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PubMed2003

Selected as the best paper in JAGS in the 1970s mission of the National Institute on Aging.

The National Institute on Aging (NIA), the newest of the 11 National Institutes of Health, is dedicated to improving the quality of life of the old in America through biomedical, social, and behavioral research. Aging is viewed as more than just decline and deterioration; it is also a process of continued development and accumulated knowledge. The NIA will encourage innovative research but will not support the delivery of health services, as that is the domain of the other agencies. In areas of overlap, such as diseases common to the old, the NIA will collaborate with other Institutes. A good target area for collaboration is senile dementia. Other areas of interest to the NIA are: encouraging the incorporation of geriatric medicine as a subspecialty, developing retirement test patterns, and investigating drug-drug and drug-age interactions, personality and social processes, and immunocompetence.

Aged↗
PubMed2003

[Genetics of schizophrenia and bipolar disorder: recent success of linkage studies with evidence of specific and shared susceptibility loci].

Results claiming linkage on two chromosomes for schizophrenia (SZ) and bipolar affective disorder (BP) were prematurely published in Nature at the end of the '80s. This ended up into disappointment. The knowledge accumulated from the first generation of unsuccessful molecular genetics studies of SZ and BP provided a stronger basis for the following generation of linkage studies that are now yielding encouraging converging results. Hence, we report several genomics susceptibility loci for SZ and BP, some of them being probably shared by the two major psychiatric illnesses whereas others could be specific to each.

Bipolar Disorder↗
PubMed2001

A molecular approach to the classification of von Willebrand disease.

The marked heterogeneity of von Willebrand disease was already recognized by von Willebrand in 1926. The accumulating knowledge of the different clinical phenotypes and the pathophysiological basis of the disease was translated into a classification that differentiated between quantitative and qualitative defects by means of quantitative and functional parameters and by analysing the electrophoretic pattern of von Willebrand factor multimers. The increasing number of different von Willebrand disease phenotypes required a revision of the nomenclature at a time when only a few types of von Willebrand disease had already been analysed at the molecular level. Consequently, the molecular data played only a minor role in the revised classification. Given the pronounced, even intra-individual, variation in the manifestation of von Willebrand disease and the diagnostic difficulties caused by a non-standardized methodology, it is clear that biochemical methods alone are insufficient for a clear classification. The advent of molecular techniques provided the opportunity for genotype-phenotype studies that recently helped to elucidate or confirm not only the important functions of von Willebrand factor and the steps of its post-translational processing, but also many disease-causing defects. The reproducible correlation between certain phenotypes and particular mutations can now be used for a molecular approach towards a final classification of von Willebrand disease, equally useful for the clinician and for research requirements.

Genetic Variation↗
PubMed2000

Tetralogy of Fallot: Late outcome after repair and surgical implications.

Cardiac surgery has transformed the outcome for patients with tetralogy of Fallot. Repair has conveyed excellent long-term results with most patients remaining well and leading normal lives. However, there are problems with late morbidity and mortality primarily due to right ventricular dysfunction, exercise intolerance, arrythmia, and sudden cardiac death. There has been a dynamic shift in our surgical approach to managing patients with tetralogy over the past 5 decades. This in part accounts for persisting difficulties in predicting late outcome for evry single patient with repaired tetralogy of Fallot. There are, however, several confounding variables, influencing long-term outcome for these patients, namely the underlying anatomical substrate, age at repair, surgical approach to repair, and residual hemodynamic abnormalities. It is gratifying to see that recent knowledge accumulated from long-term follow-up studies is influencing contemporary surgical practice. Individualized strategies aiming to minimize the potential for free pulmonary regurgitation, and the long-term detrimental effects associated with it, need to continue to develop. Preservation of right ventricular and pulmonary valve function combined with early restoration of normal pulmonary blood flow are likely to convey an even better long-term outlook for these patients. Further follow-up studies with assessment of bi-venticular function, however, are needed in both our older and contemporary cohorts with repaired tetralogy of Fallot. Copyright 2000 by W.B. Saunders Company

Journal Article↗
PubMed1979

An apraisal of the role of aldosterone and the sympathetic nervous system in essential hypertension.

Of the various hypertensive disorders in which mineralocorticoid hormones are involved mainly those are reviewed in which, apart from aldosterone, hyporeactivity of the adrenergic nervous system may play a permissive role. The simultaneous occurrence and extent of participation of these two factors in essential hypertension are being appreciated increasingly. Their share in the mosaic of hypertension may add to the accumulating knowledge of this disease entity. In exploring the underlying mechanisms of hypertension common regulatory pathways involving aldosterone and the adrenergic nervous system may lead to new aethiopathogenetic insights.

Aldosterone↗
PubMed2002

Hemophilia A--from basic science to clinical practice.

This article summarizes achievements of basic research and their implementation in clinical treatment of one of the most common inherited bleeding disorders hemophilia A, which is caused by genetic deficiency of coagulation factor VIII (FVIII). We discuss the structure of FVIII, its major interactions in the intrinsic pathway of blood coagulation, and the catabolism of FVIII. We also discuss achievements in the contemporary clinical practice of treatment of hemophilia A. Replacement therapy has substantially improved by development of purification and virus inactivation procedures, allowing preparation of safe and effective therapeutic plasma-derived FVIII concentrates. We give special attention to the principles used in the development of contemporary recombinant FVIII products, which do not inherit a potential risk for viral or prion transmission. Development of FVIII inhibitory antibodies is the major complication of FVIII replacement therapy. We summarize the accumulated knowledge regarding epitopes of FVIII inhibitors and mechanisms by which they inactivate FVIII and discuss approaches to overcome the effects of inhibitors and to prevent their formation by induction of immunotolerance. We also analyze the main concepts and scientific priorities in the gene-therapeutic approach for treatment of hemophilia A.

Animals↗
PubMed2004

[Fetal and neonatal kidney function. Implications for fetal urinary tract abnormalities].

High-resolution sonography provides the opportunity for prenatal detection of fetal anomalies of the urinary tract. In view of various options of prenatal urinary diversion to alleviate obstruction, it has become a scientific goal to measure fetal renal function and to determine the prognosis of urinary tract malformations. The article outlines the accumulated knowledge of the development of fetal renal function and the diagnostic possibilities offered by sonography and by laboratory test with focus on the chemistry of the amniotic fluid. Taking into consideration the high risks of prenatal intervention, these findings are discussed as to their relevance for the clinical management of pregnancies complicated by fetal urinary tract abnormalities. Lastly, criteria are proposed for the decision making in clinical practice.

Amniotic Fluid↗
PubMed2006

Laboratory testing for von Willebrand disease: contribution of multimer analysis to diagnosis and classification.

The stepwise diagnosis of von Willebrand disease (vWD) includes patient and family history, screening procedures (bleeding time, filter tests, platelet counts, activated partial thromboplastin time [aPTT]), confirmatory tests (von Willebrand factor [vWF]:antigen [Ag], vWF:ristocetin cofactor activity assay [RCo], vWF:collagen-binding test [CB], ristocetin-induced platelet agglutination [RIPA], and factor [F] VIII:coagulant activity [C]) and tests for final classification (multimeric analysis, vWF:factor VIII binding, and platelet vWF). Accumulating knowledge of the different clinical phenotypes and the pathophysiological basis of the disease have been translated into a classification that differentiates between quantitative and qualitative defects by means of quantitative and functional parameters and by analyzing the electrophoretic pattern of vWF multimers, but without inclusion of the genotype. Recently, it has been shown that with a sensitive method of multimer analysis, a > 90% genotype-phenotype relation may be achieved in the near future.

Clinical Laboratory Techniques↗
PubMed2003

Desmoglein as a target in autoimmunity and infection.

Clinical phenotypes of most diseases are complex. However, once the mechanism behind the scene is clarified, the nature shows amazing beauty. There is a simple logic behind a complex disease. The exact molecular mechanism of the blister formation in staphylococcal scalded skin syndrome (SSSS) remained to be elucidated for 3 decades since exfoliative toxin was discovered by Melish and Glasgow in 1970. A knowledge accumulated to understand the pathogenesis of pemphigus and cell-cell adhesion of keratinocytes led us to solve this question. Desmoglein 1, which is a cadherin type cell-cell adhesion molecule in desmosomes, is targeted in two different skin diseases, pemphigus foliaceus, and SSSS. In pemphigus foliaceus IgG autoantibodies are developed against desmoglein 1 and inhibit its adhesive function with resultant blister formation in the superficial epidermis. In SSSS, exfoliative toxin produced by Staphylococcus aureus specifically binds and cleaves desmoglein 1 with resultant blister formation at the identical site.

Animals↗
PubMed2005

Crystal structure of human T cell leukemia virus protease, a novel target for anticancer drug design.

The successful development of a number of HIV-1 protease (PR) inhibitors for the treatment of AIDS has validated the utilization of retroviral PRs as drug targets and necessitated their detailed structural study. Here we report the structure of a complex of human T cell leukemia virus type 1 (HTLV-1) PR with a substrate-based inhibitor bound in subsites P5 through P5'. Although HTLV-1 PR exhibits an overall fold similar to other retroviral PRs, significant structural differences are present in several loop areas, which include the functionally important flaps, previously considered to be structurally highly conserved. Potential key residues responsible for the resistance of HTLV-1 PR to anti-HIV drugs are identified. We expect that the knowledge accumulated during the development of anti-HIV drugs, particularly in overcoming drug resistance, will help in designing a novel class of antileukemia drugs targeting HTLV-1 PR and in predicting their drug-resistance profile. The structure presented here can be used as a starting point for the development of such anticancer therapies.

Amino Acid Sequence↗
PubMed1975

Structure-function relationships and mode of replication of animal rhabdoviruses.

Recently accumulated knowledge allows more precise comparison of the structural (and possibly evolutionary) relationships of several different animal rhabdoviruses: vesicular stomatitis virus, rabies virus, Kern Canyon virus, and spring viremia of carp virus. Each virus is composed primarily of a glycoprotein, an RNA-associated nucleoprotein, and one or two membrane proteins. Vesicular stomatitis virus group viruses contain lesser amounts of two additional distinct polypeptides, NS and L. The separate viruses undergo structural polypeptide phosphorylation in vivo according to characteristic patterns. In vesicular stomatitis virus the NS protein is selectively phosphorylated. In rabies group viruses and in spring viremia of carp virus, the nucleoprotein is the predominant phosphoprotein; in these viruses only the phosphorylated moiety is selectively cleaved off with trypsin. In Kern Canyon virus, only membrane protein and glycoprotein are weakly phosphorylated. Each virus possesses a virion-bound protein kinase. Vesicular stomatitis virus group viruses, Kern Canyon virus, and spring viremia of carp virus only contain virion-bound transcriptases of respectively decreasing levels of activity demonstrable in vitro. Vesicular stomatitis and Kern Canyon viruses replicate efficiently in enucleated cells; rabies virus does not. Based upon these observations, it is suggested that vesicular stomatitis virus may represent the most highly evolved of these rhabdoviruses, whereas spring viremia of carp and Kern Canyon viruses may represent "evolutionary links" between the vesicular stomatitis and rabies virus groups.

Animals↗
PubMed2006

Crystal structure of the HRDC domain of human Werner syndrome protein, WRN.

Werner syndrome is a human premature aging disorder characterized by chromosomal instability. The disease is caused by the functional loss of WRN, a member of the RecQ-helicase family that plays an important role in DNA metabolic pathways. WRN contains four structurally folded domains comprising an exonuclease, a helicase, a winged-helix, and a helicase-and-ribonuclease D/C-terminal (HRDC) domain. In contrast to the accumulated knowledge pertaining to the biochemical functions of the three N-terminal domains, the function of C-terminal HRDC remains unknown. In this study, the crystal structure of the human WRN HRDC domain has been determined. The domain forms a bundle of alpha-helices similar to those of Saccharomyces cerevisiae Sgs1 and Escherichia coli RecQ. Surprisingly, the extra ten residues at each of the N and C termini of the domain were found to participate in the domain architecture by forming an extended portion of the first helix alpha1, and a novel looping motif that traverses straight along the domain surface, respectively. The motifs combine to increase the domain surface of WRN HRDC, which is larger than that of Sgs1 and E. coli. In WRN HRDC, neither of the proposed DNA-binding surfaces in Sgs1 or E. coli is conserved, and the domain was shown to lack DNA-binding ability in vitro. Moreover, the domain was shown to be thermostable and resistant to protease digestion, implying independent domain evolution in WRN. Coupled with the unique long linker region in WRN, the WRN HRDC may be adapted to play a distinct function in WRN that involves protein-protein interactions.

Amino Acid Sequence↗
PubMed2001

Complex functions of the brain.

Over the course of the last 50 years it has been possible to solve a number of basic problems in neurobiology. Interest is now turning more and more to problems concerning so-called "higher" brain functions, including cognition. Examples from the visual system in primates are presented. First relatively elementary problems are illustrated, such as how long it takes to perceive an object or to respond to a stimulus or combinations of stimuli. Top-down modification of perception by expectation is demonstrated in an illusion of misdirected gaze. Interdisciplinary questions straddling the sciences and the humanities are also approached, such as which part of the brain mediates conscious perception. Finally, the problem of causality and freedom of will is addressed, taking into account the knowledge accumulated in the neurosciences during the last 5 decades.

Journal Article↗
PubMed2005

Passive and active components of neonatal innate immune defenses.

Innate immune defenses are crucial for survival in the first days and weeks of life. At birth, newborns are confronted with a vast array of potentially pathogenic microorganisms that were not encountered in utero. At this age, cellular components of the adaptive immune system are in a naive state and are slow to respond. Antibodies received from the dam are essential for defense, but represent a finite and dwindling resource. Innate components of the immune system detect pathogen-associated molecular patterns (PAMPs) on microorganisms (and their products) by means of pattern-recognition receptors (PRRs). Soluble mediators of the innate system such as complement proteins, pentraxins, collectins, ficolins, defensins, lactoferrin, lysozyme etc. can bind to structures on pathogens, leading to agglutination, interference with receptor binding, opsonization, neutralization, direct membrane damage and recruitment of additional soluble and cellular elements through inflammation. Cell-associated receptors such as the Toll-like receptors (TLRs) can activate cells and coordinate responses (both innate and adaptive). In this paper, accumulated knowledge of the receptors, soluble and cellular elements that contribute to innate defenses of young animals is reviewed. Research interest in this area has been intermittent, and the literature varies in quantity and quality. It is hoped that documentation of the limitations of our knowledge base will lead to more extensive and enlightening studies.

Animals↗
PubMed2006

Nutrition and cancer: the current epidemiological evidence.

We have examined the current scientific evidence on the relationship between nutrition and the most frequent tumours in the Spanish population: lung, colorectal, prostate, breast and stomach. Consumption of fruit is negatively associated with cancer of the lung and stomach, possibly with colorectal cancer, but probably not with prostate cancer and breast cancer. Consumption of vegetables probably reduces the risk of colorectal and stomach cancer, but probably is not associated with cancer of the lung, prostate and breast. Consumption of red and processed meat is positively associated with colorectal cancer and probably with stomach cancer. Animal fat is possibly associated with colorectal cancer and probably with prostate and breast cancer. High alcohol intake increases the risk of colorectal and breast cancer, while dairy products and calcium seem to decrease the risk of colorectal cancer. Obesity is a recognised risk factor of colorectal cancer and breast cancer in postmenopausal women, while foods with a high glycaemic index and glycaemic load possibly increase the risk of colorectal and prostate cancer. The relevance of nutrition on the cancer process is evident. Nevertheless important issues remain to be solved and further studies are needed. This accumulative knowledge should be used by public health authorities to develop recommendations and activities to reduce overweight and obesity and to promote healthy dietary habits.

Breast Neoplasms↗
PubMed2004

Why the Bush administration and the global sugar industry are determined to demolish the 2004 WHO global strategy on diet, physical activity and health.

OBJECTIVE: To indicate why the world's most powerful nation state and one powerful sector of the food and drink production and manufacturing industry are determined to demolish the 2004 WHO (World Health Organization) global strategy on diet, physical activity and health, and to disassociate it from the 2003 WHO/FAO (Food and Agriculture Organization) expert report on diet, nutrition and the prevention of chronic diseases, which with its background papers is the immediate scientific basis for the strategy. To encourage representatives of nation states at the 2004 WHO World Health Assembly to support the strategy together with the report, so that the strategy is explicit and quantified, and responds to the need expressed by member states at the 2002 World Health Assembly. This is for an effective global strategy to prevent and control chronic diseases whose prevalence is increased by nutrient-poor food low in vegetables and fruits and high in energy-dense fatty, sugary and/or salty foods and drinks and also by physical inactivity. Of these diseases, obesity, diabetes, cardiovascular diseases and cancers of several sites are now the chief causes of morbidity and mortality in most countries in the world. METHOD: A summary of the global strategy and its roots in scientific knowledge accumulated over the last half-century. Reasons why the global strategy and the expert report are opposed by the current US government and the world sugar industry, with some reference to modern historical context. A summary of the trajectory of the global strategy since its first draft made in early 2003, and a further summary of its weaknesses, strengths and potential. CONCLUSION: The 2004 WHO global strategy and the 2003 WHO/FAO expert report are perceived by the current US administration as an impediment to US trade and international policy, within a general context of current US government hostility to the UN (United Nations) system as a brake on the exercise of its power as the world's dominant nation. Policy-makers throughout the world should be aware of the contexts of current pressures put on them by powerful nation states and sectors of industry whose ideologies and commercial interests are challenged by international initiatives designed to improve public health and to leave a better legacy for future generations.

Carbohydrates↗
PubMed1999

Report on a long-term study of maternal and congenital cytomegalovirus infection in Sweden. Review of prospective studies available in the literature.

This report summarizes knowledge accumulated in a long-term study of congenital and maternal cytomegalovirus (CMV) infection in Sweden. Some new findings are included. We considered diagnostic methods, sources of maternal infection (including occupational risks), roles of primary and secondary maternal infections, transmission to foetuses, incidence, symptoms and prognosis of established congenital infection and relative importance of such infection in infantile sensorineural deafness, microcephaly and type 1 diabetes mellitus. Virus isolation testing was done 1977-1985 on 16,474 newborns. 76 (0.5%) congenitally infected infants were found, 22/76 (29%) with transient neonatal symptoms and 11/60 (18%) with neurological symptoms by the age of 7 y. Type of maternal CMV infection was serologically determined in 62/76 cases (30 primary, 32 secondary). CNS disturbances in the infants occurred after both primary (all trimesters) and secondary maternal infections. The negative potential of secondary maternal infections might be an obstacle to preventive vaccination.

Adolescent↗
PubMed1992

Recollections of pioneers in nutrition: landmarks in the development of parenteral nutrition.

Total parenteral nutrition (TPN) has been available for only 30 years. The successful development of this therapy, in a modern sense, was initiated in the late 30s. However, history in this field goes back more than 350 years, with the first landmark being the description of general blood circulation by William Harvey in 1628. His discovery is the anatomical basis for intravenous infusions. Many investigations were performed during the following centuries showing that solutions containing electrolytes and glucose could be given intravenously in man. The accumulated knowledge of protein metabolism formed the basis for studies on intravenous nutrition with protein hydrolysates, peptides and amino acids. The observation in the late 30s by Robert Elman that amino acids in the form of protein hydrolysate could be administered safely in man was the first major step toward TPN. During the following years, major efforts were made to find methods to prepare infusion solutions with a high energy content and low osmotic pressure. The most realistic alternative seemed to be fat in the form of an emulsion. Many studies of a large number of various fat emulsions were made from the 20s until the end of the 50s. However, all of these emulsions caused severe adverse reactions in man. The first safe fat emulsion, Intralipid, was made available in the early 60s. This was the second major step toward TPN. It was then no problem to include vitamins, electrolytes and trace elements in the fat emulsions and the solutions of amino acids and glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗