Gastrointestinal polyposis syndromes

Colorectal cancer is one of the leading causes of cancer-related death in the Western society, and the incidence is rising. Rare hereditary gastrointestinal polyposis syndromes that predispose to colorectal cancer have provided a model for the investigation of cancer initiation and progression in the general population. Many insights in the molecular genetic basis of cancer have emerged from the study of these syndromes. This review discusses the genetics and clinical manifestations of the three most common syndromes with gastrointestinal polyposis and an increased risk of colorectal cancer: familial adenomatous polyposis (FAP), juvenile polyposis (JP) and Peutz-Jeghers syndrome (PJS).     

Why and how to support screening strategies to prevent sudden death in athletes

Sudden death in athletes occurs because of the existence of hidden cardiovascular disorders which, during effort, may jeopardize the electrical stability of the heart, triggering ventricular tachycardia and/or fibrillation. Apart from rare conditions of ion channel diseases in the setting of a structurally normal heart, in which the disorder may be easily diagnosed on basal or stress test ECG, cardiac abnormalities at risk of causing sudden death may affect the aorta (Marfan syndrome), the coronary arteries (congenital coronary artery anomalies, premature coronary atherosclerosis), the myocardium (hypertrophic and arrhythmogenic cardiomyopathy), the valves (bicuspid aortic valve, mitral valve prolapse) and the conduction system (pre-excitation syndromes). These structural heart disorders may be detected by ECG and/or echo. The employment of these tools at pre-participation screening can help to identify concealed anomalies, which may play a major role in early diagnosis, risk stratification, and prevention of sudden death.     

Flow cytometric diagnosis of myelodysplasia and myeloproliferative disorders

The current diagnosis of both myelodysplastic syndromes and myeloproliferative disorders relies in large part on subtle and subjective morphologic findings and the presence of cytogenetic abnormalities. Consequently, diagnosis of these disorders is often difficult and tentative with diagnosis at early stages representing a particular challenge. There is a need for new diagnostic techniques to allow a more definitive and objective diagnosis for these diseases. The published literature relating to the potential diagnostic utility of flow cytometric immunophenotyping in the diagnosis of myelodysplastic syndromes and myeloproliferative disorders is reviewed, and the increasingly important contribution of this technique to the diagnosis of these disorders emphasized.     

Contiguous deletion syndromes.

In the past few years, clinical, cytogenetic and molecular analysis of patients with complex phenotypes has led to the identification of syndromes caused by deletions of adjacent disease genes on a chromosome. These conditions, referred to as contiguous deletion syndromes, are an important component of the syndromes recognized in medical genetics, and the DNA from patients affected by these disorders is useful for the mapping and cloning of disease genes.     

Debate: When should we intervene in unstable angina - Time for an old look?

Current treatment modalities for patients with acute coronary syndromes center on early diagnosis, risk stratification and, increasingly, early treatment including invasive approaches. The appropriate timing of these invasive modalities in the context of the overall treatment program remains an area of controversy. Specifically, studies in the past recommended a period of medical 'stabilization' while current approaches are considerably more aggressive. The potential hazard of early intervention, in particular, has not properly been weighed against the benefit. This article hopes to provide a framework for examining the appropriate timing of intervention, specifically percutaneous coronary intervention, in acute coronary syndromes.     

Normal and cancer-prone human cells respond differently to extremely low frequency magnetic fields

Human lymphoblastoid cells of normal origin and from genetic instability syndromes, i.e. Fanconi anemia (FA) group C and ataxia telangectasia, were continuously exposed to extremely low frequency magnetic field (ELF-MF). We report that ELF-MF, though not perturbing cell cycle progression, increases the rate of cell death in normal cell lines. In contrast, cell death is not affected in cells from genetic instability syndromes; this reflects a specific failure of the apoptotic response. Reintroduction of complementation group C in FA cells re-established the apoptotic response to ELF-MF. Thus, genes implicated in genetic instability syndromes are relevant in modulating the response of cells to ELF-MF.     

Congenital syndromes and leukemia: clues to pathogenesis

The association of specific congenital syndromes with leukemia provides an opportunity to study the process of leukemogenesis on the background of known genetic alterations. The role of the intracellular DNA damage response system in suppressing leukemia is demonstrated by the congenital disorders of genomic instability. Specific collaborations between survival and differentiation pathways characterize the leukemias observed in Down, Noonan and neurofibromatosis syndromes. As these syndromes clearly reveal, childhood leukemia arises when the delicate balance between growth, development and differentiation of the fetal and early post-natal hematopoietic system is disrupted.     

Antithrombotic recombinant antibodies

Coronary syndromes, stroke and other ischaemic arterial diseases are the leading cause of death in the world and will probably remain it at least until 2020. Cardiovascular diseases kill 17 million people each year with an expected increase to 20 million in 2020 and 24 million in 2030. The global impact of recurrence and death during the 6 months following an acute coronary syndrome remains at 8-15% in the present state of medical practice. Acute ischaemic syndromes have a common aetiology that is the formation of a platelet-rich clot at the site of severe coronary stenosis and of eroded atherosclerotic plaques. Therapy consists of medical treatments associating thrombolysis, antiplatelet drugs, and the re-opening of the coronary artery by angioplasty. But these treatments do not prevent morbidity and mortality reaching 15% at 6 months. Finally the treatment of stroke is very limited. There is thus a real clinical need to improve existing treatments and to discover new molecules. Platelet activation is a critical step in ischaemic cardiovascular diseases. This is the reason why antiplatelet drugs are most often prescribed in these cases. Currently, only one recombinant antithrombotic antibody is used in therapy. This is a chimeric Fab, c7E3 or abciximab, which inhibits the final phase of platelet aggregation. Abciximab is prescribed in acute coronary syndromes treated by angioplasty. However, treatment by abciximab can induce severe complications, principally, hemorrages and thrombopenia. Other platelet receptors involved in the earlier steps of platelet activation, such as the phases of contact with and of activation by the subendothelium matrix, have been identified as potential targets for the development of antithrombotic antibodies and are described in this revue.     

Mastalgia and total body water.

Total body water (TBW) was measured early and late in a menstrual cycle in 56 women, 39 of whom had breast pain. The remainder were asymphtomatic controls. Most women did not conform to the traditional view that there is a premenstrual increase in TBW. In some TBW decreased, while in others there was no change from the early cycle measurement. No TBW pattern correlated with any syndromes of breast pain or with any psychoneurotic profile.     

Apoptosis and oncosis in acute coronary syndromes: Assessment and implications

The rational design of therapeutic interventions for protection of ischemic myocardium from ultimate death requires an understanding of the mechanistic basis of cardiomyocyte (CM) cell death, its timing and the tools for its quantification. Until recently, CM cell death following ischemia and/or reperfusion was considered to involve necrosis or accidental cell death from very early on. Collective evidence over the past decade indicates that early CM cell death after myocardial ischemia and post-ischemic reperfusion involves apoptosis with cell shrinkage and drop-out, and/or oncosis with cell swelling followed by necrosis. This paradigm shift suggests that different approaches for cardioprotection are required. Oncologists, pathologists, anatomists and basic scientists who have studied apoptosis over the last three decades separated physiological apoptosis from inappropriate apoptosis in pathological states. Until recently, cardiologists resisted the concepts of CM apoptosis and regeneration. Cumulative evidence indicating that apoptosis in the heart may occur in different cell types, spread from one cell type to another, and occur in bursts, may have profound implications for therapies aimed at protection of ischemic myocardium by targeting CM apoptosis in acute coronary syndromes. This review focuses on a critique of the methods used for the assessment of CM apoptosis and the implications of CM apoptosis in acute coronary syndromes. (Mol Cell Biochem 270: 177–200, 2005)     

Salmonella-induced macrophage death: the role of caspase-1 in death and inflammation.

Salmonella typhimurium invades host macrophages and can induce either an almost immediate cell death or establish an intracellular niche within the phagocytic vacuole. Rapid cell death depends on the Salmonella pathogenicity island SPI1 and the host protein caspase-1, a member of the pro-apoptotic caspase family of proteases. Caspase-1-dependent cell death leads to the activation of the potent pro-inflammatory cytokines interleukin (IL)-1beta and IL-18 to produce bioactive cytokines. Animal studies indicate that the activation of these cytokines is necessary for efficient colonization of the mouse gastrointestinal tract. Salmonella that reside in the phagocytic vacuole do not cause this early cell death and can trigger a macrophage death at a much later time point. This late-phase cell death is dependent on SPI2-encoded genes and ompR.     

Genetic determinants of QT interval variation and sudden cardiac death

Electrocardiographic QT interval prolongation or shortening is a risk factor for sudden cardiac death. The study of Mendelian syndromes in families with extreme long and short QT interval duration and ventricular arrhythmias has led to the identification of genes encoding ion channel proteins important in myocardial repolarization. Rare mutations in such ion channel genes do not individually contribute substantially to the population burden of ventricular arrhythmias and sudden cardiac death. Only now are studies systematically testing the relationship between common variants in these genes--or elsewhere in the genome--and QT interval variation and sudden cardiac death. Identification of genetic variation underlying myocardial repolarization could have important implications for the prevention of both sporadic and drug-induced arrhythmias.     

A high-throughput histoarray for quantitative molecular profiling of multiple, uniformly oriented medaka (Oryzias latipes) embryos

Embryos of aquatic animal model fish have proven to be useful organisms for developmental biology and for early life stage toxicity tests. By virtue of their transparent chorions, imaging of normal and abnormal development can be detected and related to exposure or to alterations due to environmental factors. However, the detection of changes at sub-individual levels of organization is hampered by time required to detect important events within cells and tissues of affected organisms. We describe herein development of a highly cost effective embryo chip enabling stringent inter-individual comparisons and multiplex detection in embryos and eleutheroembryos. As a proof of principle we examine cell proliferation and controlled cell death in normoxic and hypoxic conditions and relate these to tissue turnover in individual organisms. Coupled with a recently developed whole adult animal platform, we can now move beyond the common approach focusing on single target organ to the detection and characterization of systemic phenomena (syndromes) affecting the organism. Taken together, we can now determine adult consequences of early life stage exposure and assess ability of exposed individuals to respond to stresses superimposed along the axis of time.     

How mitochondrial damage affects cell function

The pathophysiology of mitochondrial DNA (mtDNA) diseases is caused by increased cell death and dysfunction due to the accumulation of mutations to mtDNA. While the disruption of oxidative phosphorylation is central to mtDNA diseases, many other factors, such as Ca²⁺ dyshomeostasis, increased oxidative stress and defective turnover of mitochondrial proteins, may also contribute. The relative importance of these processes in causing cell dysfunction and death is uncertain. It is also unclear whether these damaging processes lead to the disease phenotype through affecting cell function, increasing cell death or a combination of both. These uncertainties limit our understanding of mtDNA disease pathophysiology and our ability to develop rational therapies. Here, we outline how the accumulation of mtDNA mutations can lead to cell dysfunction by altering oxidative phosphorylation, Ca²⁺ homeostasis, oxidative stress and protein turnover and discuss how these processes affect cell function and susceptibility to cell death. A better understanding of these processes will eventually clarify why particular mtDNA mutations cause defined syndromes in some cases but not in others and why the same mutation can lead to different phenotypes.     

Structural brain imaging in frontotemporal dementia

Frontotemporal dementia (FTD) is the second commonest young-onset neurodegenerative dementia. The canonical clinical syndromes are a behavioural variant (bvFTD) and two language variants (progressive nonfluent aphasia, PNFA, and semantic dementia, SD) although there is overlap with motor neurone disease and the atypical parkinsonian disorders corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS). Characteristic patterns of atrophy or hypometabolism are described in each of the variants but in reality imaging studies are rather heterogeneous. This review attempts to address four key questions in the neuroimaging of FTD: 1) what are the early imaging features of the different FTD syndromes (and how do these change as the disease progresses); 2) what do studies of presymptomatic genetic cases of FTD tell us about the very early stages of the disease; 3) can neuroimaging help to differentiate the different FTD syndromes; and 4) can neuroimaging help to differentiate FTD from other neurodegenerative diseases? This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Fortschritt in der Pathogenese des Marfan-Syndroms und verwandter Krankheiten

Heritable connective tissue disorders comprise a heterogeneous group of disorders that result from genetic defects affecting normal extracellular matrix assembly. Many of these diseases are associated with a significant cardiovascular risk leading to morbidity and mortality in childhood or young adulthood. Prime examples that represent important genetic models for cardiovascular pathology are the Marfan syndrome and related disorders. In these conditions, progressive dilatation of the aortic root leads to aortic dissection, often associated with precocious death. Over the last decade tremendous progress in clinical and molecular research has changed the prevailing concept of these syndromes as structural disorders of the connective tissue into diseases manifesting perturbed cytokine signaling with widespread developmental abnormalities. These insights opened new and unexpected targets for causally directed drug treatments for these aneurysm syndromes, and by extent, also for the more common non-syndromic forms of aneurysm formation, a major cause of morbidity and mortality in the Western world.     

Early initiation of statin therapy after a coronary event

PURPOSE OF REVIEW: Despite improvements in the early management of acute coronary syndromes, the risk of major cardiovascular complications remains high. Lipid-modifying treatment with statins has the potential to further improve outcomes through improved endothelial function, antithrombotic and antiinflammatory actions. Statins are of proven benefit in patients with stable coronary heart disease. There has been speculation on potential mechanisms of benefit but, until recently, little data on the efficacy and safety of statins in the acute setting. Recent observational studies and randomized trials have addressed some of the questions regarding early initiation of statins in acute coronary syndromes. RECENT FINDINGS: Recent observational and randomized trials have shown that early commencement of statins in acute coronary syndromes is safe as early as 6 hours after the event and is likely to improve longer-term compliance. The current data are not sufficient to draw conclusions about the efficacy of statins early in the course of acute coronary syndromes. SUMMARY: Current management for acute coronary syndromes should include the commencement of statin therapy during initial hospital admission. This recommendation is based on safety and compliance data. More randomized trial evidence is required to determine whether early initiation will produce better outcomes than later initiation after an acute coronary event.     

Immortalization of Werner syndrome and progeria fibroblasts.

Human fibroblast cells from two different progeroid syndromes, Werner syndrome (WS) and progeria, were established as immortalized cell lines by transfection with plasmid DNA containing the SV40 early region. The lineage of each immortalized cell line was confirmed by VNTR analysis. Each of the immortalized cell lines maintained its original phenotype of slow growth. DNA repair ability of these cells was also studied by measuring sensitivity to killing by uv or the DNA-damaging drugs methyl methansulfonate, bleomycin, and cis-dichlorodiamine platinum. The results showed that both WS and progeria cells have normal sensitivity to these agents.