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Biomedical subjects

K S Warren

Publications and source records attributed to K S Warren.

At least 37 records · Page 2Linked to original sources
PubMed1996

Mutations affecting the formation and function of the cardiovascular system in the zebrafish embryo.

As part of a large-scale mutagenesis screen of the zebrafish genome, we have identified 58 mutations that affect the formation and function of the cardiovascular system. The cardiovascular system is particularly amenable for screening in the transparent zebrafish embryo because the heart and blood vessels are prominent and their function easily examined. We have classified the mutations affecting the heart into those that affect primarily either morphogenesis or function. Nine mutations clearly disrupt the formation of the heart. cloche deletes the endocardium. In cloche mutants, the myocardial layer forms in the absence of the endocardium but is dysmorphic and exhibits a weak contractility. Two loci, miles apart and bonnie and clyde, play a critical role in the fusion of the bilateral tubular primordia. Three mutations lead to an abnormally large heart and one to the formation of a diminutive, dysmorphic heart. We have found no mutation that deletes the myocardial cells altogether, but one, pandora, appears to eliminate the ventricle selectively. Seven mutations interfere with vascular integrity, as indicated by hemorrhage at particular sites. In terms of cardiac function, one large group exhibits a weak beat. In this group, five loci affect both chambers and seven a specific chamber (the atrium or ventricle). For example, the weak atrium mutation exhibits an atrium that becomes silent but has a normally beating ventricle. Seven mutations affect the rhythm of the heart causing, for example, a slow rate, a fibrillating pattern or an apparent block to conduction. In several other mutants, regurgitation of blood flow from ventricle to atrium is the most prominent abnormality, due either to the absence of valves or to poor coordination between the chambers with regard to the timing of contraction. The mutations identified in this screen point to discrete and critical steps in the formation and function of the heart and vasculature.

Animals↗
PubMed1996

Rationalizing health care in a changing world: the need to know.

The World Development Report 1993 announced that global life expectancy was then 65. Experience in the developed world suggests that the World Health Organization's dictum, "health is a state of complete physical, mental and social well-being', is simply not attainable for the foreseeable future. As physical health has improved, mental problems have become more prominent and a sense of well-being has declined. Furthermore, as the population ages and medical technology improves, the cost of health care grows almost exponentially. Since the population of the developed world is continuing to age and aging is spreading rapidly throughout the developing world, knowledge is the principal way of dealing with this seemingly intractable problem: we must know, quantitatively, the age-specific causes of ill health, and we must know which means of prevention and treatment are effective. Finally, we must apply that knowledge rationally.

Aging↗
PubMed1995

Forced expression of chimeric human fibroblast tropomyosin mutants affects cytokinesis.

Human fibroblasts generate at least eight tropomyosin (TM) isoforms (hTM1, hTM2, hTM3, hTM4, hTM5, hTM5a, hTM5b, and hTMsm alpha) from four distinct genes, and we have previously demonstrated that bacterially produced chimera hTM5/3 exhibits an unusually high affinity for actin filaments and a loss of the salt dependence typical for TM-actin binding (Novy, R.E., J. R. Sellers, L.-F. Liu, and J.J.-C. Lin, 1993. Cell Motil. & Cytoskeleton. 26: 248-261). To examine the functional consequences of expressing this mutant TM isoform in vivo, we have transfected CHO cells with the full-length cDNA for hTM5/3 and compared them to cells transfected with hTM3 and hTM5. Immunofluorescence microscopy reveals that stably transfected CHO cells incorporate force-expressed hTM3 and hTM5 into stress fibers with no significant effect on general cell morphology, microfilament organization or cytokinesis. In stable lines expressing hTM5/3, however, cell division is slow and sometimes incomplete. The doubling time and the incidence of multinucleate cells in the stable hTM5/3 lines roughly parallel expression levels. A closely related chimeric isoform hTM5/2, which differs only in the internal, alternatively spliced exon also produces defects in cytokinesis, suggesting that normal TM function may involve coordination between the amino and carboxy terminal regions. This coordination may be prevented in the chimeric mutants. As bacterially produced hTM5/3 and hTM5/2 can displace hTM3 and hTM5 from actin filaments in vitro, it is likely that CHO-expressed hTM5/3 and hTM5/2 can displace endogenous TMs to act dominantly in vivo. These results support a role for nonmuscle TM isoforms in the fine tuning of microfilament organization during cytokinesis. Additionally, we find that overexpression of TM does not stabilize endogenous microfilaments, rather, the hTM-expressing cells are actually more sensitive to cytochalasin B. This suggests that regulation of microfilament integrity in vivo requires stabilizing factors other than, or in addition to, TM.

Actin Cytoskeleton↗
PubMed1995

From information statics to information dynamics. The developing world has no alternative.

Libraries as presently constituted are essentially static paper-containing information systems often enclosed in massive specific spaces. The new electronic systems are by their very nature dynamic global systems that take up almost no space. Static information systems evolved from clay tablets to papyrus scrolls to parchment and finally to paper produced in vast quantities by the printing press. Medical and scientific journals have been growing exponentially since the seventeeth century as have the static paper-based libraries. This growth has been non-Darwinian, being outside of the laws of natural selection and survival of the fittest. Thus, the great majority of medical information is uncited and unread. Moreover, the vast investment in static libraries in the developed world has inhibited the development of modern electronic systems. In contrast, the developing world is largely bereft of such institutions, and has the unique opportunity to leap unencumbered by the static past into the far more efficient and dynamic electronic future.

Developing Countries↗
PubMed1994

Drugs.

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Journal Article↗
PubMed1994

The effectiveness of means of controlling communicable diseases.

Most communicable diseases are caused by infectious agents that are not visible to the naked eye, which led earlier societies to believe in miasmas and control by quarantine. Although microscopes revealed the agents in the eighteenth century, they were not associated with disease syndromes until the late nineteenth century. Today, vaccines are the most cost-effective means of control.

Child Welfare↗
PubMed1994

Overexpression of human fibroblast caldesmon fragment containing actin-, Ca++/calmodulin-, and tropomyosin-binding domains stabilizes endogenous tropomyosin and microfilaments.

Fibroblast caldesmon is a protein postulated to participate in the modulation of the actin cytoskeleton and the regulation of actin-based motility. The cDNAs encoding the NH2-terminal (aa.1-243, CaD40) and COOH-terminal (aa.244-538, CaD39) fragments of human caldesmon were subcloned into expression vectors and we previously reported that bacterially produced CaD39 protein retains its actin-binding properties as well as its ability to enhance low M(r) tropomyosin (TM) binding to actin and to inhibit TM-actin-activated HMM ATPase activity in vitro (Novy, R. E., J. R. Sellers, L.-F. Liu, and J. J.-C. Lin. 1993. Cell Motil. Cytoskeleton. 26:248-261). Bacterially produced CaD40 does not bind actin. To study the in vivo effects of CaD39 expression on the stability of actin filaments in CHO cells, we isolated and characterized stable CHO transfectants which express varying amounts of CaD39. We found that expression of CaD39 in CHO cells stabilized microfilament bundles as well as endogenous TM. CaD39-expressing clones displayed an increased resistance to cytochalasin B and Triton X-100 treatments and yielded increased amounts of TM-containing actin filaments in microfilament isolation procedures. In addition, analysis of these clones with immunoblotting and indirect immunofluorescence microscopy with anti-TM antibody revealed that stabilized endogenous TM and enhanced TM-containing microfilament bundles parallel increased amounts of CaD39 expression. The increased TM observed corresponded to a decrease in TM turnover rate and did not appear to be due to increased synthesis of endogenous TM. Additionally, the phenomenon of stabilized TM did not occur in stable CHO clones expressing CaD40. Therefore, it is likely that CaD39 can enhance TM's binding to F-actin in vivo, thus reducing TM's rate of turnover and stabilizing actin microfilament bundles.

Actin Cytoskeleton↗
PubMed1993

For the new millennium: control of helminth diseases throughout the world.

In the latter half of this century there has been a dramatic change in the treatment of helminthic infections. Two factors have contributed to this: an understanding of the major differences between helminths and other infectious agents, and the development of effective low-cost, single-dose, broad spectrum drugs. A program of administration of these drugs to school-aged children in developing countries is now being implemented and will result in a significant improvement in their health at a crucial time in their growth and development.

Anthelmintics↗
PubMed1993

Forced expression and assembly of rat cardiac troponin T isoforms in cultured muscle and nonmuscle cells.

Cardiac troponin T (cTnT), a tropomyosin (TM)-binding subunit of the troponin complex, undergoes a developmentally regulated isoform switch from embryonic form to adult form in the rat heart. To investigate the in vivo assembly of cTnT isoforms, we transiently transfected cDNA clones of either rat cTnT isoform into nonmuscle CHO cells and chick embryo myogenic (CEM) cells. As determined by Western blotting, both isoforms can be expressed in CHO and CEM cells. The expressed proteins had the same mobility as native rat cTnT proteins on SDS polyacrylamide gels and were recognized by anti-TnT antibodies. Conventional and confocal microscopy of transfected cells, double-labelled with antibodies against cTnT and against TM, revealed that neither isoform appears to associate with the nonmuscle TM in CHO cells, although both are able to colocalize with muscle TM-containing microfilament bundles in the myogenic CEM cells. There was no appreciable cTnT isoform-related difference in association with TM, suggesting that the functional significance of isoform variability in rat cTnT does not correspond to an assembly advantage for the maturing cardiac thin filament. To help determine whether cTnT nonassembly in CHO environment is primarily due to the nonmuscle nature of the endogenous TM, or if it involves the absence of other factors specific to muscle, we have isolated several stably-transfected clones of skeletal beta TM-expressing CHO cells which incorporate this muscle TM onto stress fibres. When either isoform of cTnT was transiently expressed in these beta TM-CHO cells, the strictly filamentous beta TM staining pattern was no longer observed. Instead, beta TM codistributed with cTnT in brightly staining aggregates not associated with the intact stress fibres. This suggests that both isoforms of cTnT are interacting with the beta TM in the nonmuscle environment and that other muscle-specific proteins may indeed be required for stable assembly of cTnT onto microfilaments. It also suggests that the interaction between cTnT and muscle TM is stronger than that between muscle TM and nonmuscle microfilaments.

Actin Cytoskeleton↗
PubMed1990

An integrated system for the control of the major human helminth parasites.

Disease due to virtually all of the human helminth parasites can be prevented simultaneously by a simple system based on the following premises: 1) helminths do not multiply within their definitive hosts, and their distribution in host populations is overdispersed; 2) disease manifestations occur largely in the small proportion of hosts, often school children, with heavy worm burdens; and 3) a few single-dose, broad-spectrum anthelmintics given in low doses at prolonged intervals can maintain worm burdens below pathogenic levels for almost all of the major human helminth parasites. The three drugs might be albendazole or one of the other benzimidazoles for hookworm, ascaris and trichuris; ivermectin for the filaria, including onchocerca and many other nematodes such as strongyloides; and praziquantel for virtually all trematodes and cestodes. The target group would be school children treated at intervals set to maintain worm burdens below the disease-inducing threshold. It is possible that all three drugs could be administered in low doses simultaneously at yearly intervals. Studies will be necessary to examine drug interactions, development of drug resistance, optimal dosages and timing, and effects on morbidity.

Animals↗
PubMed1988

Hookworm control.

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Ancylostoma↗
PubMed1988

The evolution of selective primary health care.

This paper traces the evolution of the selective primary health care (SPHC) concept, from its presentation at a meeting in Bellagio, Italy, and its subsequent publication in the New England Journal of Medicine in 1979. It reviews the early debate between those in favor of selectivity and those in favor of comprehensive primary health care (CPHC). While this debate was going on, a breakthrough in terms of implementation came with UNICEF's launching of its Children's Revolution in 1982/83, promoting four specific 'social and scientific advances' for improving the health and nutrition of the world's children. They were growth monitoring, oral rehydration therapy, breastfeeding and immunization. Meanwhile the interest of a number of people for achieving 'Health For All' by targeting for action an essential short list of diseases was the impetus for another conference in 1985, Good Health at Low Cost. Through analysis of the achievements of four societies (Cost Rica, China, Kerala and Sri Lanka) efforts were made to define further a prioritized health development strategy, and a number of measures were identified as helping countries achieve good health. While some have argued that SPCH and CPHC are irreconcilable and diametrically opposed, this paper suggests that both SPCH and CPHC are both acceptable. Technology has its place. The field of view of SPHC has enlarged drastically, from individual diseases to the role of other sectors such as education and agriculture. The concept of SPHC has broadened to accept Rifkin's and Walt's assertion that "developmental processes need further exploration and research strengthening capabilities within countries".(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗