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Biomedical subjects

M Pollack

Publications and source records attributed to M Pollack.

At least 19 recordsLinked to original sources
PubMed1992

Antibacterial and protective properties of monoclonal antibodies reactive with Escherichia coli O111:B4 lipopolysaccharide: relation to antibody isotype and complement-fixing activity.

In vitro and in vivo antibacterial and protective properties of murine monoclonal antibodies (MAbs) to Escherichia coli O111:B4 lipopolysaccharide (LPS) were evaluated in relation to antibody isotype and complement-fixing activity. Six O side chain-specific MAbs, including two IgMs and one of each IgG subclass, were analyzed for quantitative binding and C3 deposition on intact bacteria, complement-mediated bactericidal and opsonophagocytic activity, and protection against intraperitoneal infections in mice. Although C3 was deposited on bacteria in the presence of normal human serum (NHS) alone, LPS-specific MAbs increased C3 attachment in a dose-dependent manner. Bacterial killing occurred only in the presence of both antibody and complement NHS and required an intact alternative pathway. The efficiency of bacterial killing varied by antibody isotype (IgM greater than IgG2a greater than other IgG subclasses) and correlated with C3-fixing capacity. Opsonophagocytic activity of MAbs exhibited a similar isotype-related rank order. Likewise, IgM was more active than IgG, and IgG2a was superior to other IgG subclasses, in MAb-mediated protection against intraperitoneal infection. These data document the interdependent antibacterial and complement-fixing properties of LPS-reactive MAbs and the degree to which both activities are determined by antibody class and isotype.

Animals↗
PubMed1992

Lipopolysaccharide heterogeneity in Escherichia coli J5 variants: analysis by flow cytometry.

A lipopolysaccharide O-side chain-producing phenotypic variant was isolated from a uridine 5'-diphosphogalactose 4-epimeraseless Escherichia coli J5 rough mutant strain by fluorescence-activated cell sorting with a monoclonal antibody (MAb) specific for the O-side chain of E. coli O111:B4 smooth parent lipopolysaccharide. The variant (J5-2) was recognized by both core- and O-side chain-specific MAbs, while the "original" rough mutant (J5-1) and smooth parent strains stained only with core- and O-side chain-specific MAb, respectively. J5-2 produced complete and incomplete (Rc chemotype) core and O polysaccharide in the presence of galactose. Three other E. coli J5 variants were either phenotypically similar to J5-1 (J5-UK) or distinct from J5-1 and J5-2 (J5-A, -B). The latter phenotype had a lower-molecular-weight core, compared with J5-1 and J5-2, and distinct MAb specificities. Various J5 phenotypes also differed in galactokinase levels, the ability to use galactose, and susceptibility to core-specific MAb binding on solid media. The J5-2 strain showed reciprocal changes in O-side chain and core expression during log-phase growth. E. coli J5 thus undergoes spontaneous alterations in lipopolysaccharide phenotype.

Antibodies, Monoclonal↗
PubMed1992

Cholera in Piura, Peru: a modern urban epidemic.

In late January 1991, epidemic cholera appeared in Peru. Within 2 months, 7922 cases and 17 deaths occurred in Piura, a Peruvian city of 361,868. A hospital-based culture survey showed that 79%-86% of diarrhea cases were cholera. High vibriocidal antibody titers were detected in 34% of the asymptomatic population. A study of 50 case-patients and 100 matched controls demonstrated that cholera was associated with drinking unboiled water (odds ratio [OR], 3.9; 95% confidence interval [CI], 1.7-8.9), drinking beverages from street vendors (OR, 14.6; CI, 4.2-51.2), and eating food from street vendors (OR, 24.0; CI, 3.0-191). In a second study, patients were more likely than controls to consume beverages with ice (OR, 4.0; CI, 1.1-18.3). Ice was produced from municipal water. Municipal water samples revealed no or insufficient chlorination, and fecal coliform bacteria were detected in samples from 6 of 10 wells tested. With epidemic cholera spreading throughout Latin America, these findings emphasize the importance of safe municipal drinking water.

Adolescent↗
PubMed1991

Pharmacodynamic and protective properties of a murine lipopolysaccharide-specific monoclonal antibody in experimental Pseudomonas aeruginosa pneumonia in mice.

We employed a Pseudomonas aeruginosa mouse pneumonia model to evaluate the ability of a murine monoclonal antibody (MAb) specific for the O-side chain of P. aeruginosa Fisher Immunotype-1 lipopolysaccharide (LPS) to achieve and sustain therapeutic levels in plasma and lung tissue, reduce bacterial populations in the lung, and prevent pneumonia-associated mortality. An IgG3 MAb (Y1-5A4) administered to mice i.v. over a dose range of 125-1,000 micrograms/mouse produced plasma and lung tissue levels at 2 hr of 61-507 micrograms/ml and 4.3-150 micrograms/g, respectively. The 1,000 micrograms MAb dose reduced bacterial counts in lung tissue (log10 cfu/g +/- S.D.) and blood (log10 cfu/ml +/- S.D.) 20 hr post-treatment (18 hr post-challenge) from 10.00 +/- 0.66 to 7.66 +/- 0.91 (P less than 0.01) and from 4.39 +/- 0.81 to less than 3.0, respectively. Administration of MAb to mice in doses of 125-500 micrograms 2 hr prior to a 3 x 50% lethal bacterial challenge produced significant protection against death, with a calculated 50% protective dose of 167 micrograms. Protection was noted following administration of 1,000 micrograms of MAb up to 6 hr after bacterial challenge (P less than 0.05, compared with untreated control). Histological examination of lung tissue from infected mice revealed less acute inflammation, necrosis, and hemorrhage in MAb-treated compared with untreated control animals and greater localization of Pseudomonas antigen within the phagocytic cells in alveolar space. These findings document the in vivo therapeutic efficacy of an LPS-specific IgG MAb in a murine model of acute P. aeruginosa pneumonia, based in part upon the achievability of effective MAb concentrations in plasma and lung tissue.

Animals↗
PubMed1990

Specificity and function of monoclonal antibodies reactive with discrete structural elements of bacterial lipopolysaccharide.

We examined the binding and functional activities of monoclonal antibodies (mAbs) reactive with different structural elements of Escherichia coli and Salmonella minnesota LPS. O-side chain-reactive mAbs were highly specific for homologous, smooth LPS, bound avidly to intact bacteria, mediated complement-dependent bactericidal and/or opsonic activity, and protected against live, homologous IP challenges in mice. Core- and lipid A-specific mAbs, on the other hand, were more cross-reactive, although this cross-reactivity was severely restricted by the relative inaccessibility of epitopes in the core/lipid A region. This was reflected in the general inability of these mAbs to react with isolated smooth LPS or wild type bacteria, or to mediate bactericidal or opsonic functions. No LPS-reactive mAbs, regardless of molecular specificity, was able to block LPS- or lipid A-induced TNF production by RAW 264.7 macrophages, thus raising doubts concerning the putative endotoxin-neutralizing properties of mAbs reactive with the core/lipid A complex. Bacterial lipopolysaccharides (LPS) exhibit a complex identity. They represent an essential structural element of the outer membrane of all Gramnegative bacteria (7); they are toxins (5); they mediate a variety of immunomodulatory activities; and they are important bacterial surface antigens (2). In general, LPS macromolecules consist of three genetically, biochemically, and antigenetically distinct regions or domains: the O-side chain, core oligosaccharide, and lipid A moiety (15). Of these three regions, the O-side chain is the most phylogenetically diverse. It also represents the most antigenetically exposed element on isolated or cell-associated, native LPS. The core and lipid A structures, in contrast, are relatively conserved among different bacteria and are less accessible to antibody attack by virtue of overlying sugars contained in the O-side chain or outer core (8). In this study, we investigated selected functional activities of monoclonal antibodies (mAbs) specific for different epitopes within the three major structural domains of Escherichia coli and Salmonella minnesota LPS. The possible endotoxin-neutralizing and antibacterial properties of these mAbs were our particular focus.

Animals↗
PubMed1990

Fluorescence-activated cell sorter analysis of binding by lipopolysaccharide-specific monoclonal antibodies to gram-negative bacteria.

Sixteen murine monoclonal antibodies (MAbs) reactive with the O-side chain, core oligosaccharide, or lipid A of Escherichia coli O111:B4 and Salmonella minnesota lipopolysaccharide (LPS) were evaluated for binding activity against wild-type and rough mutant strains using a fluorescence-activated cell sorter (FACS) and fluorescein-conjugated antiimmunoglobulin probe. O-side-chain-reactive MAbs produced immunofluorescence against homologous, smooth strains up to 500-fold higher than controls. Many core- and lipid A-reactive MAbs exhibited limited reactivity with smooth bacteria. Some core- and lipid A-associated epitopes, however, were better recognized by MAbs on intact bacteria than on isolated LPS. FACS analysis of binding by the core-reactive MAb, J8-4C10, to E. coli O26:B6 smooth bacteria revealed staining and non-staining bacterial phenotypes that were sorted and stably expressed in subculture. FACS analysis thus documented differences in the whole-cell reactivity of MAbs specific for various LPS subcomponents, differences in MAb reactivity with isolated and cell-associated LPS, and spontaneous changes in the phenotypic expression of certain LPS-associated epitopes on intact bacteria.

Antibodies, Bacterial↗
PubMed1989

C4A gene deletion and HLA associations in black Americans with systemic lupus erythematosus.

In North America and European Caucasoids with systemic lupus erythematosus (SLE) there is an increased frequency of a C4A, CYP21A gene deletion, largely associated with the HLA-B8,DR3,C4A*QO extended haplotype. There have been no consistent HLA associations reported for SLE in blacks, although an increased frequency of serologically determined C4A null alleles has been reported in two studies. We studied 79 black American SLE patients and 68 black controls by restriction fragment length polymorphism analysis to determine if a C4A gene deletion was a genetic risk factor for SLE. Moreover, the nature of the deletion and any HLA phenotypic associations were sought. Nineteen of 79 (24%) patients compared to 5 of 68 (7.4%) controls had a phenotypic C4A,CYP21A gene deletion (P = .005; RR = 4). A homozygous deletion in four patients gave a genotypic frequency of 23/158 (14.5%) SLE patients vs 5/136 (3.7%) controls (P = .001; RR = 4.5). The deletion was associated with HLA-DR2 (P = .03) and HLA-DR3 (P = .03). Moreover, all subjects with the deletion had HLA-DR2 or DR3 (P = 7.7 x 10(-6). HLA-B44 was also associated with the deletion (P = .02), and eight of the nine HLA-B44 positives also carried HLA-DR2. HLA-B8 approached significance (P = .08) and was always accompanied by HLA-DR3. Finally, this black population demonstrated a unique C4B gene size polymorphism with 80% C4B "short" as compared to the 40% C4B "short" frequency reported in whites. We conclude that a large C4A,CYP21A gene deletion, particularly associated with the HLA-B44, -DR2, and -DR3 alleles, is the strongest genetic risk factor thus far identified for SLE susceptibility in black Americans. Furthermore, the unique preponderance of the C4B "short" gene form may be a factor in the actual formation of the deletion.

Black People↗
PubMed1989

Specificity and cross-reactivity of monoclonal antibodies reactive with the core and lipid A regions of bacterial lipopolysaccharide.

Twenty-nine murine monoclonal antibodies (MAbs) were prepared against antigenic determinants in the core and lipid A regions of Escherichia coli and Salmonella minnesota lipopolysaccharide (LPS). At least eight distinct MAb specificities were identified. Epitopes recognized by MAbs bearing these specificities were localized in the hexose, heptose, and 2-keto-3-deoxy-D-manno-octulosonic acid regions of the core oligosaccharide and on lipid A. Two groups of MAbs exhibited multispecificity for similar but distinct core- and lipid A-related epitopes. Some core-reactive MAbs cross-reacted with corresponding E. coli and Salmonella rough mutant chemotypes; others were specific for E. coli J5 LPS. Lipid A-specific MAbs reacted with free lipid A from diverse sources. Few MAbs reacted with smooth LPS. Antibody cross-reactivity was restricted by inter- and intraspecies differences in covalent core structure and by epitope concealment by overlying O-side chain and core sugars. The putative cross-reactive and antiendotoxic properties of MAbs specific for the core-lipid A complex may be limited by the inability of such MAbs to recognize determinants on "native" LPS.

Animals↗
PubMed1989

Lipopolysaccharide (LPS)-reactive monoclonal antibodies fail to inhibit LPS-induced tumor necrosis factor secretion by mouse-derived macrophages.

Murine monoclonal antibodies (MAbs) reactive with epitopes on the O-side chain, core oligosaccharide, or lipid A of Escherichia coli and Salmonella minnesota lipopolysaccharide (LPS) were evaluated for their ability to inhibit LPS-induced tumor necrosis factor (TNF) secretion by mouse-derived RAW 264.7 macrophages. As little as 50 ng of purified LPS or lipid A stimulated macrophages to produce TNF detectable as cytotoxic activity in an L-929 fibroblast assay. None of 13 MAbs (concentration range, 0.1-1,000 micrograms/mL) blocked LPS- or lipid A (0.025-0.1 micrograms/mL)-induced TNF secretion by RAW 264.7 cells. Rabbit antiserum to synthetic lipid A also failed to block lipid A-induced TNF activity. Similar negative results were obtained when intact bacteria or membrane vesicles were used as TNF inducers. In contrast, polymyxin B, but not the less hydrophobic polymyxin B nonapeptide, produced almost complete inhibition of macrophage TNF secretion induced by LPS, lipid A, membrane vesicles, and intact bacteria. Thus, antibody reactivity with predominantly hydrophilic elements of LPS or lipid A may not affect hydrophobic interactions between lipid A and target cell membranes necessary and sufficient for the induction of TNF. These findings raise doubts concerning the existence of true endotoxin-neutralizing antibodies.

Animals↗
PubMed1989

Isolation, structure, and immunogenicity of Pseudomonas aeruginosa immunotype 4 high-molecular-weight polysaccharide.

A high-molecular-weight, immunogenic form of the lipopolysaccharide O side chain of Pseudomonas aeruginosa Fisher immunotype 4 (type 4, International Antigenic Typing System 1, Lanyi O:6) was isolated and characterized. Analysis by nuclear magnetic resonance spectroscopy confirmed the structural similarity of this high-molecular-weight polysaccharide and the type 4 O side chain. The polysaccharide was immunogenic in rabbits and mice, eliciting opsonophagocytic killing antibodies. Immunization with the polysaccharide produced significant protection against homologous challenge in both burned and granulocytopenic mice. Naturally acquired opsonic killing antibodies to type 4 polysaccharide were present in sera from unimmunized normal adults at levels comparable to postimmunization levels achieved after immunization with other type-specific polysaccharides. The specificity of the naturally occurring antibodies for the O side chain was documented by immunoblot analysis and inhibition studies. Naturally occurring polysaccharide-specific antibodies were comparable in their protective activity against live challenge in neutropenic animals to immunization-induced murine antibodies with similar specificity. These data suggest that naturally occurring serum antibody to P. aeruginosa type 4 lipopolysaccharide O side chains in most adults is not distinguishable in quantity or quality from immunization-induced antibodies in mice; evaluation of type 4-specific vaccines in humans may be complicated by this finding.

Animals↗
PubMed1989

Cost-effectiveness of routine and campaign vaccination strategies in Ecuador.

A national household coverage survey of 3697 Ecuadorean children, carried out in July 1986, provided an opportunity for a cost-effectiveness analysis of (1) routine vaccination services based in fixed facilities and (2) mass immunization campaigns. A major purpose of the campaigns was to complement the routine services and to accelerate immunization activities. Based on the coverage survey, the Program for Reduction of Maternal and Childhood Illness (PREMI) and earlier campaigns increased the proportion of children under 5 years who were fully vaccinated from 43% to 64%. In one year, the PREMI campaign was responsible for fully vaccinating 11% of children under one year, 21% of 1-2-year-old children, and 13% of all children under 5 years. The campaign also helped ensure that vaccinations were completed when children were still very young and at greatest risk. The average cost per vaccination dose (in 1985 US$ prices) was approximately $0.29 for fixed facilities and $0.83 for the PREMI campaign. Total national costs were $675,000 and $1,665,000 for routine and campaign services respectively. The cost per fully vaccinated child (FVC) was $4.39 for routine vaccination services and $8.60 for the campaign. The cost per death averted was about $1900 for routine vaccination services, $4200 for the PREMI campaign, and $3200 for the combined programme. Because of Ecuador's lower mortality rates, the costs per death averted in Ecuador from both vaccination strategies are not as low as those from studies of vaccinations in Africa. The campaigns, though less cost-effective than routine services, significantly improved the vaccination coverage of younger children who had been missed by the routine services. The costs per FVC of both the campaign and the routine services compare favourably with such programmes in other countries.

Child↗
PubMed1989

Assignment of autosomal dominant spinocerebellar ataxia (SCA1) centromeric to the HLA region on the short arm of chromosome 6, using multilocus linkage analysis.

A 7-generation kindred with the HLA-linked form of spinocerebellar ataxia (SCA1) was studied to determine whether the SCA1 gene maps centromeric or telomeric to the HLA loci. The DNA markers flanking the HLA-(A-B) region were used for polymorphism studies and multilocus linkage analysis. These two markers are the cDNA for the beta-subunit of HLA-DP, which is centromeric to HLA-(A-B), and the cDNA for coagulation factor XIIIa (F13A), which is telomeric to HLA-(A-B). Haplotypes were constructed using multiple polymorphisms for these two DNA markers, and pairwise linkage analysis revealed a maximum lod score of 2.18 for SCA1 versus HLA-DP at a recombination fraction of .05 and a maximum lod score of 0 for SCA1 versus F13A at a recombination fraction of .50. A possible crossover between HLA-(A-B) and HLA-DP was identified, but lack of samples from key individuals hampered the analysis. To clarify the phase and improve the analysis, the two chromosomes 6 for the crossover individual were separated in somatic cell hybrids. The results strongly favored the probability that the crossover occurred between HLA-(A-B-DR) and HLA-DP with SCA1 segregating with HLA-DP, consistent with a location centromeric to HLA-(A-B). Multilocus linkage analysis was used to evaluate further the location of SCA1 relative to F13A, HLA-(A-B), and HLA-DP; the results indicated that the SCA1 gene locus is centromeric to HLA-DP with odds of 46:1 favoring this most likely location over the second most likely location, i.e., telomeric to HLA-(A-B) between the HLA complex and F13A.

Animals↗
PubMed1988

Widowhood, sexuality and aging: a life span analysis.

In an attempt to evaluate how widows of various ages adapt sexually to loss of a marital partner, 100 relatively healthy, community-dwelling widows between the ages of 40 and 89 completed a reliable 101-item questionnaire which evaluated three major areas: 1) barriers to sexual expression posed by age-related changes in body image, mood state and environmental context; 2) degree of unhappiness associated with loss of various marriage-oriented activities; and 3) perceived utility of various activities which indirectly might satisfy sexual and affectional needs. Controlling for income, education, heterosocial involvement, and family contact, and using level of morale and depression as corroborative measures, results showed specific age differences across variables assessed. In particular, younger widows, when compared with their older counterparts, viewed changes in body image, the dearth of unattached men, and limited financial resources for social activities as representing significant sexual barriers. Increasing age of the widow was associated with lower unhappiness ratings with loss of marriage-related activities. For the sample as a whole, greater unhappiness was expressed with the loss of nonsexual, heterosocial activity (e.g., conversation with a man, going places with a man). Results also indicated that, regardless of the widow's age, activities pertaining to her children and grandchildren, wearing attractive clothing, and expressing her spirituality are all effective in meeting affectional and sexual needs. Results are discussed within the context of older female sexuality, affectional adaptation to widowhood, and therapeutic implications directed at this neglected group.

Adaptation, Psychological↗