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PubMed2006

ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors.

A disintegrin and metalloprotease (ADAM) is a membrane-anchored metalloprotease implicated in the ectodomain shedding of cell surface proteins, including the ligands for epidermal growth factor (EGF) receptors (EGFR)/ErbB. It has been well documented that the transactivation of the EGFR plays critical roles for many cellular functions, such as proliferation and migration mediated through multiple G protein-coupled receptors (GPCRs). Recent accumulating evidence has suggested that ADAMs are the key metalloproteases activated by several GPCR agonists to produce a mature EGFR ligand leading to the EGFR transactivation. In this review, we describe the current knowledge on ADAMs implicated in mediating EGFR transactivation. The major focus of the review will be on the possible upstream mechanisms of ADAM activation by GPCRs as well as downstream signal transduction and the pathophysiological significances of ADAM-dependent EGFR transactivation.

ADAM Proteins↗

PubMed2000

The influence of the gender of patient and analyst in the psychoanalytic relationship.

An overview of current explorations of the influence of gender on the psychoanalytic situation is presented. The topic does not lend itself to simple generalizations because the accumulated experience of several generations of psychoanalysts is now merging with newer views of psychoanalytic technique, while at the same time psychoanalytic theory is being influenced by changing ideological crosscurrents and by new knowledge regarding the similarities and differences in the development of both genders. Major issues still open are the relationship between gender and sexuality and between erotic desire and love; the challenges of the boundary of the psychoanalytic relationship as a facilitating and containing frame for the exploration of oedipal conflicts; and the related temptations, prohibitions, and derivatives of the erotic tension in the transference-countertransference.

Culture↗

PubMed2003

Involvement of cardiomyocyte survival-apoptosis balance in hypertensive cardiac remodeling.

The balance between cell death and cell survival is a tightly controlled process, especially in terminally differentiated cells, such as the cardiomyocyte. Accumulating data support a role for cardiomyocyte apoptosis in the development of several cardiac diseases, including the transition from hypertensive compensatory hypertrophy to heart failure. This review briefly summarizes the status of the knowledge regarding the death-survival balance of cardiomyocytes in the context of hypertensive heart disease. Several molecular and cellular aspects as well as the most relevant pathophysiological implications are presented. Moreover, diagnosis tools under development and the possibilities for pharmacological intervention are also examined.

Animals↗

PubMed2006

Innervation of the atrioventricular and semi-lunar heart valves: a review.

Heart valves were historically considered passive structures that function through the haemodynamic forces created by the contraction and relaxation of the myocardium. However, research into valvular structures has revealed that heart valves are very complex, specialized structures that contain both smooth muscle cells and nerve fibres. This is particularly true for the atrioventricular valves, which are by far the most well studied to date. The various heart valves have been shown to contract independently during different moments of the heart cycle, suggesting that compensatory adaptation mechanisms exist to mediate the timing and efficacy of heart valve closure. These adaptations occur via different mechanisms, including neural mechanisms that influence the heart valves. Accumulating evidence continues to improve our understanding of the nerve fibres in the heart (adrenergic, cholinergic, etc.). Future studies will no doubt add to this exciting picture. Here, we review the current morphological knowledge of human and animal heart valve innervation, including discussions of the chordae tendineae and the papillary muscles, as well as the differences between the atrioventricular (AV) valves and the semi-lunar (SL) valves.

Animals↗

PubMed2000

Action pattern and substrate specificity of the hyaluronan lyase from group B streptococci.

The hyaluronan lyase of group B streptococci rapidly cleaves hyaluronan by an elimination mechanism to yield the unsaturated disaccharide 2-acetamido-2-deoxy-3-O-(beta-D-gluco-4-enepyranosyluronic acid)-D-glucose. Additionally, it has been shown that the enzyme has limited specificity for achondroitin sulphate and cleaves the chain at unsulphated sites [Baker,Yu, Morrison, Averett and Pritchard (1997) Biochem. J. 327,65-71]. In the present extension of that study it was found that 6-sulphated regions of chondroitin sulphate are also susceptible to cleavage by this hyaluronan lyase. Of the four 6- and/or 4-sulphated tetrasaccharides which can be isolated from testicular hyaluronidase digests of chondroitin sulphate, only those two tetrasaccharides with a6-sulphated disaccharide at the reducing end were cleaved. From thisand other data, a model is proposed for the cleavage specificity of hyaluronan lyase on a chondroitin sulphate. Evidence is presented in support of an action pattern for hyaluronan lyase which involves aninitial random endolytic cleavage followed by rapid exolytic and processive release of unsaturated disaccharide. Since the on lyoligosaccharides which tend to accumulate in near-complete digests of hyaluronan are unsaturated, it is argued that the processive cleavage occurs from the non-reducing to the reducing end of a hyaluronan chain. This detailed knowledge of substrate specificity contributes to our understanding of the enzyme's role in Group B streptococcal pathogenesis. In addition, the hyaluronan lyase may find application in sequence studies of chondroitin sulphates.

Animals↗

PubMed2002

[ABO blood-group system: past and present].

The ABO blood group system was discovered one hundred years ago; the respective ABH antigens were found in the protein and lipid membrane components of various cells (most importantly, erythrocytes) and soluble blood group substances. The genetics of the ABO system was also elucidated. This old knowledge is still useful, bringing new applications. Although we do not really know the complete biological role of blood group systems, including that of the major ABO system, data, which is still being accumulated, ensure scientists and physicians of its importance in research and the diagnosis and therapy of diseases. For example, susceptibility to some diseases has been shown to be connected with the blood group of the patient, or the phenotype changes of the ABH determinants may indicate the presence of defined form of cancer. The data presented in this article clearly suggest the validity of the ABO blood group system in medical and biological sciences.

ABO Blood-Group System↗

PubMed1984

Renal osteodystrophy.

As is apparent from the preceding discussion, renal osteodystrophy is a complex entity with multiple causes and many manifestations. Significant problems have included the identification and management of the various forms of bone disease seen in uremia. The prevention and therapy of osteitis fibrosa and secondary hyperparathyroidism have been significantly improved as a result of adequate phosphate restriction and the use of active forms of vitamin D (primarily calcitriol in the U.S., dihydrotachysterol and 1 alpha-hydroxyvitamin D in Europe). Recently, a major problem has been the recognition of bone disease due to aluminum accumulation. The therapy of this bone disease was generally unsuccessful until recent preliminary data suggested that deferoxamine therapy may be useful in these patients. The study of renal osteodystrophy has certainly advanced our knowledge of mineral metabolism, with clarification of the metabolism and action of PTH and vitamin D metabolism and identification of the pathogenic role for aluminum. In the future, most manifestations of renal osteodystrophy may be preventable or adequately treated.

Alkaline Phosphatase↗

PubMed1999

[Non-enzymatic glycation and oxidative stress in chronic illnesses and diabetes mellitus].

UNLABELLED: New approaches in biochemistry and molecular biology have increased the knowledge on the pathophysiology of chronic diseases as late diabetic complications, Alzheimer's disease, arteriosclerosis and vascular disease by defining the concept of "AGE-formation and oxidative stress." Nonenzymatic glycation, in which reducing sugars are covalently bound to free aminogroups of macromolecules, results in the formation of Advanced Glycation End products (AGEs) which accumulate during aging and at accelerated rate during the course of diabetes. Glycation accompanying oxidation processes support AGE-formation. AGE-formation changes the physicochemical properties of proteins, lipids and nucleic acids. In addition, binding of AGEs to specific surface receptors induces cellular signalling and cell activation. Interaction of AGEs with one of the receptors, RAGE, generates intracellular oxidative stress, which results in activation of the transcription factor NF-kappa B and subsequent gene expression, which might be relevant in late diabetic complications. CONCLUSION: Knowledge of the basis molecular mechanisms allows to understand the interplay of different inducers such as redicals, cytokines, AGE-proteins and amyloid-beta-peptids and to define oxidative stress as a "common endpoint" of cell dysfunction. With respect to therapeutic options it is now possible not only to optimize blood glycemic control, but also to design drugs such as AGE-inhibitors and AGE-"cross-link" breakers. In addition patients with chronic disease associated with increased oxidative stress ay benefit from an antioxidant rich (and AGE protein poor?) nutrition.

Alzheimer Disease↗

PubMedDate not supplied

DNA damage metabolism and aging.

As a result of permanent exposure to low levels of various endogenous and exogenous genotoxic agents, large numbers of lesions are continuously induced in the DNA of cells of living organisms. Such lesions could lead to dysfunction of cells and tissues, and they might well be the underlying cause of the age-related reduction of homeostatic capacity and the increased incidence of cancer and other diseases of old age. The rate of damage induction as well as the persistence of the lesions depends on the activity, efficiency and reliability of a wide variety of molecular defense systems. However, a certain degree of imperfection seems to be a general characteristic of most of these defense systems and this could lead to a gradual accumulation of DNA alterations during aging. Even when the original lesions are quickly removed, they can still lead to secondary changes in the DNA, such as DNA-sequence changes and changes in gene expression. This process would be accelerated in case of the occurrence of an age-related decline in the efficiency of these molecular defense systems. This review deals with the present knowledge on the occurrence of 'spontaneous' DNA damage in aging organisms, its potential sources, the influence of preventive and processive cellular defense mechanisms and its consequences in terms of DNA-sequence changes, DNA conformational and configurational changes and changes in gene expression. In general, it can be concluded from the data discussed here that, in spite of a number of discrepancies and conflicting results, an age-related accumulation of DNA alterations occurs at all levels, e.g., chemical structure, DNA-sequence organization and gene expression.

Aging↗

PubMed2002

Development of transition state analogues of purine nucleoside phosphorylase as anti-T-cell agents.

Newborns with a genetic deficiency of purine nucleoside phosphorylase (PNP) are normal, but exhibit a specific T-cell immunodeficiency during the first years of development. All other cell and organ systems remain functional. The biological significance of human PNP is degradation of deoxyguanosine, and apoptosis of T-cells occurs as a consequence of the accumulation of deoxyguanosine in the circulation, and dGTP in the cells. Control of T-cell proliferation is desirable in T-cell cancers, autoimmune diseases, and tissue transplant rejection. The search for powerful inhibitors of PNP as anti-T-cell agents has culminated in the immucillins. These inhibitors have been developed from knowledge of the transition state structure for the reactions catalyzed by PNP, and inhibit with picomolar dissociation constants. Immucillin-H (Imm-H) causes deoxyguanosine-dependent apoptosis of rapidly dividing human T-cells, but not other cell types. Human T-cell leukemia cells, and stimulated normal T-cells are both highly sensitive to the combination of Imm-H to block PNP and deoxyguanosine. Deoxyguanosine is the cytotoxin, and Imm-H alone has low toxicity. Single doses of Imm-H to mice cause accumulation of deoxyguanosine in the blood, and its administration prolongs the life of immunodeficient mice in a human T-cell tissue xenograft model. Immucillins are capable of providing complete control of in vivo PNP levels and hold promise for treatment of proliferative T-cell disorders.

Animals↗

PubMed2002

Promotion of physical activity in a developing country: the Agita São Paulo experience.

The purpose of this paper is to present key points of an intervention programme (Agita São Paulo Program) to promote physical activity in a developing country. Agita is a multi-level, community-wide intervention designed to increase knowledge about the benefits and the level of physical activity in a mega-population of 34 million inhabitants of São Paulo State, Brazil. The main message was taken from the Centers for Disease Control/American College of Sports Medicine (CDC/ACSM) recommendation that: 'everyone should accumulate at least 30 minutes of physical activity, on most days of the weeks, of moderate intensity, in one single or in multiple sessions'. Activities were encouraged in three settings: home, transport and leisure time. Focus groups were students from elementary schools through to college, white and blue collar workers, and elderly people. Innovative aspects included: (1) a research centre leading the process, (2) scientific and institutional partnerships (over 160 groups), (3) a feasible approach--the 'one-step-ahead' model, (4) empowerment, (5) inclusion, (6) non-paid media, (7) social marketing, and (8) culture-linked. Data were obtained from 645 random, home-based questionnaires over four years--stratified by sex, age, education and socio-economic level. These data show that the Agita message reached 55.7% of the population, and among these, 23.1% knew the main message. Recall of Agita and knowledge of its purpose were well distributed among different socioeconomic levels, being known by 67% of the most educated. The prevalence of people reaching the recommendation was 54.8% (men 48.7%, women 61%); and risk of being sedentary was quite smaller among those who knew the Agita message (7.1%) compared with those who did not know (13.1%). In conclusion, based upon the Agita São Paulo experience, it appears that a multi-level, community-wide intervention to promote physical activity may obtain good results if the model contains the items listed above.

Adolescent↗

PubMed1996

"Don't think zebras": uncertainty, interpretation, and the place of paradox in clinical education.

Working retrospectively in an uncertain field of knowledge, physicians are engaged in an interpretive practice that is guided by counterweighted, competing, sometimes paradoxical maxims. "When you hear hoofbeats, don't think zebras," is the chief of these, the epitome of medicine's practical wisdom, its hermeneutic rule. The accumulated and contradictory wisdom distilled in clinical maxims arises necessarily from the case-based nature of medical practice and the narrative rationality that good practice requires. That these maxims all have their opposites enforces in students and physicians a practical skepticism that encourages them to question their expectations, interrupt patterns, and adjust to new developments as a case unfolds. Yet medicine resolutely ignores both the maxims and the tension between the practical reasoning they represent and the claim that medicine is a science. Indeed, resolute epistemological naivete is part of medicine's accommodation to uncertainty; counterweighted, competing, apparently paradoxical (but always situational) rules enable physicians simultaneously to express and to ignore the practical reason that characterizes their practice.

Art↗

PubMed2007

Human microvascular endothelial synthesis of interleukin-8 during in vitro ischemia and reperfusion.

These studies were undertaken to evaluate human microvascular endothelial cell (MEC) synthesis of interleukin-8 (IL-8), a potent neutrophil chemoattractant, under in vitro conditions of ischemia and reperfusion. IL-8 and other related CXC chemokines are believed to mediate tissue injury in a variety of pathologic conditions in humans. MEC grown on microcarrier beads were exposed to 3 or 6 h of in vitro ischemia followed by 2 h of reperfusion. Conditioned medium, MEC protein, and total RNA extracts were assayed for IL-8 using an ELISA. During ischemia alone, MEC increased intracellular, but not extracellular levels of IL-8 secretion. In contrast, reperfusion markedly stimulated both intracellular and extracellular IL-8 secretion. Neither 3 h of ischemia alone or followed by reperfusion altered steady-state levels of IL-8 mRNA when compared to pre-ischemic levels. In contrast, after 6 h of ischemia alone and ischemia followed by reperfusion, IL-8 mRNA was increased eight- and sixfold, respectively, when compared to pre-ischemic levels. These studies demonstrate an inverse relationship between the rate of IL-8 protein secretion and the steady-state levels of IL-8 mRNA during ischemia and reperfusion. During ischemia and reperfusion both the increase in cell-associated IL-8 protein and the release of IL-8 into the medium is dependent on de novo protein synthesis rather than the intracellular accumulation of IL-8. These experiments indicate that post-ischemic modulation of IL-8 release and synthesis following ischemia reperfusion will require strategies directed towards inhibition of IL-8 transcription and in depth knowledge of the mechanisms regulating IL-8 secretion.

Cell Survival↗

PubMed1990

Proteinases and the glomerulus: their role in glomerular diseases.

Degradation of matrix in normal glomeruli occurs through the action of neutral metalloproteinases which are in turn regulated by specific inhibitors. Both of these proteins are secreted by mesangial cells. Macrophages and IL-1 enhance the secretion of the proteinase. Decreased production of the metalloproteinase and for increased secretion of its inhibitor may lead to matrix accumulation. Neutrophil serine paternases degrade glomerular basement membrane (GBM) in vitro. In both animal and human disease urine excretion of these enzymes is accompanied by proteinuria and the presence of GBM-fragments. Further knowledge of the processes involved in matrix degradation may lead to improved therapy of glomerular disease.

Basement Membrane↗

PubMed2002

Gaucher disease: Perspectives on a prototype lysosomal disease.

Gaucher disease is an autosomal recessive trait and the most common lysosomal storage disease. The pathogenesis evolves from the diminished activity of the lysosomal hydrolase, acid beta-glucosidase and the resultant accumulation of glucosylceramide within lysosomes. The pathogenic mechanisms are poorly understood. During the past 2 decades, progress has been made in understanding the biochemical basis and molecular biology of the disease, but more fundamental knowledge is required to relate these advances to the cell and whole body phenotypes. Despite this lack of understanding, enzyme replacement therapy has proved a successful and effective management for Gaucher disease. However, basic details of this therapeutic efficacy require elucidation. Here, we review the current state of the molecular pathogenesis and provide our perspective of some major issues for continued advances in this prototype lysosomal storage disease.

Animals↗

PubMed2006

Facilitating physiologic self-regeneration: a step beyond islet cell replacement.

Type 1 diabetes (T1D) is an autoimmune disease, the clinical onset of which most frequently presents in children and adolescents who are genetically predisposed. T1D is characterized by specific insulin-producing beta cell destruction. The well-differentiated and specialized islet beta cells seem to physiologically retain the ability to compensate for the cells lost by reproducing themselves, whereas undifferentiated cell sources may help in generating new ones, even while the autoimmune process takes place. Diabetes clinical onset, i.e., establishment of a detectable, chronic hyperglycemia, occurs at a critical stage when autoimmunity, having acted for a while, supersedes the regenerative effort and reduces the number of beta cells below the physiologic threshold at which the produced insulin becomes insufficient for the body's needs. Clinical solutions aimed at avoiding cumbersome daily insulin administrations by the reestablishment of physiologic insulin production, like whole pancreas or pancreatic islet allotransplantation, are limited by the scarcity of pancreas donors and by the toxic effects of the immunosuppressive drugs administered to prevent rejection. However, new accumulating evidence suggests that, once autoimmunity is abrogated, the endocrine pancreas properties may be sufficient to allow the physiological regenerative process to restore endogenous insulin production, even after the disease has become clinically manifest. Knowledge of these properties of the endocrine pancreas suggests the testing of reliable and clinically translatable protocols for obliterating autoimmunity, thus allowing the regeneration of the patient's own endocrine cells. The safe induction of an autoimmunity-free status might become a new promising therapy for T1D.

Animals↗

PubMed2006

Study of the mechanisms of uptake of 5-aminolevulinic acid derivatives by PEPT1 and PEPT2 transporters as a tool to improve photodynamic therapy of tumours.

Endogenous porphyrin accumulation after administration of 5-aminolevulinic acid is employed in photodynamic therapy of tumours. Due to its low membrane permeability, esterified 5-aminolevulinic acid derivatives less hydrophilic than the parental compound are under investigation. Knowledge of the mechanisms of 5-aminolevulinic acid derivatives uptake into target cells is essential to understand and improve photodynamic therapy and useful in the design of new derivatives with better affinity and with higher selectivity for tumour cells in specific tissues. The aim of this work was to assess the interaction of 5-aminolevulinic acid derivatives with the intestinal PEPT1 and renal transporter PEPT2 expressed in Pichia pastoris yeasts. We found that Undecanoyl, Hexyl, Methyl and 2-(hydroxymethyl)tetrahydropyranyl 5-aminolevulinic acid esters and the dendron 3m-ALA inhibited (14)C-5-aminolevulinic acid uptake by PEPT2. However, only the Undecanoyl ester inhibited 5-aminolevulinic acid uptake by PEPT1. We have also found through a new developed colorimetric method, that Hexyl and 2-(hydroxymethyl)tetrahydropyranyl 5-aminolevulinic acid esters display more affinity than 5-aminolevulinic acid for PEPT2 whereas none of the compounds surpass 5-aminolevulinic acid affinity for PEPT1. In addition, the Undecanoyl ester binds with high affinity to the membranes of PEPT2 and PEPT1-expressing yeasts and to the control yeasts. The main finding of this work was that some derivatives have the potential to improve 5-aminolevulinic acid-based photodynamic therapy by increased efficiency of transport into cells expressing PEPT2 such as kidney, mammary gland, brain or lung whereas in tissues expressing exclusively PEPT1 the parent 5-aminolevulinic acid remains the compound of choice.

Aminolevulinic Acid↗

PubMed2005

Implicit motor learning of a balancing task.

This study examined the implicit learning of a balancing task. Three treatment conditions were constructed using different motor learning strategies. In two of the treatment conditions, explicit learning of the balancing task was impeded by using either an analogy or an errorless learning technique. In the third treatment condition, participants learnt the task by discovery learning, which typically results in explicit knowledge. It was hypothesised that in the analogy and errorless learning conditions, learning of the balancing task would be implicit in character. Three criteria of implicit learning were used to test this hypothesis; the accumulation of few explicit rules, robustness under secondary task loading and durability over time. Although the discovery learners acquired more explicit rules, all groups appear to have acquired the skill implicitly, in that all groups were robust to imposition of a concurrent task load and over time. Indeed, balance performance with a concurrent verbal task was better than balance performance alone. Discussion focuses on the contribution of verbal and non-verbal processes to balancing.

Adult↗

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