Prion: disease or relief?

The self-perpetuating amyloid isoform, or prion, of the yeast translation termination factor eRF3 modulates programmed translational frameshifting that controls a regulatory circuit determining the polyamine levels in a yeast cell. But it is still unclear whether this effect is adaptive or pathological.     

Epigenetics in disease: Leader or follower?

Epigenetic silencing is a pervasive mode of gene regulation in multicellular eukaryotes: stable differentiation of somatic cell types requires the maintenance of subsets of genes in an active or silent state. The variety of molecules involved, and the requirement for active maintenance of epigenetic states, creates the potential for errors on a large scale. When epigenetic errors - or epimutations - activate or inactivate a critical gene, they may cause disease. An epimutation that occurs in the germline or early embryo can affect all, or most, of the soma and phenocopy genetic disease. But the stochastic and reversible nature of epigenetic phenomena predicts that epimutations are likely to be mosaic and inherited in a nonmendelian manner; epigenetic diseases will thus rarely behave in the comfortably predictable manner of genetic diseases but will display variable expressivity and complex patterns of inheritance. Much phenotypic variation and common disease might be explained by epigenetic variation and aberration. The known examples of true epigenetic disease are at present limited, but this may reflect only the difficulty in distinguishing causal epigenetic aberrations from those that are merely consequences of disease, a challenge further extended by the impact of environmental agents on epigenetic mechanisms. The rapidly developing molecular characterization of epigenomes, and the new ability to survey epigenetic marks on whole genomes, may answer many questions about the causal role of epigenetics in disease; these answers have the potential to transform our understanding of human disease.     

Adynamia episodica hereditaria: Gamstorp's disease or Eulenburg's paramyotonia?

Over seven generations owing 71 identified and studied persons, 18 (12 males and 6 females) suffered paroxystically adynamic paralysis or myotonic accesses. A such association is rare and according to the proeminent symptoms is denominated as hyperkaliemic periodic paralysis or as congenital paramyotonia. In the both forms of the diseases: cold injury, fasting, long time resting, or efforts are able to provoke crisis and so does an oral potassium loading. Studies on Ka+Na membrane permeability suggest the responsibility of Na+ K+ pump and may explain the physiopathology of the alternative manifestations at the muscle cellular level but may be are rather a marker than a cause of permeability disturbances. In the present family, some clinical, biological and electrophysiological arguments suggest the unicity of the disease. A better way to confirm that would be the localisation of a unique gene in the patient. DNA samples of several members are in study for molecular biology in the hope to precise a identical location. Some informations from molecular biologists suggest a probable location near the myotonic dystrophy (M.D.) in the 19 q12 but not identical with it.     

Oxidative stress in cardiovascular disease: myth or fact?

Oxidative stress is a mechanism with a central role in the pathogenesis of atherosclerosis, cancer, and other chronic diseases. It also plays a major role in the aging process. Ischemic heart disease is perhaps the human condition in which the role of oxidative stress has been investigated in more detail: reactive oxygen species and consequent expression of oxidative damage have been demonstrated during post-ischemic reperfusion in humans and the protective role of antioxidants has been validated in several experimental studies addressing the pathophysiology of acute ischemia. Although an impressive bulk of experimental studies substantiate the role of oxidative stress in the progression of the damage induced by acute ischemia, not a single pathophysiologic achievement has had a significant impact on the treatment of patients and randomized, controlled clinical trials, both in primary and secondary prevention, have failed to prove the efficacy of antioxidants in the treatment of ischemic cardiovascular disease. This dichotomy, between the experimental data and the lack of impact in the clinical setting, needs to be deeply investigated: certainly, the pathophysiologic grounds of oxidative stress do maintain their validity but the concepts of the determinants of oxidative damage should be critically revised. In this regard, the role of intermediate metabolism during myocardial ischemia together with the cellular redox state might represent a promising interpretative key.     

Gene-environment interactions in human disease: nuisance or opportunity?

Many environmental risk factors for common, complex human diseases have been revealed by epidemiologic studies, but how genotypes at specific loci modulate individual responses to environmental risk factors is largely unknown. Gene-environment interactions will be missed in genome-wide association studies and could account for some of the 'missing heritability' for these diseases. In this review, we focus on asthma as a model disease for studying gene-environment interactions because of relatively large numbers of candidate gene-environment interactions with asthma risk in the literature. Identifying these interactions using genome-wide approaches poses formidable methodological problems, and elucidating molecular mechanisms for these interactions has been challenging. We suggest that studying gene-environment interactions in animal models, although more tractable, might not be sufficient to shed light on the genetic architecture of human diseases. Lastly, we propose avenues for future studies to find gene-environment interactions.     

Airway imaging in disease: Gimmick or useful tool?

Airway remodeling is an important pathophysiological mechanism in a variety of chronic airway diseases. Historically investigators have had to use invasive techniques such as histological examination of excised tissue to study airway wall structure. The last several years has seen a proliferation of relatively noninvasive techniques to assess the airway branching pattern, wall thickness, and more recently, airway wall tissue components. These methods include computed tomography, magnetic resonance imaging, and optical coherence tomography. These new imaging technologies have become popular because to understand the physiology of lung disease it is important we understand the underlying anatomy. However, these new approaches are not standardized or available in all centers so a review of their validity and clinical utility is appropriate. This review documents how investigators are working hard to correct for inconsistencies between techniques so that they become more accepted and utilized in clinical settings. These new imaging techniques are very likely to play a frontline role in the study of lung disease and will, hopefully, allow clinicians and investigators to better understand disease pathogenesis and to design and assess new therapeutic interventions.     

Autophagy defects in Lafora disease: cause or consequence?

Lafora disease (LD) is an inherited and fatal form of neurodegenerative disorder characterized by the presence of an abnormal form of glycogen inclusions, called Lafora bodies, in neurons and other tissues. While Lafora bodies have been thought to underlie the neuropathology in LD, the specific process by which these inclusions might affect the neuronal functions was not very well understood. Here we review one of our recent studies on the LD animal model, wherein we have shown that the Lafora bodies might contribute to the impairment in the endosomal-lysosomal and autophagy pathways.     

Genetic polymorphisms in lung disease: bandwagon or breakthrough?

The study of genetic polymorphisms has touched every aspect of pulmonary and critical care medicine. We review recent progress made using genetic polymorphisms to define pathophysiology, to identify persons at risk for pulmonary disease and to predict treatment response. Several pitfalls are commonly encountered in studying genetic polymorphisms, and this article points out criteria that should be applied to design high-quality genetic polymorphism studies.     

Symptoms and signs: physical disease or illness behaviour?

The amount of treatment received by 380 patients with backache was found to have been influenced more by their distress and illness behaviour than by the actual physical disease. Patients showing a large amount of inappropriate illness behaviour had received significantly more treatment (p less than 0.001). The symptoms and signs of illness behaviour need to be clearly distinguished from those of physical disease, and better assessment of illness behaviour is essential if everyday clinical practice is to fulfil the ideal of treating patients as well as diseases.     

Tau phosphorylation in Alzheimer's disease: pathogen or protector?

During the past decade, hypotheses concerning the pathogenesis of most neurodegenerative diseases have been dominated by the notion that the aggregation of specific proteins and subsequent formation of cytoplasmic and extracellular lesions represent a harbinger of neuronal dysfunction and death. As such, in Alzheimer's disease, phosphorylated tau protein, the major component of neurofibrillary tangles, is considered a central mediator of disease pathogenesis. We challenge this classic notion by proposing that tau phosphorylation represents a compensatory response mounted by neurons against oxidative stress and serves a protective function. This novel concept, which can also be applied to protein aggregates in other neurodegenerative diseases, opens a new window of knowledge with broad implications for both the understanding of mechanisms underlying disease pathophysiology and the design of new therapeutic strategies.     

Myocyte autophagy in heart disease: friend or foe?

In the setting of hemodynamic stress, such as occurs in hypertension or following myocardial infarction, the heart undergoes a compensatory hypertrophic growth response. Left unchecked, this hypertrophic response triggers myocyte death, ventricular dilation, diminished contractile performance, and a clinical syndrome of heart failure. For some years, autophagy has been implicated in heart failure. More recently, mechanistic studies have emerged which provide new insights into the molecular underpinnings of hemodynamic stress-induced cardiomyocyte autophagy. Further, these studies have begun to provide clues as to whether cardiomyocyte autophagy is adaptive, mitigating disease pathogenesis, or maladaptive, contributing to disease progression. Here, we discuss recent studies that both answer some questions and pose new ones.