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Biomedical subjects

A Friedlander

Publications and source records attributed to A Friedlander.

At least 19 recordsLinked to original sources
PubMed2002

Determination of the virulence of the pigmentation-deficient and pigmentation-/plasminogen activator-deficient strains of Yersinia pestis in non-human primate and mouse models of pneumonic plague.

The current human plague vaccine, a killed Yersinia pestis whole-cell preparation, does not protect against aerosol challenge and is reactogenic and antigenically undefined. Live attenuated Y. pestis, such as pigmentation-deficient (Pgm-) strains, have been used frequently as vaccines and are efficacious. They are used widely in plague research and assumed to be safe. However, they can cause serious adverse reactions, and their aerosol infectivity is not known. We tested the virulence of a defined Pgm- variant of the C092 strain of Y. pestis in mouse and non-human primate models of pneumonic plague. The ten-fold lower median lethal dose by the aerosol compared to the subcutaneous (s.c.) routes of the Pgm- strain in mice suggested that the Pgm- strain might be less attenuated by the former than by the latter route. After exposure of 16 African green monkeys to inhaled doses ranging from 1.1 x 10(4) to 8.1 x 10(7)cfu, eight died and eight survived. The terminal cultures collected from five of the non-survivors were all positive for Y. pestis. Two of the remaining three non-survivors were culture-negative but had pathologic and immunologic evidence of infection with Y. pestis, specimens could not be obtained nor the cause of death determined for the third one. The deaths were not dose-related, and there were some differences in the pathology associated with infection by the Pgm- strain compared to the wild-type (wt) strain. However, the Pgm- derivative was clearly virulent for monkeys by the aerosol route. A mutant of the Pgm- strain, which has a deletion in the plasminogen activator (Pla) virulence locus (pla), appeared to be more attenuated than was either the Pgm- single mutant (in NHPs and mice) or the Pla- single mutant strain (in mice) and has potential as a live vaccine.

Administration, Inhalation↗
PubMed2002

Anti-V antigen antibody protects macrophages from Yersinia pestis -induced cell death and promotes phagocytosis.

The pathogenic Yersinia spp. harbor a common plasmid (pYV) essential for virulence. The plasmid encodes a type III secretion system that functions to translocate Yersinia outer proteins (Yops) into the host cytosol. Within the host cell, the Yops act to inhibit phagocytosis and induce apoptosis. One of the plasmid-encoded proteins, virulence antigen (V), is a major protective immunogen that is involved in Yop translocation. Yersinia pestis, like the enteric Yersinia spp., was both resistant to phagocytosis by and cytotoxic for J774.A1, a murine macrophage cell line. Both of these activities were dependent on culture of the bacteria at 37 degrees C for 1.5-2 h before infection. However, extending the preculture period at 37 degrees C to 24 h, which induced formation of a capsule, completely blocked cytotoxicity. Treating the bacteria with either rabbit polyclonal anti-V antibodies (R anti-V) or monoclonal antibody (MAb) 7.3, antibodies specific for V and protective against plague in vivo, protected J774.A1 cells from Y. pestis -induced cell death and also reversed the inhibition of phagocytosis. Whereas protection against cell cytotoxicity was afforded by the F(ab')(2) portion of R anti-V, the ability of anti-V to induce uptake of Y. pestis appeared to be dependent on the Fc portion of the Ab. The protective epitope(s) recognized by R anti-V was contained in the central region of Y. pestis V (aa 135-275) and were partially cross reactive with Y. pseudotuberculosis and Y. enterocolitica serotype 08 V antigens.

Animals↗
PubMed2002

In-vitro characterisation of the phagocytosis and fate of anthrax spores in macrophages and the effects of anti-PA antibody.

Antibodies (Abs) to the protective antigen (PA) component of the anthrax toxins have anti-spore as well as anti-toxin activities. Anti-PA antisera and purified anti-PA Abs enhance the phagocytosis by murine-derived macrophages (MQs) of spores of the Ames and Sterne strains and retard the germination of extracellular spores in vitro. The fate after phagocytosis of untreated and anti-PA-treated spores was further studied in culture medium that supported phagocytosis without stimulating spore germination (Dulbecco's minimal essential medium with horse serum 10%). The spores germinated within cells of primary peritoneal murine MQs (C3H/HeN) and MQs of the RAW264.7 MQ-like cell line; germination was associated with a rapid decline in spore viability. Exposure of MQs to inhibitors of phago-endosomal acidification (bafilomycin A and chloroquine) reduced the efficiency of MQ killing and allowed outgrowth and replication of the organisms. Treatment of spores with anti-PA Abs stimulated their phagocytosis and was associated with enhanced MQ killing of the spores. The enhanced killing of spores correlated with the greater extent of germination of anti-PA-treated spores after phagocytosis. A PA null mutant of the Ames strain exhibited none of the effects associated with anti-PA Ab treatment ofthe parental strain. Thus, the anti-PA Ab-specific immunity induced by vaccines has anti-spore activities and its role in impeding the early stages of infection with Bacillusanthracis needs to be assessed.

Animals↗
PubMed1999

Endogenous proviruses.

Sequences related to different retroviruses are present in the mammalian genome, being inherited through the germ line, and some of these sequences are expressed as RNA and protein products. The ubiquitous presence of these viral sequences suggests that they are related to some essential cellular functions. However, these functions remain to be defined. The possible role of endogenous provirus expression in cell differentiation and proliferation as well as in tumorigenic processes remains enigmatic. Available evidence strongly suggests that endogenous retroviruses present in the human and nonhuman mammalian genome are not oncogenic.

Animals↗
PubMed1998

Weak anamnestic responses of inbred mice to Yersinia F1 genetic vaccine are overcome by boosting with F1 polypeptide while outbred mice remain nonresponsive.

The role of immunity to intracellular Ags in resistance to infection by Yersinia is not well established. The enteropathogenic bacteria Yersinia pseudotuberculosis and Yersinia enterocolitica actively translocate Ags to the cytosol of eukaryotic cells. Whereas Yersinia pestis does not always express the requisite cellular adhesins, results have varied as to whether similar cytosolic translocation of Ags occurs in vitro. We used a genetic vaccine to induce intracellular expression of the fraction 1 (F1) capsular protein of Y. pestis within host mammalian cells and examined the ensuing immune response. The F1 genetic vaccine stimulated only weak CTL responses in BALB/c mice. Substantial Ab responses to the F1 genetic vaccine were obtained in all inbred strains of mice tested, but Ab levels were less than those resulting from vaccination with the F1 polypeptide. In contrast, outbred mice did not respond to the F1 plasmid, suggesting that some inbred mouse strains may exhibit exaggerated responses to plasmid vaccines. A primary immunization with the F1 genetic vaccine followed by a boost with recombinant F1 polypeptide produced a vigorous Ab response from inbred mice that was equivalent to three injections of F1 polypeptide. We conclude that cytosolic expression of the F1 Ag efficiently primes immunity, while secondary exposure to the F1 polypeptide is required for optimal Ab induction.

Animals↗
PubMed1998

V antigen of Yersinia pestis inhibits neutrophil chemotaxis.

V antigen (V), a secreted protein encoded by the 70 kb low-calcium response plasmid of Yersinia pestis, is an essential virulence factor. In animal models, it inhibits the early host inflammatory response to infection which is associated with decreased blood and tissue levels of proinflammatory cytokine synthesis. To elucidate further the pathogenetic mechanism(s) of V, in vitrosystems are needed to measure and analyse relevant functional activities of V. We studied the effect of V on the migration of neutrophils to a chemoattractant both in vivo and in vitro. Peripheral injection of V was associated with a reduction in the number of PMN migrating into s.c. sponges and i.p. exudates. Similarly, pre-incubating human peripheral blood neutrophils with >/=ng/ml V significantly inhibited the in vitro chemotactic response to the peptide chemoattractant FMLP. The inhibitory activity of V was inactivated by heat and was neutralized by rabbit polyclonal anti-V IgG as well as by sera from mice surviving infection with Y. pestis. Recombinant polyhistidine-tagged V fusion proteins retained biological activity compared to V proteins lacking the tag. Inhibition of chemotaxis appears to be the first demonstration of an in vitro biological effect of V and may be a useful model to elucidate its molecular mechanism of action.

Animals↗
PubMed1995

Experimental anthrax vaccines: efficacy of adjuvants combined with protective antigen against an aerosol Bacillus anthracis spore challenge in guinea pigs.

The efficacy of several human anthrax vaccine candidates comprised of different adjuvants together with Bacillus anthracis protective antigen (PA) was evaluated in guinea pigs challenged by an aerosol of virulent B. anthracis spores. The most efficacious vaccines tested were formulated with PA plus monophosphoryl lipid A (MPL) in a squalene/lecithin/Tween 80 emulsion (SLT) and PA plus the saponin QS-21. The PA+MPL in SLT vaccine, which was lyophilized and then reconstituted before use, demonstrated strong protective immunogenicity, even after storage for 2 years at 4 degrees C. The MPL component was required for maximum efficacy of the vaccine. Eliminating lyophilization of the vaccine did not diminish its protective efficacy. No significant alteration in efficacy was observed when PA was dialyzed against different buffers before preparation of vaccine. PA+MPL in SLT proved superior in efficacy to the licensed United States human anthrax vaccine in the guinea pig model.

Adjuvants, Immunologic↗
PubMed1995

Adoptive CD8+ T-cell immunotherapy of AIDS patients with Kaposi's sarcoma.

This article reviews published and original findings from two clinical trials of adoptive CD8+ T-cell immunotherapy of patients with acquired immunodeficiency syndrome (AIDS) and Kaposi's sarcoma (KS). In the first trial, AIDS patients with either KS or oral hairy leukoplakia (OHL) received five rounds of reinfusions of 10(8)-10(10) ex vivo expanded and activated autologous CD8+ T cells. Recombinant interleukin-2 (rIL-2) was coadministered only with the fifth and final infusion. Improvement, and in some cases, resolution of OHL, KS, and candidiasis was observed with no side effects. The observation that clinical improvement of KS was more pronounced when reinfusion of CD8+ T cells was followed by rIL-2 infusion led to a second clinical trial designed to examine the effect of repeated infusions of autologous CD8+ T cells with concomitant rIL-2 administration in the treatment of AIDS-related KS. Improvement of KS status was observed in four out of the eight patients studied (three partial and one complete response). The CD8+ T-cell immunotherapy protocol also provided the opportunity to comparatively study CD8+ T-cell-associated genetic programs. Baseline expression patterns of soluble and surface immune markers by CD8+ T cells from AIDS patients and uninfected controls were predominantly of the type 1 type and differed mainly at a quantitative or kinetic level. Deficiencies in immune mediator expression by CD8+ T cells from AIDS patients tended to dissipate with progression through the protocol. Findings are discussed in the context of current knowledge and therapeutic implications of CD8+ T-cell function in AIDS and neoplasia.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Central arteriovenous malformations of the maxillofacial skeleton: case report.

Central arteriovenous malformation of the maxillofacial skeleton, though rare, is a well-documented entity. Past treatments have usually included some form of surgical intervention. Surgical resection as an attempt to cure has been effective but costly, ie, in relationship to patient morbidity and hospital expenditures. A case of vascular malformation is presented in which selective angiography and embolization as a primary treatment were used rather than ablative surgery. The patient tolerated the procedures well, with complete resolution of bleeding.

Adult↗
PubMed1990

Spinal bone mineral density measured with quantitative CT: effect of region of interest, vertebral level, and technique.

This study documents the relationship between different vertebral bone compartments with quantitative computed tomography (CT). Four distinct patient groups were investigated: healthy pre- and early postmenopausal women as well as healthy and osteoporotic late postmenopausal women. Three different regions of interest (ROIs) were employed: the elliptical ROI located in the anterior trabecular portion of the vertebral body, the peeled ROI of irregular shape that circumscribes most of the trabecular bone, and the integral ROI including all bone except for the transverse processes. Both single- and dual-energy quantitative CT techniques were employed at T-12 through L-3. Correlation between measurements in the elliptical and peeled ROIs was high (r = .985). The authors concluded that either ROI is acceptable for clinical use. The decrements in bone mineral density (BMD) for the integral ROI were smaller than those for the elliptical ROI. Dual-energy measurements were consistently higher than single-energy measurements. BMD as a function of vertebral level decreased systematically from T-12 to L-3. However, the average density of T-12 through L-3 can be accurately predicted by the average density of L-1 and L-2 (r = .997). Precision did not deteriorate significantly when BMD was expressed as the average of L-1 and L-2 (1.5%) instead of T-12 through L-3 (1.4%). In this study the data suggest a modified quantitative CT protocol for clinical applications in which BMD of only L-1 and L-2 are measured at a fixed gantry tilt.

Adult↗
PubMed1989

Preventing osteoporosis with exercise: a review with emphasis on methodology.

Exercise is thought to have considerable potential as a preventive for osteoporosis. We critically examined 27 studies that address the prophylactic role of exercise in osteoporosis. The results from both cross-sectional and longitudinal studies showed that differences in bone mass were more pronounced in the axial skeleton as opposed to the peripheral compact skeleton. The 17 cross-sectional studies demonstrated greater bone mass among highly trained athletes compared with sedentary subjects, while results among recreational athletes were inconsistent. The 10 prospective investigations examining the effect of exercise on bone mass yielded conflicting results; only one study of six found an overall positive response in compact bone mass at the radial site, and only one study examining the spine showed a significant gain among the exercisers. Additionally, all the prospective investigations included serious methodologic flaws; most failed to employ a randomized design, appropriate estimates of sample size were lacking, none provided information on blind outcome assessment, and most studies were of short duration. Current evidence suggests that exercise may have only limited value in affecting bone mass in the short term and widespread recommendations for the prophylactic use of exercise should await further validation using better methodological rigor.

Bone and Bones↗
PubMed1986

Immunological aspects of murine infection with the rat nematode Strongyloides ratti Sandground, 1925.

In a study of the immune response of the rat to infection with the nematode Strongyloidis ratti, the antigens of the infective larval stage (L3) and of the parasitic, parthenogenetic female (Fp) were investigated. From both the larvae and the adult females, one metabolic (exoantigen) and two somatic antigens were extracted. Of the two somatic antigens, one was soluble and obtainable by physical means while the other was separated by chemical means from the tegument of the parasite. Humoral responses to the various antigens were evaluated by immunodiffusion and ELISA techniques, while the overall immune response was assayed by the worm burden in the immunized and subsequently infected rats. Agar-gel double diffusion yielded precipitin bands only with larval somatic antigens. ELISA proved positive at a titer of 20,000 with larval metabolic antigen and sera of rats immunized against either larval metabolic or somatic antigens. By 20 days post challenge infection, however, this titer diminished to 4000. In vivo studies of worm burden in rats immunized with the various antigens and then exposed to the live L3 of the nematode showed that there were significantly fewer adult worms in the rats immunized with larval somatic antigen and adult metabolic antigen than in those immunized with adult somatic antigen or larval metabolic antigen.

Amino Acids↗
PubMed1985

Effects of anthrax toxin components on human neutrophils.

The virulence of Bacillus anthracis has been attributed to a tripartite toxin composed of three proteins designated protective antigen, lethal factor, and edema factor. The effects of the toxin components on phagocytosis and chemiluminescence of human polymorphonuclear neutrophils were studied in vitro. Initially, it was determined that the avirulent Sterne strain of B. anthracis (radiation killed) required opsonization with either serum complement or antibodies against the Sterne cell wall to be phagocytized. Phagocytosis of the opsonized Sterne cells was not affected by the individual anthrax toxin components. However, a combination of protective antigen and edema factor inhibited Sterne cell phagocytosis and blocked both particulate and phorbol myristate acetate-induced polymorphonuclear neutrophil chemiluminescence. These polymorphonuclear neutrophil effects were reversible upon removal of the toxin components. The protective antigen-edema factor combination also increased intracellular cyclic AMP levels. These studies suggest that two of the protein components of anthrax toxin, edema factor and protective antigen, increase host susceptibility to infection by suppressing polymorphonuclear neutrophil function and impairing host resistance.

Anthrax↗
PubMed1984

The glutathione status of Ephestia cautella (Walker) pupae exposed to carbon dioxide.

The exposure of E. cautella pupae, 0-24 hr old, to controlled atmospheres high in carbon dioxide reduces their tissue glutathione levels. If the period of exposure is not too long the levels return to control values after three days. Evidence is presented to show that exposure to CO2 inhibits the biosynthesis of glutathione. The implications of such inhibition at cellular and higher levels are discussed.

Animals↗
PubMed1982

A study of handicapped children in a typical urban community in Cape Town.

The provision of health, welfare, education and community services for children with severe mental retardation and for those with cerebral palsy, and the extent to which these were made use of, were examined. There was found to be a lack of day training facilities and educational services for mentally handicapped children. Day training and educational facilities for the less severely affected children with cerebral palsy were good, but there were no facilities for the untrainable, severely handicapped children. The presence and management of additional handicaps were examined, as were the needs of patients and their families in the regard. The prevalence of mental handicap was 2,5/1000 children aged under 18 years and that of cerebral palsy 1,25/1000.

Adolescent↗
PubMed1979

Triglyceride metabolism in Ephestia cautella pupae exposed to carbon dioxide.

The triglyceride content of Ephestia cautella pupae exposed to increased carbon dioxide atmospheres at low relative humidity was not markedly affected. There was a significant increase in weight loss of pupae exposed to low relative humidity. Results indicate that for E. cautella, metabolic water formation by fat utilization can hardly regulate water exigencies for the pupae and cannot fully compensate for water losses in high carbon dioxide atmospheres.

Animals↗