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Biomedical subjects

A Horwitz

Publications and source records attributed to A Horwitz.

At least 19 recordsLinked to original sources
PubMed1992

High-affinity binding of the bactericidal/permeability-increasing protein and a recombinant amino-terminal fragment to the lipid A region of lipopolysaccharide.

Bactericidal/permeability-increasing protein (BPI) is a 55-kDa cationic protein (nBPI55) elaborated by polymorphonuclear neutrophils (PMN). BPI has potent bactericidal activity against a wide variety of gram-negative organisms and neutralizes endotoxin activities. An N-terminal fragment of nBPI55 exhibits the bactericidal and antiendotoxin properties of the holoprotein. To further characterize the biological activities of the N-terminal fragment, a recombinant protein (rBPI23) corresponding to the first 199 amino acids of human BPI was produced and purified. rBPI23 had antibacterial activity equivalent to that of nBPI55 against Escherichia coli J5. Furthermore, both rBPI23 and nBPI55 bound identically to a broad range of R- and S-form lipopolysaccharides (LPS) and to natural and synthetic lipid A. Binding of radiolabeled nBPI55 to LPS was inhibited in an identical fashion by either nBPI55 or rBPI23. The binding of both proteins to immobilized E. coli J5 lipid A was inhibited in a comparable fashion by long- or short-chain LPS or lipid A. The binding of both rBPI23 and nBPI55 was specific, saturable, and of high affinity, with an apparent Kd of approximately 2 to 5 nM for all ligands tested. These results demonstrate that BPI recognizes the highly conserved lipid A region of bacterial LPS via residues contained within the amino-terminal portion of the BPI molecule.

Antimicrobial Cationic Peptides↗
PubMed1992

Human bactericidal/permeability-increasing protein and a recombinant NH2-terminal fragment cause killing of serum-resistant gram-negative bacteria in whole blood and inhibit tumor necrosis factor release induced by the bacteria.

The bactericidal/permeability-increasing protein (BPI) of neutrophils and BPI fragments neutralize the effects of isolated Gram-negative bacterial lipopolysaccharides both in vitro and in vivo. Since endotoxin most commonly enters the host as constituents of invading Gram-negative bacteria, we raised the question: Can BPI and its bioactive fragments also protect against whole bacteria? To determine whether the bactericidal and endotoxin-neutralizing activities of BPI/fragments are expressed when Gram-negative bacteria are introduced to the complex environment of whole blood we examined the effects of added BPI and proteolytically prepared and recombinant NH2-terminal fragments on: (a) the fate of serum-resistant encapsulated Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa that survive the antibacterial actions of whole blood and (b) the ability of these bacteria to trigger cytokine release. Added BPI in nanomolar concentrations killed each of three encapsulated strains of E. coli and in closely parallel fashion inhibited tumor necrosis factor (TNF) release. Holo-BPI and its NH2-terminal fragment were equipotent toward a rough LPS chemotype K1-encapsulated strain, but the fragment was substantially more potent than holo-BPI toward two encapsulated smooth LPS chemotype strains. TNF release induced by K. pneumoniae and P. aeruginosa was also inhibited by both holo-BPI and fragment but, at the protein concentrations tested, P. aeruginosa was killed only by the fragment and K. pneumoniae was not killed by either protein. The bactericidal action of BPI/fragment toward E. coli is inhibited by C7-depleted serum, but accelerated by normal serum, indicating that BPI, acting in synergy with late complement components, enhances extracellular killing of serum-resistant bacteria. Thus, BPI and an even more potent NH2-terminal fragment may protect against Gram-negative bacteria in the host by blocking bacterial proliferation as well as endotoxin-mediated effects, not only as components of the intracellular antibacterial arsenal of the neutrophil, but also as potentially therapeutic extracellular agents.

Antimicrobial Cationic Peptides↗
PubMed1992

[The Chilean National Health Service: an intellectual and humanitarian adventure].

This is the speech delivered by Dr Abraham Horwitz, Emeritus Director of the Panamerican Health Organization, when he was granted a decoration from the Chilean Government. I believe--he said--that protection and promotion of health are not only an ethical imperative but also a basic political need of nations and peoples, a foundation for peace and development of human beings and society. Analyzing the origin and development of the Chilean National Health Service in 1952, he concludes that this was an intellectual and humanitarian endeavour of a group of idealists who devoted their best to improve the condition of the Chilean people.

Chile↗
PubMed1991

[From cell to society: in search of just social welfare].

This is a speech delivered by Dr Abraham Horwitz upon receiving the Professor Honoris Causa degree from the University of Chile. Dr Horwitz was the Director of the Panamerican Health Organization for 4 consecutive periods (1958-1975). Preventive Medicine and Health Promotion are effective means to increase social wellbeing. They should be implemented at all levels of health care. By increasing the span of healthy and productive life, the health industry makes a direct contribution to development and the economy. Government investment in health reflects the value attributed by society to social wellbeing. Research and better administration of health resources will allow to reduce costs and increase productivity of health and nutritional programs.

Chile↗
PubMed1991

Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations.

Four subjects with thermolabile methylenetetrahydrofolate reductase (MTHFR) were discovered among 16 "obligate" heterozygotes for severe MTHFR deficiency and their family members. All four subjects had less than 25% of normal mean MTHFR specific activity in lymphocyte extracts. Three of them with normal serum folate and cyanocobalamin had intermediate hyperhomocysteinemia, and one with high serum folate and cyanocobalamin had no excessive accumulation of serum homocysteine. The biochemical features in these four subjects are distinguishable from subjects homozygous for the thermolabile MTHFR, whose specific activity is approximately 50% of the normal mean, and from heterozygotes for severe MTHFR deficiency, in whom the enzyme is thermostable and has a specific activity of about 50% of the normal mean. We propose that these four subjects are genetic compounds of the allele for the severe mutation and the allele for thermolabile mutation of the MTHFR gene. It is postulated that subjects with this genetic compound are more susceptible to the development of intermediate hyperhomocysteinemia despite normal folate and B12 levels. Nonetheless, hyperhomocysteinemia due to this compound heterozygosity is correctable by oral folic acid therapy.

Adolescent↗
PubMed1990

Expression and function of chicken integrin beta 1 subunit and its cytoplasmic domain mutants in mouse NIH 3T3 cells.

Chicken integrin beta 1 cDNA and its site-directed mutants were cloned into a mammalian expression vector and introduced into mouse NIH 3T3 cells. Stable transfectants expressing the chicken beta 1 subunit or its site-directed mutants were identified by immunostaining with antibodies specific for the chicken integrin beta 1 subunit. The chicken beta 1 proteins were expressed predominately in the endoplasmic reticulum of transfectants and to a lesser degree in the plasma membrane. Immunoblots and immunoprecipitations, using anti-chicken integrin antibodies, revealed three different sizes of the chicken subunit (90, 95, and 120 kD) and a mouse 140-kD alpha subunit. Immunoprecipitations of the cell surface receptors showed only two peptides, an 120-kD beta 1 and an 140-kD alpha subunit. Antibodies perturbing mouse and chicken integrin-specific cell adhesions were used to demonstrate that the chimeric receptors functioned in adhesion to both laminin and fibronectin. Immunofluorescent staining with antibodies specific for either the chicken or mouse receptors showed that both the wild type and the chimeric receptors localized in focal contacts. Several mutations in the cytoplasmic domain were synthesized and used in the transfection experiments. In one mutant the tyrosine (Tyr 788) in the consensus sequence for phosphorylation was replaced by a phenylalanine. In another the lysine (Lys 757) at the end of the membrane spanning region was replaced by a leucine. Both of these mutants formed dimers with mouse alpha subunits, participated in adhesion, localized in focal contacts, and displayed biological properties indistinguishable from the wild-type transfection. In contrast, mutants containing deletions greater than 5-15 amino acids nearest the carboxyl end in the cytoplasmic domain neither promoted adhesion nor localized in focal contacts. They did, however, form heterodimers that were expressed on the cell surface.

Amino Acid Sequence↗
PubMed1989

Integrins isolated from Rous sarcoma virus-transformed chicken embryo fibroblasts.

Avian integrins are a complex of three integral membrane glycoproteins that are thought to have a role both in anchoring the cytoskeleton to the plasma membrane and establishing linkages to the extracellular matrix. We previously demonstrated that bands 2 and 3 of integrin are phosphorylated on both tyrosine and serine residues in chicken embryo fibroblasts (CEF) transformed with Rous Sarcoma virus (RSV) and other oncogenic retroviruses. The effects of RSV transformation on integrins from chick cells are now further characterized. The major site of tyrosine phosphorylation on band 3 in RSV transformed CEF has been identified as tyrosine 788. We also demonstrate that the product of the RSV oncogene, pp60v-src, can phosphorylate integrin in vitro, at the same residue. Tryptic peptide mapping and tunicamycin treatment indicates that a previously observed 4-8 k increase in the Mr of integrins from RSV-transformed cells can be attributed to an alteration in a post-translational modification such as glycosylation. Equilibrium gel filtration assays were used to test the ability of integrins from RSV-transformed CEF to interact with talin and fibronectin. Tyrosine phosphorylated integrins showed a decreased ability to interact with both these ligands in vitro. Conversely, integrins isolated from RSV-transformed CEF metabolically labeled in the absence of phosphatase inhibitor contained only low levels of phosphotyrosine and showed an almost normal ability to interact with ligands. Competition experiments indicated that the region of integrin containing tyrosine 788 is also important for talin binding to integrins.

Animals↗
PubMed1986

Phosphorylation of the fibronectin receptor complex in cells transformed by oncogenes that encode tyrosine kinases.

The fibronectin (FN) receptor in avian cells has been characterized previously as a complex of three membrane glycoproteins of about Mr 160,000, Mr 140,000, and Mr 120,000 (simply termed protein band 1, band 2, and band 3, respectively). Monoclonal antibodies to the band 3 protein of the complex prevent FN and laminin binding both in vivo and in vitro and enable the detection of the receptor proteins in the plasma membrane and in adhesion plaques. Association of the FN receptor proteins with the adhesion-plaque protein talin also has been reported. We now find that the band 2 and band 3 proteins in the complex are phosphorylated in Rous sarcoma virus-transformed chicken cells but not in normal chicken cells. Phosphorylation occurs predominantly on tyrosine and is accompanied by a reorganization of the receptor complex in the membrane of the transformed cells. Whereas normal cells contain the FN receptor in focal contacts and cellular processes between cells, v-src-transformed cells exhibit a more diffuse distribution of this receptor. In addition to the viral v-src oncogene, cells transformed by other avian oncogenes that also encode tyrosine kinases (v-fps, v-erbB, and v-yes) also express the receptor complex proteins in the phosphorylated state regardless of whether the transforming protein is detectable in adhesion plaques. These results suggest that the altered FN and laminin receptor proteins may contribute to the transformed phenotype, but their significance and role in the transformed state remain to be established.

Animals↗
PubMed1985

The cell substrate attachment (CSAT) antigen has properties of a receptor for laminin and fibronectin.

The cell substrate attachment (CSAT) antigen is an integral membrane glycoprotein complex that participates in the adhesion of cells to extracellular molecules. The CSAT monoclonal antibody, directed against this complex, inhibited adhesion of cardiac and tendon fibroblasts and skeletal myoblasts to both laminin and fibronectin, thus implicating the CSAT antigen in adhesion to these extracellular molecules. Equilibrium gel filtration was used to explore the hypothesis that the CSAT antigen functions as a cell surface receptor for both laminin and fibronectin. In this technique, designed for rapidly exchanging equilibria, the gel filtration column is pre-equilibrated with extracellular ligand to ensure receptor occupancy during its journey through the column. Both laminin and fibronectin formed complexes with the CSAT antigen. The association with laminin was inhibited by the CSAT monoclonal antibody; the associations with both fibronectin and laminin were inhibited by synthetic peptides containing the fibronectin cell-binding sequence. Estimates of the dissociation constants by equilibrium gel filtration agree well with those available from other measurements. This suggests that these associations are biologically significant. SDS PAGE showed that all three glycoproteins comprising the CSAT antigen were present in the antigen-ligand complexes. Gel filtration and velocity sedimentation were used to show that the three bands comprise and oligomeric complex, which provides an explanation for their functional association. The inhibition of adhesion by the CSAT monoclonal antibody and the association of the purified antigen with extracellular ligands are interpreted as strongly implicating the CSAT antigen as a receptor for both fibronectin and laminin and perhaps for other extracellular molecules as well.

Animals↗
PubMed1978

Congenital tyrosinemia.

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Amino Acid Metabolism, Inborn Errors↗
PubMed1978

[Urological problems and genesis of the abdominal musculature aplasia syndrome].

Judging according to the frequent description of the syndrome of aplasia of the abdominal muscle above all in paediatric literature (up to now more than 250 cases), the knowledge of the symptomocomplex (aplasia of the abdominal muscle, malformations of the kidneys and the urinary tracts, cryptorchism) might be of particular interest for the urologist, since the urologic malformations decisively determine the prognosis quoad vitam of these patients. On the basis of three own cases the importance of the removal of infravesical obstruction is emphasized, whereas the reconstructive intervention for dilatation of upper urinary tracts is seldom mandatory.

Abdominal Muscles↗