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PubMed1985

Bacterial and viral pathogens causing fever in infants less than 3 months old.

We studied 182 sick, febrile (temperature greater than 38 degrees C) infants less than 3 months of age, who presented at our Tripler Army Medical Center, Honolulu, during a one-year period, to determine the relative causes of fever in this age group. Blood, cerebrospinal fluid, urine, nasopharyngeal secretions, and stool specimens were cultured for bacterial and viral pathogens. Paired acute and convalescent sera were collected to serologically confirm infection in infants from whom viral isolations were obtained only from the nasopharynx or stool. A viral pathogen was isolated in 75 infants (41%) and a bacterial pathogen was isolated in 27 infants (15%). Nonpolio enteroviruses were the most common pathogens demonstrated. They were isolated from 64 infants (35%), and 40 (62%) of these infants had aseptic meningitis, the most frequently made diagnosis. Urinary tract infection was the most common bacterial infection observed. It occurred in 20 infants (11%) and was most often seen without associated pyuria in uncircumcised male infants. Salmonellosis, the second most common bacterial infection, was observed in six infants (3%), and two of these did not have diarrhea or other gastrointestinal tract symptoms. No infant had septicemia and only one infant had bacterial (group B streptococcal) meningitis.

Bacterial Infections↗
PubMed1996

Generation of autonomously pathogenic neo-autoreactive Th1 cells during the development of the determinant spreading cascade in murine autoimmune encephalomyelitis.

Chronic progression of autoimmune disease is accompanied by the acquisition of autoreactivity to new self-determinants. Recent evidence indicates that this process, commonly referred to as determinant spreading, may be pathogenic for chronicity. Our studies on experimental autoimmune encephalomyelitis (EAE), a murine model widely used in multiple sclerosis (MS) studies, have shown that determinant spreading develops as a predictable sequential cascade of neo-autoimmunity during progression to chronic disease. By 7-8 weeks after immunization of (SWR x SJL)F1 mice with the immunodominant myelin proteolipid protein determinant (PLP 139-151), splenocytes consistently respond to the immunodominant myelin basic protein determinant (MBP 87-99). In the present study, we directly address the pathogenicity of neo-autoimmunity resulting from endogenous self-priming during the course of disease. Our results indicate that T cells responding to the spreading MBP 87-99 determinant produce a proinflammatory cytokine profile consistent with type 1 helper T cells (Th1) cells. In addition, splenocytes activated to the spreading MBP 87-99 determinant consistently transfer acute EAE in naive recipients even when T cells reactive to the priming PLP 139-151 immunogen are eliminated by bromodeoxyuridine (BUdR)-mediated photolysis. Our data indicate that endogenous neo-autoantigen priming during chronic autoimmune disease generates type 1 helper T cells (Th1) cells that are autonomously pathogenic. These results provide further evidence supporting the view that determinant spreading is a pathogenic process that leads to chronic progression of autoimmune disease.

Adoptive Transfer↗
PubMed2004

Is alpha-actinin a target for pathogenic anti-DNA antibodies in lupus nephritis?

OBJECTIVE: Following recent reports that pathogenic murine anti-DNA antibodies bind to alpha-actinin, it was obviously of interest to assess the ability of human pathogenic anti-double-stranded DNA (anti-dsDNA) antibodies to bind this antigen. Both human monoclonal anti-DNA antibodies and antibodies affinity purified from the sera of patients with systemic lupus erythematosus (SLE) were investigated. METHODS: An enzyme-linked immunosorbent assay was established to measure immunoglobulin binding to alpha-actinin. Antibodies binding dsDNA were purified from the sera of SLE patients who either had active renal disease or had never had renal disease. Serum samples were selected at times when the patients' sera exhibited high IgG binding to dsDNA. The binding of supernatants from 3 high-affinity human anti-dsDNA IgG hybridomas (RH14, B3, and DIL-6) and 7 human IgM anti-DNA hybridomas was also investigated. RESULTS: A greater proportion of anti-dsDNA IgG-binding antibodies purified from patients with renal disease bound to alpha-actinin than did those purified from the sera of patients without renal disease. The specificity of binding to the 100-kd alpha-actinin molecule was confirmed by Western blotting. The pathogenic human antibodies RH14 and B3 bound strongly to alpha-actinin, while nonpathogenic DIL-6 bound very weakly. RT84, the IgM antibody that binds dsDNA with the highest affinity, exhibited the greatest binding to alpha-actinin. CONCLUSION: The results of our study support the findings of previous studies using murine anti-DNA monoclonal antibodies, which suggest that pathogenic anti-dsDNA antibodies cross-react with alpha-actinin.

Actinin↗
PubMed2006

PAMP recognition and the plant-pathogen arms race.

Plants have evolved systems analogous to animal innate immunity that recognise pathogen-associated molecular patterns (PAMPs). PAMP detection is an important component of non-host resistance in plants and serves as an early warning system for the presence of potential pathogens. Binding of a PAMP to the appropriate pattern recognition receptor leads to downstream signalling events and, ultimately, to the induction of basal defence systems. To overcome non-host resistance, pathogens have evolved effectors that target specific regulatory components of the basal defence system. In turn, this has led to the evolution in plants of cultivar-specific resistance mediated by R proteins, which guard the targets of effectors against pathogen manipulation; the arms race continues.

Flagellin↗
PubMed2006

Potential of the marine sponge Hymeniacidon perleve as a bioremediator of pathogenic bacteria in integrated aquaculture ecosystems.

The aim of this article is to investigate the potential of using sponges as a bioremediator to remove pathogenic bacteria in integrated aquaculture ecosystems. Using the inter-tidal marine sponge Hymeniacidon perleve as a model system, the ability of removing the most common pathogens Escherichia coli and Vibrio anguillarum II in aquaculture waters was screened in laboratory tests. In sterilized natural seawater (SNSW) supplemented with E. coli at (7.0-8.3) x 10(6) cells/mL, H. perleve can remove an average 96% of E.coli within 10.5 h at a filter rate of ca. (7.53-8.03) x 10(7) cells/h x g of fresh sponge in two independent tests. Despite the removal efficiency and filter rate are similar; the clearance rates (CR) vary significantly among individual sponge specimens and between two batches. For the tests on V. anguillarum II in SNSW, about 1.5 g fresh sponges can keep the pathogen growth under control at a lower initial density 3.6 x 10(4) cells/mL of 200 mL water volume. Further tests were done for 24 h using about 12 g fresh sponge in 2-L actual seawater collected from two aquaculture sites that have ca. eightfold difference in pathogenic bacteria load. The concentrations of E. coli, Vibrio, and total bacteria at 24 h in treatment groups were markedly lower, at about 0.9%, 6.2%-34.5%, and 13.7%-22.5%, respectively, of those in the control. Using a fluoresce stain 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, E. coli, and V. anguillarum II cells were stained and fed to sponges in two independent tests. The confocal microscope observation confirmed that the sponges filtering-retained and digested these bacteria by phagocytosis.

Animals↗
PubMed1992

Cationic residues in pathogenic anti-DNA autoantibodies arise by mutations of a germ-line gene that belongs to a large VH gene subfamily.

The F1 progeny of autoimmune NZB and normal SWR mice uniformly develop severe and accelerated lupus nephritis. The (SWR x NZB)F1 mice produce an oligoclonally expanded population of nephritogenic anti-DNA autoantibodies that share a recurrent cross-reactive idiotype (Id564), use highly homologous VH genes and surprisingly have the CH region allotype of the normal SWR parent. From extensive library analyses, we isolated 15 SWR germ-line genes which are most closely related to the pathogenic autoantibody VH564 gene and which also belong to the NPb subfamily of J558 VH genes. We found that the pathogenic VH genes are probably somatic variants of a SWR germ-line VH gene, SW6-3, and they have several basic amino acid substitutions, in addition to those already present in the SW6-3 germ-line gene. Since these pathogenic autoantibodies are not detectable in the sera of the normal SWR mice despite the presence of the SW6-3 gene, strong selection and expansion of B cells expressing the SW6-3 VH gene is probably occurring in (SWR x NZB)F1 lupus-prone mice. We also isolated eight germ-line genes from the NZB mouse which are homologous to SW6-3. The autoimmune NZB parent that rarely develops nephritis lacks the SW6-3 gene, but has several highly homologous germ-line VH genes that would encode less cationic antibodies. These results establish a correlation between structure and pathogenic potential of VH genes.

Amino Acid Sequence↗
PubMed2005

The Mycobacterium tuberculosis cell wall component mycolic acid elicits pathogen-associated host innate immune responses.

Recognition of conserved pathogen-associated molecular patterns constitutes a crucial step in the initiation of innate immune responses. We studied the contribution to the host-pathogen interaction of mycolic acid (MA), a major lipid component of the cell envelope of the macrophage intracellular pathogen Mycobacterium tuberculosis and other mycobacteria. MA administered to the peritoneal cavity or to the airways induced a unique macrophage morphotype, similar to the foamy macrophage derivatives observed in tuberculous granulomas and characterized by intracellular accumulation of neutral lipids and entry into mitosis. When assayed for production of inflammatory mediators, a conditioning rather than a direct activation of the MA-elicited foamy macrophages was observed. MA enabled production of IFN-gamma and myeloperoxidase, enhanced TNF-alpha production and suppressed IL-10 upon renewed exposure to innate triggers. Intratracheal instillation of MA mimicked additional features of the airway response to M. tuberculosis infection, namely a rapid but transient neutrophil influx and IL-6 production and a chronic IL-12 production. These MA-elicited cellular innate defenses and the accompanying formation of foamy macrophages identify for the first time the foamy macrophage morphotype as part of the host response to a pathogen-associated structure. Furthermore, these results characterize MA as a direct trigger of innate immunity, distinct from Toll-like receptor ligands.

Animals↗
PubMed2006

Identification of peptides from human pathogens able to cross-activate an HIV-1-gag-specific CD4+ T cell clone.

Antigen recognition by T cells is degenerate both at the MHC and the TCR level. In this study, we analyzed the cross-reactivity of a human HIV-1 gag p24-specific CD4(+) T cell clone obtained from an HIV-1-seronegative donor using a positional scanning synthetic combinatorial peptide library (PS-SCL)-based biometrical analysis. A number of decapeptides able to activate the HIV-1 gag-specific clone were identified and shown to correspond to sequences found in other human pathogens. Two of these peptides activated the T cell clone with the same stimulatory potency as the original HIV-1 gag p24 peptide. These findings show that an HIV-1-specific human T helper clone can react efficiently with peptides from other pathogens and suggest that cellular immune responses identified as being specific for one human pathogen (HIV-1) could arise from exposure to other pathogens.

Amino Acid Sequence↗
PubMed2003

Pathogenicity and antigenicity of a new influenza A (H5N1) virus isolated from duck meat.

Avian influenza A viruses are the ancestral origin of all human influenza viruses. The outbreak of highly pathogenic (HP) avian H5N1 in Hong Kong in 1997 highlighted the potential of these viruses to infect and cause severe disease in humans. Since 1999, HP H5N1 viruses were isolated several times from domestic poultry in Asia. In 2001, a HP H5N1 virus, A/Duck/Anyang/AVL-1/2001 (Dk/Anyang), was isolated from imported frozen duck meat in Korea. Because of this novel source of HP H5N1 virus isolation, concerns were raised about the potential for human exposure and infection; we therefore compared the Dk/Anyang virus with HP H5N1 viruses isolated from humans in 1997 in terms of antigenicity and pathogenicity for mammals. At high doses, Dk/Anyang virus caused up to 50% mortality in BALB/c mice, was isolated from the brains and lymphoid organs of mice, and caused lymphopenia. Overall Dk/Anyang virus was substantially less pathogenic for mice than the H5N1 virus isolated from a fatal human case in 1997. Likewise, Dk/Anyang virus was apathogenic for ferrets. Dk/Anyang virus was antigenically distinguishable by hemagglutination-inhibition (HI) assay from human H5N1 viruses isolated in 1997 and avian H5N1 viruses isolated in 2001 in Hong Kong. Nevertheless, prior infection with Dk/Anyang virus protected mice from death after secondary infection with HP human H5N1 viruses. These results indicate that compared with HP human H5N1 viruses, Dk/Anyang virus is substantially less pathogenic for mammalian species. Nevertheless, the novel source of isolation of this avian H5N1 virus must be considered when evaluating the potential risk to public health.

Animals↗
PubMed1991

Use of alpha-aminoadipate and lysine as sole nitrogen source by Schizosaccharomyces pombe and selected pathogenic fungi.

alpha-Aminodipate, an intermediate of the lysine biosynthetic pathway of fungi, or lysine when used as the sole nitrogen source in the medium was growth inhibitory and toxic to Saccharomyces cerevisiae. The fission yeast Schizosaccharomyces pombe and pathogenic fungi Candida albicans, Filobasidiella neoformans and Aspergillus fumigatus grew in the medium containing alpha-aminoadipate as the sole nitrogen source. C. albicans, A. fumigatus, and one of the strains of F. neoformans also grew in the medium containing lysine as the sole nitrogen source. When grown in the alpha-aminoadipate medium, only S. pombe accumulated a significant amount of alpha-ketoadipate in the culture supernatant. Also, 14C-alpha-aminoadipate was converted to 14C-alpha-ketoadipate in vivo. In the ammonium sulfate medium, S. pombe cells converted 14C-alpha-aminoadipate to lysine. The levels of glutamate-alpha-ketoadipate transaminase, an enzyme responsible for the conversion of alpha-aminoadipate to alpha-ketoadipate, and alpha-aminoadipate reductase, an enzyme required for the conversion of alpha-aminoadipate to lysine, were similar in S. pombe cells grown in the alpha-aminoadipate or ammonium sulfate medium. However, the level of homoisocitrate dehydrogenase, an enzyme before the alpha-ketoadipate step, was twelvefold lower in S. pombe cells grown in the alpha-aminoadipate medium compared to the level in cells grown in the ammonium sulfate medium. Pathogenic fungi used in this study did not accumulate alpha-ketoadipate and alpha-aminoadipate-delta-semialdehyde when grown in medium containing alpha-aminoadipate and lysine, respectively, as sole nitrogen source. However, only pathogenic fungi used both lysine and alpha-aminoadipate as sole nitrogen source. This unique metabolic property could be useful for the identification of these pathogens.

2-Aminoadipic Acid↗
PubMed2005

Rapid identification of pathogenic bacteria by capillary electrophoretic analysis of rRNA genes.

Molecular diagnosis is playing an increasingly important role in the rapid detection and identification of pathogenic organisms in clinical samples. The genetic variation of ribosomal genes in bacteria offers an alternative to culturing for the detection and identification of these organisms. Here 16S rRNA and 16S-23S rRNA spacer region genes were chosen as the amplified targets for single-strand conformation polymorphism (SSCP) and restriction fragment length polymorphism (RFLP) capillary electrophoresis analysis and bacterial identification. The multiple fluorescence based SSCP method for the 16S rRNA gene and the RFLP method for the 16S-23S rRNA spacer region gene were developed and applied to the identification of pathogenic bacteria in clinical samples, in which home-made short-chained linear polyacrylamide (LPA) was used as a sieving matrix; a higher sieving capability and shorter analysis time were achieved than with a commercial sieving matrix because of the simplified template preparation procedure. A set of 270 pathogenic bacteria representing 34 species in 14 genera were analyzed, and a total of 34 unique SSCP patterns representing 34 different pathogenic bacterial species were determined. Based on the use of machine code to represent peak patterns developed in this paper, the identification of bacterial species becomes much easier.

Bacteria↗
PubMed2005

Comparative proteome analysis of secretory proteins from pathogenic and nonpathogenic Listeria species.

Extracellular proteins of bacterial pathogens play a crucial role in the infection of the host. Here we present the first comprehensive validation of the secretory subproteome of the Gram positive pathogen Listeria monocytogenes using predictive bioinformatic and experimental proteomic approaches. The previous original signal peptide (SP) prediction (Glaser et al., Science 2001, 294, 849-852) has been greatly improved by an in-depth analysis using seven different bioinformatic tools. Subsequent careful classification of the resulting data gives a probability dependent annotation of 121 putatively secreted proteins of which 45 are novel. Complementary proteomic analysis using both two-dimensional gel electrophoresis/matrix assisted laser desorption/ionization mass spectrometry and high performance liquid chromatography/electrospray ionization-mass spectrometry has identified 105 proteins in the culture supernatant of L. monocytogenes. Among these, we were able to detect all the currently known virulence factors with an SP showing the importance of this subproteome and demonstrating the reliability of the techniques used. The comparison between the L. monocytogenes wildtype and the nonpathogenic species Listeria innocua was performed to reveal proteins probably involved in pathogenicity and/or the adaptation to their respective lifestyles. In addition to the eight known virulence factors, all of which have no orthologous genes in L. innocua, eight additional proteins have been identified that exhibit the typical key feature defining the known listerial virulence factors. Further significant differences between the two species are evident in the group of cell wall and secretory proteins that warrant further study. Our investigation clearly demonstrates that the major difference between the pathogenic and nonpathogenic species, noted in the comparative genome analysis, manifests itself strongest in the secretome.

Bacterial Proteins↗
PubMed2005

Pathogen elicitor-induced changes in the maize extracellular matrix proteome.

The extracellular matrix is a vital compartment in plants with a prominent role in defence against pathogen attack. Using a maize cell suspension culture system and pathogen elicitors, responses to pathogen attack that are localised to the extracellular matrix were examined by a proteomic approach. Elicitor treatment of cell cultures induced a rapid change in the phosphorylation status of extracellular peroxidases, the apparent disappearance of a putative extracellular beta-N-acetylglucosamonidase, and accumulation of a secreted putative xylanase inhibitor protein. Onset of the defence response was attended by an accumulation of glyceraldehyde-3-phosphate dehydrogenase and a fragment of a putative heat shock protein. Several distinct spots of both proteins, which preferentially accumulated in cell wall protein fractions, were identified. These three novel observations, viz. (i) secretion of a new class of putative enzyme inhibitor, (ii) the apparent recruitment of classical cytosolic proteins into the cell wall and (ii) the change in phosphorylation status of extracellular matrix proteins, suggest that the extracellular matrix plays a complex role in defence. We discuss the role of the extracellular matrix in signal modulation during pathogen-induced defence responses.

Cell Wall↗
PubMed2006

Cytochrome b gene structure and consequences for resistance to Qo inhibitor fungicides in plant pathogens.

The cytochrome b (cyt b) gene structure was characterized for different agronomically important plant pathogens, such as Puccinia recondita f sp tritici (Erikss) CO Johnston, P graminis f sp tritici Erikss and Hennings, P striiformis f sp tritici Erikss, P coronata f sp avenae P Syd & Syd, P hordei GH Otth, P recondita f sp secalis Roberge, P sorghi Schwein, P horiana Henn, Uromyces appendiculatus (Pers) Unger, Phakopsora pachyrhizi Syd & P Syd, Hemileia vastatrix Berk & Broome, Alternaria solani Sorauer, A alternata (Fr) Keissl and Plasmopara viticola (Berk & Curt) Berlese & de Toni. The sequenced fragment included the two hot spot regions in which mutations conferring resistance to QoI fungicides may occur. The cyt b gene structure of these pathogens was compared with that of other species from public databases, including the strobilurin-producing fungus Mycena galopoda (Pers) P Kumm, Saccharomyces cerevisiae Meyer ex Hansen, Venturia inaequalis (Cooke) Winter and Mycosphaerella fijiensis Morelet. In all rust species, as well as in A solani, resistance to QoI fungicides caused by the mutation G143A has never been reported. A type I intron was observed directly after the codon for glycine at position 143 in these species. This intron was absent in pathogens such as A alternata, Blumeria graminis (DC) Speer, Pyricularia grisea Sacc, Mycosphaerella graminicola (Fuckel) J Schröt, M fijiensis, V inaequalis and P viticola, in which resistance to QoI fungicides has occurred and the glycine is replaced by alanine at position 143 in the resistant genotype. The present authors predict that a nucleotide substitution in codon 143 would prevent splicing of the intron, leading to a deficient cytochrome b, which is lethal. As a consequence, the evolution of resistance to QoI fungicides based on G143A is not likely to evolve in pathogens carrying an intron directly after this codon.

Amino Acid Substitution↗
PubMed2002

Phytophthora infestans: populations, pathogenicity and phenylamides.

Isolates of Phytophthora infestans (Mont) de Bary (the potato and tomato late blight pathogen) resistant to phenylamides appeared in Europe and North America in the late 1970s and early 1990s respectively. Concurrent, but coincidentally, with both these events there were radical structural shifts in the pathogen populations as immigrant genotypes from Mexico displaced the indigenous populations. Both A1 and A2 mating type isolates are now present in blighted crops, permitting alternative inoculum via germinating sexually produced oospores to influence dynamics of late blight populations. Studies of inheritance of ploidy, host-specific pathogenicity, mating type and resistance to antibiotics and phenylamide fungicides have provided insight into mechanisms of variation in this potent pathogen.

Drug Resistance, Fungal↗
PubMed2004

The potential role of arbuscular mycorrhizal (AM) fungi in the bioprotection of plants against soil-borne pathogens in organic and/or other sustainable farming systems.

Sustainable farming systems strive to minimise the use of synthetic pesticides and to optimise the use of alternative management strategies to control soil-borne pathogens. Arbuscular mycorrhizal (AM) fungi are ubiquitous in nature and constitute an integral component of terrestrial ecosystems, forming symbiotic associations with plant root systems of over 80% of all terrestrial plant species, including many agronomically important species. AM fungi are particularly important in organic and/or sustainable farming systems that rely on biological processes rather than agrochemicals to control plant diseases. Of particular importance is the bioprotection conferred to plants against many soil-borne pathogens such as species of Aphanomyces, Cylindrocladium, Fusarium, Macrophomina, Phytophthora, Pythium, Rhizoctonia, Sclerotinium, Verticillium and Thielaviopsis and various nematodes by AM fungal colonisation of the plant root. However, the exact mechanisms by which AM fungal colonisation confers the protective effect are not completely understood, but a greater understanding of these beneficial interactions is necessary for the exploitation of AM fungi within organic and/or sustainable farming systems. In this review, we aim to discuss the potential mechanisms by which AM fungi may contribute to bioprotection against plant soil-borne pathogens. Bioprotection within AM fungal-colonised plants is the outcome of complex interactions between plants, pathogens and AM fungi. The use of molecular tools in the study of these multifaceted interactions may aid the optimisation of the bioprotective responses and their utility within sustainable farming systems.

Agriculture↗
PubMed1999

Infusion of bispecific monoclonal antibody complexes into monkeys provides immunologic protection against later challenge with a model pathogen.

Heteropolymers (HP), bispecific mAbs which bind target pathogens to primate erythrocytes via complement receptor 1, facilitate clearance of pathogens from the bloodstream by targeting them for destruction in the liver without causing lysis or clearance of the erythrocytes. We show that when HP prepared with mouse IgG are intravenously infused into monkeys one or more times prior to exposure to a prototype pathogen, they bind to erythrocytes and remain in the circulation long enough to act as "sentinels," preventing pathogen invasion of the bloodstream. The effectiveness of HP as sentinels is limited both by the monkey's immune response to the HP and, prior to the immune response, by a gradual loss of the HP from monkey erythrocytes over a period of 1 week, and we have investigated possible causes of this HP loss. In overview, our results suggest that HP prepared with mouse IgG are able to effectively function as sentinels for a minimum of 4 days and, after repeat infusion, possibly for up to 2 weeks.

Animals↗
PubMed2002

The role of leukocytes following cerebral ischemia: pathogenic variable or bystander reaction to emerging infarct?

Data accumulated over the last 10 years have led to the popular hypothesis that neutrophils and other inflammatory cells play a prominent role in the neuropathology of cerebral ischemia. This hypothesis was derived from a large number of studies involving three general observations: (1) leukocytes, particularly neutrophils, are present in ischemic tissue at the approximate time that substantial neuronal death occurs; (2) neutropenia is sometimes associated with reduced ischemic damage; and (3) treatments that prevent leukocyte vascular adhesion and extravasation into the brain parenchyma can be neuroprotective. This review reexamines the literature to ascertain its support for a pathogenic role for neutrophils in ischemia-induced neuronal loss. To accomplish this goal, we employed several logical theorems of "cause-effect" relationships, as they pertain to leukocytes and ischemic brain damage. Since the majority of studies focused on neutrophils as the most likely pathogenic inflammatory cell, this review necessarily does so here. We reasoned that if neutrophils play an important pathogenic (i.e., cause-effect) role in the neuronal damage that follows a stroke, then one should expect to find clear evidence that: (1) neutrophils invade the ischemic area prior to terminal stage infarction, (2) greater numbers of early appearing neutrophils are accompanied by evidence of greater neuronal loss, and (3) dose-related inhibition of neutrophil trafficking or activity produces a corresponding decrease in the degree of brain damage following ischemia. This review of the literature reveals that the existing evidence does not readily support any of these predictions and that, therefore, it consistently falls short of establishing a clear cause-effect relationship between leukocyte recruitment and the pathogenesis of ischemia. While the available evidence does not necessarily rule out a potential pathogenic role of neutrophils and other leukocytes, it nevertheless does expose serious weaknesses in the existing studies intended to support that hypothesis. For this reason we also offer suggestions for additional experiments and the inclusion of control groups that, in the future, might provide more effective or conclusive tests of the hypothesis.

Animals↗