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PubMed2001

[Adult Gaucher disease].

PURPOSE: This review presents the clinical, biological and therapeutic aspects of adult Gaucher disease. CURRENT KNOWLEDGE AND KEY POINTS: Gaucher disease is an uncommon inborn recessive autosomal disease, due to a deficient activity of the lysosomal enzyme beta-glucocerebrosidase. The enzymatic defect leads to the accumulation of the lipid glucocerebroside in liver, spleen and bone marrow. Patients with Gaucher disease have been classified into three types. Type 1 is the most frequent and non-neuronopathic, with enlarged liver and spleen and bone damage. Biological abnormalities are found: visceral infiltration (pancytopenia, cholestasis), macrophage damage (angiotensin-converting enzyme increase, ferritin increase, immunoglobulin increase, hemostasis abnormalities) and lysosomal damage (acid phosphatase tartrate-resistant increase, chitotriosidase increase). Enzyme replacement therapy has become available, has proven effectiveness in many patients and has successfully reversed many of the manifestations of the disorder. FUTURE PROSPECTS AND PROJECTS: The new biological abnormalities must help in treatment management. Gene transfer and oral treatment must be taken into account and validated in large clinical studies.

Adult↗

PubMed1992

Evolution of the growth hormone-releasing factor (GRF) family of peptides.

1. The primordial GRF may have arisen quite early in evolutionary history, at or prior to (i.e. should immunoreactivity data be confirmed in invertebrates) the appearance of jawed vertebrates (Gnathostomates). A common evolutionary pathway using gene duplication may have been utilized to generate the GRF super-family of peptides. As most members of this peptide superfamily are produced in the gastrointestinal tract, the question is posed whether the GRF may have similar origins. 2. It is suggested that the GRF superfamily has two major branches: a) GRF; PRP/PACAP; VIP/PHI; secretin and b) Glucagon/GLP-1/GLP-2. GIP is likely to be a member of the glucagon branch. The two branches may be attributable to gene duplication encoding an ancestral molecule. These gene duplications are likely to have occurred prior to the evolution of vertebrates (conservatively 400-500 million years ago, and possibly 1 billion years ago). It is probable that peptides homologous to GRF, VIP and glucagon will be isolated from invertebrates. These invertebrate sequences will shed further light upon the evolution of this peptide superfamily. 3. Throughout the GRF superfamily, amphiphilic alpha-helical secondary structures represent preferred bioactive conformations. It is assumed that stable, ordered secondary structures conferring enhanced ligand-receptor interactions were conserved due to selective pressures. 4. It is well documented that hypothalamic GRF stimulates adenohypophyseal GH secretion in a variety of species. Thus far, the physiological effects of GRF have been attributed thus to the elevation of GH, and possibly also IGF-I. Recent data suggests a more liberal view; that GRF may also have direct actions in fetal/placental development, reproduction and immune function. Furthermore these direct effects may be mediated via GRF from either hypothalamic or extrahypothalamic (e.g. placenta, testes, ovary, leukocyte) sources. In conclusion, a great wealth of information has accumulated since the discovery of GRF. Examination of the GRF peptide superfamily from an evolutionary perspective has revealed new insights into the synthesis, processing, degradation, conformation and activities of these molecules. Knowledge obtained from these evolutionary comparisons has also become particularly useful in contemporary peptide drug design, which may be liberally viewed as a form of 'artificial evolution' (i.e. the selective pressure being clinical/veterinary requirements for more potent, long-acting GRF analogs).

Amino Acid Sequence↗

PubMed1991

Stimulation of 45Ca uptake and amylase release by cationic amino acids in parotid cells.

L-arginine, L-ornithine, L-lysine and L-histidine (each 10 mM) stimulated amylase release from rat parotid cells. The secretory response to the cationic amino acids was suppressed in the absence of extracellular Ca2+ and, at physiological Ca2+ concentration, coincided with stimulation of 45Ca net uptake by the parotid cells. All cationic amino acids also accumulated inside the parotid cells. Nevertheless, the concept that the stimulation of amylase release is merely attributable to depolarization of the plasma membrane, secondary to the accumulation of these positively charged amino acids in the parotid cells, is questioned in view of both the inverse correlation found between their secretory effects and degree of ionization and the knowledge that parotid cells are electrically inexcitable.

Amino Acids↗

PubMed1992

Fetal drug therapy: an overview of selected conditions.

Fetal drug therapy may be defined as the administration of any drug for the primary or sole purpose of treating a fetal disorder or in the hope of improving the capacity for later intrauterine or postnatal adaptation. In several intrauterine conditions, the drug exposure has been directed at the fetus rather than the mother. Progress in clinical investigation has been slowed by often unfounded fears of malformations and potential litigation. Since 1975, federal regulations have required that the fetus be protected and subjected to no more than minimal additional risk. Although no large-scale trials have been reported, drug administration has been proven to aid the fetus in many circumstances. Such treatment has been administered primarily during the second or third trimester and is generally short-term, preventive, and without apparent risk to the consenting mother. The published reports have made obstetricians aware of both the limits of our knowledge in this area and new applications for innovative fetal monitoring by the latest technology. Whether such therapy has a role in the care of the unborn infant will depend on accumulation of a larger body of information and the continued cooperation of basic scientists and clinical investigators.

Clinical Trials as Topic↗

PubMed1987

Role of prostaglandins in human reproduction: recent advances.

Our knowledge of the importance of PGs for the physiological regulation of male and female reproductive organs is rapidly increasing. In this presentation two examples have been described in detail. Data are accumulating indicating that PGs in semen are of major importance for sperm motility and the functional capacity of sperms. Recording of intrauterine pressure in early pregnant patients has shown that treatment with an antiprogestin depriving the myometrium from progesterone influence, will induce regular uterine contractions. The data support the hypothesis that the uterine activity is regulated by the balance between PGF2 alpha and progesterone.

Female↗

PubMed1977

Intralysosomal lipid in long-term maintenance transplant atherosclerosis.

Intralysosomal accumulation of lipid has been implicated as an important mechanism in the pathogenesis of atherosclerosis. Although atherosclerosis develops frequently in organ transplants maintained on a long-term basis, to our knowledge no studies to date have demonstrated the intracellular localization of the lipid in this setting. Light and electron microscopic study of a renal artery branch from a transplanted kidney maintained for 3 1/2 years demonstrates that the lipid is sequestered within intimal smooth muscle cell lysosomes. The features of the atherosclerotic plaque in long-term transplantation appear to be identical to spontaneous lesions or those induced experimentally.

Arteriosclerosis↗

PubMed1982

High risk groups and screening for cancer.

Selective screening for cancer in high risk groups is attractive. For cancer of the breast and cervix uteri, evidence is accumulating regarding the beneficial effects of lowering morbidity and mortality from these diseases. Although a number of risk factors are known for both breast and cervical cancer, the use of such knowledge in selecting high risk groups for screening has been disappointing. Experience from existing mass screening programs shows that a large proportion of cases arise in the low risk individuals. Age represents, so far, the only characteristic of use for the selection of screenees. It is proposed that risk factors be identified as part of an initial unselective screening program to individualize further screenings, for example, by shorter intervals between screenings for high risk than for low risk groups.

Adult↗

PubMed1994

Roles of the nucleational core complex and collagens (types II and X) in calcification of growth plate cartilage matrix vesicles.

Matrix vesicles (MV) were shown to initiate mineralization in cartilage and other vertebrate tissues. However, the factors that drive this process remain to be fully elucidated. Recent studies have shown that a preformed nucleational core consisting mainly of a Ca(2+)-phosphatidylserine-Pi complex, is necessary for the accumulation of Ca2+ by MV. In addition, the collagens attached to the MV surface were shown to play an important role in stimulating Ca2+ uptake. In this study, we extend this knowledge by showing that both, the nucleational core and the collagens (types II and X), are co-requirements for rapid influx of Ca2+ into intact MV. MV to which collagen fragments were attached were released from hypertrophic chicken cartilage by trypsin and collagenase digestion (trypsin/collagenase-released MV (TCRMV), while "collagen-free" MV were released by hyaluronidase and collagenase digestion (hyaluronidase/collagenase-released MV (HCRMV). In contrast to TCRMV which showed active uptake of Ca2+, HCRMV showed only little uptake. However, binding of native type II collagen to HCRMV stimulated uptake of Ca2+. Sucrose gradients separated TCRMV and HCRMV into three different density fractions: a low density top fraction (SI), an intermediate density middle fraction (SII), and a high density pellet fraction (SIII). The SIII fractions of TCRMV and HCRMV contained significantly higher levels of mineral ions than did the SI and SII fractions. Only the SIII fraction of TCRMV which contained a stable nucleational core and surface-attached collagens, showed active Ca2+ uptake; all other sucrose fractions of TCRMV and HCRMV showed little or no uptake. Detergent treatment to purposely rupture the membrane greatly enhanced Ca2+ uptake by the SIII fraction of HCRMV, presumably by exposing the internal nucleational core. Addition of either native type II or type X collagen to the intact SIII fraction of HCRMV stimulated Ca2+ uptake to a level similar to that of the SIII fraction of TCRMV; however, incubation of the SI and SII fractions of either TCRMV or HCRMV with type II or X collagen did not activate Ca2+ uptake. These findings indicate that both a functional nucleational core and surface-attached collagens need to be present to support active mineralization of MV.

Animals↗

PubMed1993

Toward an interim standard for patient-centered knowledge-access.

Most care-giver "knowledge" needs arise at the point of care and are "patient-centered." Many of these knowledge needs can be met using existing on-line knowledge sources, but the process is too time-consuming, currently, for even the computer-proficient. We are developing a set of public domain standards aimed at bringing potentially relevant knowledge to the point of care in a straight-forward and timely fashion. The standards will a) make use of selected items from a Computer-based Patient Record (CPR), e.g., a diagnosis and measure of severity, b) anticipate certain care-giver knowledge needs, e.g., "therapy," "protocols," "complications," and c) try to satisfy those needs from available knowledge sources, e.g., knowledge-bases, citation databases, practice guidelines, and on-line textbooks. The standards will use templates, i.e., fill-in-the-blank structures, to anticipate knowledge needs and UMLS Metathesaurus enhancements to represent the content of knowledge sources. Together, the standards will form the specification for a "Knowledge-Server" (KS) designed to be accessed from any CPR system. Plans are in place to test an interim version of this specification in the context of medical oncology. We are accumulating anecdotal evidence that a KS operating in conjunction with a CPR is much more compelling to users than either a CPR or a KS operating alone.

Artificial Intelligence↗

PubMed1993

The role of interleukin-8 in inflammation and mechanisms of regulation.

Interleukin-8 (IL-8) is a chemoattractant cytokine produced by a variety of tissue and blood cells. Unlike many other cytokines, it has a distinct target specificity for the neutrophil, with only weak effects on other blood cells. Interleukin-8 attracts and activates neutrophils in inflammatory regions. The importance of neutrophil functions has been recognized in periodontal disease for many years. Neutrophils represent the major population of immigrant cells in periodontitis. In diseases with neutrophil dysfunctions periodontal tissue is lost very rapidly. The response of neutrophils to IL-8 is characterized by migration of the cells, the release of granule enzymes, and other intra- and extracellular changes. Connective tissue constituents are efficiently degraded by neutrophil enzymes, released upon activation. Interleukin-8 is a member of the Interleukin-8 supergene family that includes other small chemotactic peptides with structural homology. It also shares with other cytokines DNA sequence features that suggest common regulatory pathways. In vivo intracutaneous application of IL-8 induces local exudation and a massive, long-lasting accumulation of neutrophils. Though IL-8 plays a role in the cytokine network, its major pathophysiological role lies in affecting neutrophils. This article presents a review of literature on the current knowledge of IL-8, its mechanisms of expression, and the effects it exerts on the neutrophil.

Chemotactic Factors↗

PubMed1998

Bioaccumulation of contaminants in fish.

The term bioaccumulation is defined as uptake, storage, and accumulation of organic and inorganic contaminants by organisms from their environment. Bioaccumulation therefore results from complex interactions between various routes of uptake, excretion, passive release, and metabolization. For fish, the bioaccumulation process includes two routes of uptake: aqueous uptake of water-borne chemicals, and dietary uptake by ingestion of contaminated food particles. The contribution to bioaccumulation that results from aqueous exposure and is taken up by the gills is called bioconcentration. The contribution to bioaccumulation resulting from dietary exposure via uptake by intestinal mucosa is termed biomagnification. In both cases, important co-determinants for bioaccumulation are the various elimination mechanisms. This chapter presents a short historical survey of the problem of bioaccumulation with particular reference to fish and of the various approaches to study bioaccumulation. This is followed by an overview of our present knowledge about basic physico-chemical determinants that either increase or reduce the bioaccumulation potential of various chemicals, and about the physiological basis of gills, blood circulation and intestines, as far as they are crucial for our understanding of uptake and accumulation. Finally, selected quantitative data and modelings of bioaccumulation in fish will be discussed, with regard to such problems as the relative importance of aqueous and dietary uptake.

Animals↗

PubMed2002

Defining the mandate of proteomics in the post-genomics era: workshop report.

Research in proteomics is the next step after genomics in understanding life processes at the molecular level. In the largest sense proteomics encompasses knowledge of the structure, function and expression of all proteins in the biochemical or biological contexts of all organisms. Since that is an impossible goal to achieve, at least in our lifetimes, it is appropriate to set more realistic, achievable goals for the field. Up to now, primarily for reasons of feasibility, scientists have tended to concentrate on accumulating information about the nature of proteins and their absolute and relative levels of expression in cells (the primary tools for this have been 2D gel electrophoresis and mass spectrometry). Although these data have been useful and will continue to be so, the information inherent in the broader definition of proteomics must also be obtained if the true promise of the growing field is to be realized. Acquiring this knowledge is the challenge for researchers in proteomics and the means to support these endeavors need to be provided. An attempt has been made to present the major issues confronting the field of proteomics and two clear messages come through in this report. The first is that the mandate of proteomics is and should be much broader than is frequently recognized. The second is that proteomics is much more complicated than sequencing genomes. This will require new technologies but it is highly likely that many of these will be developed. Looking back 10 to 20 years from now, the question is: Will we have done the job wisely or wastefully? This report summarizes the presentations made at a symposium at the National Academy of Sciences on February 25, 2002.

Computational Biology↗

PubMed2006

Gender aspects of treatment and drug related toxicity in medical oncology.

The whole field of Oncology benefits from the huge amount of basic science "invested" and from the experience accumulated during several decades that enables more patients with malignant diseases to be cured or to survive for longer periods. Incidence and mortality rates from cancer have been decreasing by around 1 % per year since the mid-nineties of the past century in the European Union. However, the spectrum of malignant diseases and the outcome is not equally distributed between the two sexes. Startlingly, in advanced cancers, women receiving the same treatment schemes as men fare better. Until recently, however, the pharmacological knowledge of the pharmacokinetic and pharmacodynamic action of cytotoxic drugs was scarce for women, as like in other fields of medicine, studies recruited far more men than women and because results were often not reported separately for both sexes. These practices are slowly changing and gender specific outcome data are progressively accumulating. Such data on gender-specific differences or similarities are essential for building newer, more adequate tools for dosing drugs than the current form based on a "falsely accurate and individualzed" estimation of the body surface area. Nevertheless, the socioeconomical and sociocultural context of living remains genderspecifically different, influencing the coping of individuals with a life-threatening disease. On the other hand, as recently shown for chronic lymphocytic leukaemia, gender-specific analysis might open new insights in the biology of the disease and modify treatment strategies.

Adaptation, Psychological↗

PubMed1994

The two faces of growth: benefits and risks to bone integrity.

Bones grow by two processes: cortical bone is made by periosteal apposition (growth in width), and cancellous bone is made by endochondral ossification (growth in length). In both the axial and appendicular skeleton, about half of peak adult bone mass is accumulated during the adolescent growth spurt, which occurs two years earlier in girls than in boys, and is under pituitary control via interactions between growth hormone and sex hormones. Throughout growth, but particularly during adolescence, the ability of bone to adapt to mechanical loading is much greater than after maturity. This is the main reason why the effects of physical activity on bone are greater in cross-sectional studies in young athletes than in longitudinal studies in previously sedentary adults. In wild animals, by the time growth has ceased, the bones must be as strong as they will ever need to be, and attainment of further strength after cessation of growth would serve no biologic purpose. Adaptation of growing bone to mechanical loading is the purpose of the mechanostat, which enables physiologic adaptation in individuals to establish and maintain a species-specific property of the bones that is determined by evolutionary adaptation in populations. But growth confers risks as well as benefits to the skeleton. The large increase in incidence of upper extremity (particularly lower forearm) fractures, coincident with the adolescent growth spurt in both sexes, is due to an increase in cortical porosity as a consequence of an increase in intracortical bone turnover, which supplies some of the calcium needed by the growing ends of the long bones. This enables an increased demand for calcium to be spread over a longer time, analogous to the cyclic physiologic osteoporosis which occurs during the antler growth cycle in deer. The subsequent decline in cortical porosity is responsible for the continued increase in radial bone density after cessation of growth, referred to as consolidation. In the present state of knowledge, an increased incidence of fracture during the adolescent growth spurt is the inescapable consequence of an appropriate level of physical activity, and is the price that has to be paid in order to maximize bone accumulation during growth and minimize fracture risk in old age.

Adolescent↗

PubMed1992

Germanium and silver resistance, accumulation, and toxicity in microorganisms.

Germanium is an inert metal with no known biological function in prokaryotic or eukaryotic organisms. Its toxicity is low compared to that of silver. Germanium is accumulated in certain bacterial strains by either energy-independent passive binding or an energy-dependent mechanism. Little is known about the molecular aspects of silver resistance, toxicity, and accumulation in bacterial strains. This is surprising because silver has been used as an antimicrobial agent in the medical field for centuries. It is likely that silver ions are excluded (resulting in decreased silver accumulation) from certain bacterial strains or immobilized intracellularly to prevent toxic effects from being exerted. These mechanisms of silver resistance have not been fully elucidated. This review examines the toxicity and accumulation of germanium and silver in selected microbial species. In addition, resistance mechanisms to these biologically nonessential metals is discussed, with more emphasis placed on silver-resistant bacteria due to the knowledge available.

Bacteria↗

PubMed1995

Role of heterotrimeric G-proteins in epidermal growth factor signalling.

Since in 1986 it was reported that a pertussis toxin-sensitive substrate was involved in the Ca2+ signal induced by epidermal growth factor (EGF) in rat hepatocytes, much evidence accumulated to implicate heterotrimeric G-proteins in EGF action. EGF can also induce a cyclic AMP signal, but while the generation of a Ca2+ signal appears to be quite general in EGF action, the increase in cyclic AMP occurs only in few cell types. In non-transformed cell types these effects appear to involve G-proteins. EGF not only induces cell proliferation but also interacts with hormones in the short-term control of cell function in quiescent cells. Most of the known interactions are on cyclic AMP mediated hormone effects, and in many cases, the interaction between EGF and hormones involves G-proteins. Here we review the evidence accumulated in recent years that implicate G-proteins in EGF action. An understanding of the mechanisms involved may reveal new mechanisms of G-protein regulation and will contribute to our knowledge of EGF function and signal transduction.

Animals↗

PubMed1998

Mitochondrial permeability transition as induced by cross-linking of the adenine nucleotide translocase.

Mitochondrial permeability transition is caused by the opening of a transmembrane pore whose chemical nature has not been well established yet. The present work was aimed to further contribute to the knowledge of the membrane entity comprised in the formation of the non-specific channel. The increased permeability was established by analyzing the inability of rat kidney mitochondria to take up and accumulate Ca2+, as well as their failure to build up a transmembrane potential, after the cross-linking of membrane proteins by copper plus ortho-phenanthroline. To identify the cross-linked proteins, polyacrylamide gel electrophoresis was performed. The results are representative of at least three separate experiments. It is indicated that 30 microM Cu2+ induced the release of 4.3 nmol Ca2+ per mg protein. However, in the presence of 100 microM ortho-phenanthroline only 2 microM Cu2+ was required to attain the total release of the accumulated Ca2+; it should be noted that such a reaction is not inhibited by cyclosporin. The increased permeability corresponds to cross-linking of membrane proteins in which approximately 4 nmol thiol groups per mg protein appear to be involved. Such a linking process is inhibited by carboxyatractyloside. By using the fluorescent probe eosin-5-maleimide the label was found in a cross-linking 60 kDa dimer of two 30 kDa monomers. From the data presented it is concluded that copper-o-phenanthroline induces the intermolecular cross-linking of the adenine nucleotide translocase which in turn is converted to non-specific pore.

Animals↗

PubMed2003

Anti-beta(2)-glycoprotein I antibodies and the antiphospholipid syndrome.

The mechanism of antiphospholipid syndrome (APS) development is still not completely understood. Accumulating evidence indicates that beta(2)-glycoprotein I (beta(2)GPI), is the major target antigen for antiphospholipid (aPL) antibodies, which play a crucial role in the pathogenesis of this autoimmune condition. Knowledge about the molecular structure, biological characteristics and function of beta(2)GPI has been expanding in recent years. In this review, we have focused on some recent important findings on beta(2)GPI and anti-beta(2)GPI antibodies in patients and animal models with APS.

Animals↗