depend on the production of free radicals, although this mechanism has yet to be defined. Besides toxicity, other drugs have been targeted to mitochondria to treat mitochondrial dysfunctions. Many drugs have been recently developed to target the mitochondria of cancer cells in order to trigger apoptosis or necrosis. The aim of this chapter is to underline the role of mitochondria in pharmacology and toxicology, stressing all the potential therapeutic approaches being due to iatrogenic modulation of the multitude of mitochondrial activities © 2012 Springer Science+Business Media B.V.

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