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C Haslett

Publications and source records attributed to C Haslett.

At least 127 records · Page 7Linked to original sources
PubMed1989

The neutrophil.

In 'beneficial inflammation', which is the major component of our innate immune system, it is possible to predict an 'ideal' sequence of cellular events: neutrophil migration would be rapid; time of contact with endothelial cells minimized; matrix degradation localized, with specific turn-on and turn-off of degradation mechanisms; neutrophil secretion and disintegration would be kept to a minimum during bacterial killing; and finally, rapid cessation of neutrophil migration and rapid removal of intact senescent cells would occur. Any doubts that the cellular events of the early stages of acute inflammation normally involve highly sophisticated cellular interactions, presumably designed to minimize tissue perturbation, should be dispelled by two elegant recent studies of neutrophil-endothelial interaction. Clearly, defects in the control of these processes could tip the balance towards cell injury or excessive matrix degradation and initiate amplification mechanisms leading to persistent inflammation and disease. The further identification of molecular mechanisms of these events should permit specific intervention in neutrophil-mediated disease. However, it is important to remember, firstly, that the neutrophil is just a part of the highly redundant inflammatory process and the removal of one 'strand' does not mean that the whole 'web' breaks down, and secondly, that impairment of neutrophil mechanisms may critically impair our anti-bacterial defences. Therefore, continued attempts should be made to define how cells and mediators interact in concert, to determine the fine specificity of molecular mechanisms and, in parallel, to identify 'time windows' in diseases, during which these mechanisms are more critical to the processes damaging the host than they are essential to its defences.

Acute-Phase Reaction↗
PubMed1989

Oligosaccharide-mediated interactions of the envelope glycoprotein gp120 of HIV-1 that are independent of CD4 recognition.

In this study carbohydrate-mediated interactions of the envelope glycoprotein, gp120, of HIV-1 were investigated. Oligosaccharide probes (neoglycolipids), prepared from the N-glycosidically-linked chains of the natural and recombinant forms of gp120, were used in conjunction with the intact glycoprotein to investigate reactivities with a soluble carbohydrate-binding protein (lectin) known as mannose-binding protein in human serum. Evidence is presented that the high-mannose-type oligosaccharides with seven, eight and nine mannose residues from both forms of gp120 are recognized by the serum lectin, and that these reactivities are unrelated to CD4 recognition. Reactivities of the two forms of envelope glycoprotein with macrophages derived from human blood monocytes and with the mannose-specific macrophage endocytosis receptor isolated from human placental membranes were also investigated. Evidence is presented that both forms of gp120 bind to the macrophage surface by multiple interactions in addition to CD4 binding, and that among these interactions is a carbohydrate-mediated binding to the endocytosis receptor. We propose that such carbohydrate-mediated interactions could form the basis of viral attachment to a variety of healthy and diseased tissues.

CD4 Antigens↗
PubMed1989

111Indium-labeled neutrophil migration into the lungs of bleomycin-treated rabbits assessed noninvasively by external scintigraphy.

Factors controlling neutrophil migration into the lung are poorly understood, but their identification is important for our understanding of the pathogenesis of inflammatory lung diseases. Pulmonary inflammation is difficult to quantify, and neutrophils in tissues and BAL may not accurately represent cell migration. In this study, intravenously delivered pulses of rabbit neutrophils labeled with Indium-111 (111In-neutrophils) were used to monitor neutrophil migration into the lungs. Radioactivity quantified in the lung "region of interest" (ROI) of external gamma camera scintigrams recorded 24 h after intravenous 111In-neutrophil injection accurately reflected the actual neutrophil-associated lung tissue radioactivity. ROI radioactivity at 24 h also correlated closely with the percent of 111In-neutrophils that had migrated into lavageable air spaces, and this parameter therefore provided an index of total lung 111In-neutrophil migration. Using 24-h ROI radioactivity and percent of injected 111In-neutrophils recovered in BAL at 24 h as indices of neutrophil migration into the lung, it was found that intratracheal saline caused only a transient neutrophil migration, whereas 10 U/kg intratracheal bleomycin induced migration that persisted for as long as 3 wk. 111In-neutrophil migration into the lung, assessed by external scintigraphy, correlated with total neutrophils quantified in histologic sections (r = 0.71, p = 0.006). The data suggest that this approach will be valuable in investigating mechanisms controlling neutrophil migration in lung inflammation, and that 111In-neutrophil scintigraphy may provide a noninvasive index of total lung neutrophil load that might be useful in staging inflammation in patchy diseases such as idiopathic pulmonary fibrosis.

Animals↗
PubMed1989

Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages.

Mechanisms governing the normal resolution processes of inflammation are poorly understood, yet their elucidation may lead to a greater understanding of the pathogenesis of chronic inflammation. The removal of neutrophils and their potentially histotoxic contents is one prerequisite of resolution. Engulfment by macrophages is an important disposal route, and changes in the senescent neutrophil that are associated with their recognition by macrophages are the subject of this investigation. Over 24 h in culture an increasing proportion of human neutrophils from peripheral blood or acutely inflamed joints underwent morphological changes characteristic of programmed cell death or apoptosis. Time-related chromatin cleavage in an internucleosomal pattern indicative of the endogenous endonuclease activation associated with programmed cell death was also demonstrated. A close correlation was observed between the increasing properties of apoptosis in neutrophils and the degree of macrophage recognition of the aging neutrophil population, and a direct relationship between these parameters was confirmed within aged neutrophil populations separated by counterflow centrifugation into fractions with varying proportions of apoptosis. Macrophages from acutely inflamed joints preferentially ingested apoptotic neutrophils and histological evidence was presented for occurrence of the process in situ. Programmed cell death is a phenomenon of widespread biological importance and has not previously been described in a cell of the myeloid line. Because it leads to recognition of intact senescent neutrophils that have not necessarily disgorged their granule contents, these processes may represent a mechanism for the removal of neutrophils during inflammation that also serves to limit the degree of tissue injury.

Arthritis↗
PubMed1989

Phagocytosis of aged human neutrophils by macrophages is mediated by a novel "charge-sensitive" recognition mechanism.

The removal of neutrophils and their histotoxic contents from the inflamed site is a prerequisite for resolution of tissue injury, and a point at which factors critical to the pathogenesis of chronic inflammation may act. Engulfment of intact, senescent neutrophils by macrophages represents an important neutrophil disposal process. In this study the mechanism by which human monocyte-derived macrophages (M phi) recognized and ingested human neutrophils that had been aged in culture was studied using an in vitro phagocytic assay. Inhibition of M phi receptors for Ig Fc and the opsonic complement fragments C3b and iC3b with MAbs to M phi FcR, CR1, CR3, and CR4 had no effect on recognition, and the pattern of inhibition observed when polyanions were included in the medium at 1 mg/ml was different from that reported for the M phi receptor for protein advanced glycosylation end products (AGE), indicating a recognition mechanism different from those proposed for M phi phagocytosis of senescent erythrocytes. Furthermore, although aging neutrophils undergo programmed cell death (or apoptosis), which is directly related to recognition by M phi, the pattern of inhibition observed with monosaccharides was different from that reported to inhibit the binding of apoptotic mouse thymocytes to isologous M phi. By contrast, evidence was obtained for a novel recognition mechanism inhibitable by cationic sugars and amino acids in a charge-dependent fashion, and directly modulated by pH but not affected by inhibitors of the mannose-6-phosphate, sheep erythrocyte, mannosyl-fucosyl, asialoglycoprotein, and scavenger receptors of the macrophage. These observations suggest that hydrogen ions and charged molecules may modulate M phi uptake of senescent neutrophils at inflamed sites, and that recognition itself may involve charged structures on the cells.

Acetylglucosamine↗
PubMed1988

The intensity of chronic lung inflammation and fibrosis after bleomycin is directly related to the severity of acute injury.

Interstitial lung disease is thought to result from progression of an initial lung injury and alveolitis into a chronic inflammatory process that produces fibrosis. However, the relationship between the severity of the initial phase of acute injury and alveolitis and the amount of subsequent chronic inflammation and fibrosis remains unclear. We induced a wide spectrum of acute lung injury in rabbits by using various amounts of intratracheal bleomycin (5 or 10 U/kg) with and without oxygen supplementation (100% O2 for 2 min). The arterial oxygen tension on Day 12 after the bleomycin correlated with the extent of acute lung injury, as well as with the amount of chronic inflammation and fibrosis present on Day 56, as determined by physiologic parameters (lung volume, DLCO/VA, and PO2), and morphometry (volume proportions abnormal parenchyma made up of intra-alveolar macrophages, intra-alveolar granulocytes, abnormal alveoli, abnormal airways, fibrosis, consolidation, and honeycombing). We conclude that in bleomycin-induced interstitial lung disease in the rabbit, there is a direct relationship between the severity of acute lung injury after intratracheal bleomycin and the amount of subsequent chronic inflammation and fibrosis. This suggests that the mechanisms regulating the development of fibrosis are directly influenced by the extent of initial injury.

Acute Disease↗
PubMed1988

Monocyte retention and migration in pulmonary inflammation. Requirement for neutrophils.

The acute inflammatory process is characterized by an orderly progression of events; an initial phase of early neutrophil accumulation and a later phase of mononuclear cell (including monocyte) accumulation. The mechanisms which control the transition from one phase to the other are largely unknown. We present a rabbit model of C5 fragment (C5f)-induced lung inflammation in which purified radiolabeled peripheral blood neutrophils and monocytes were used as probes to monitor the retention and emigration of these leukocytes into well localized areas of inflammation. Neutrophil preparations (greater than 95% pure) were isolated by discontinuous plasma-Percoll density gradients, and monocyte preparations (greater than 91% pure) were isolated by counterflow cell elutriation, labeled with 111Indium-tropolonate, and intravenously infused into separate recipient animals. The monocytes circulated with a half-life of approximately 30 hours. The retention of labeled monocytes or neutrophils within the lung was monitored scintigraphically. C5f-induced monocyte lung retention was delayed 2 to 4 hours compared with neutrophil lung retention. Radiolabeled neutrophils were selectively retained in the area of C5f-induced inflammation (right cranial lung lobe, RCL) as early as 20 minutes after the induction of the inflammatory response, reached a maximum by 2 hours, and were not retained by 48 hours after C5f instillation. The signal inducing C5f-induced monocyte lung retention was shown to be transient. Monocytes were selectively retained in the RCL if the area of inflammation was induced 2 to 4 hours but not 15 minutes or 16 hours before their infusion. The time course of C5f-induced monocyte migration into the alveolar space determined by lavage analysis was delayed 2 to 3 hours compared with neutrophil migration. Neutrophils selectively migrated into the RCL 1 to 2 hours after the induction of the inflammatory response, reached a maximum by 4 hours, and had disappeared by 48 hours. Radiolabeled monocytes selectively migrated into the RCL 3 to 4 hours after the induction of the inflammatory response, reached a maximum by 4 hours, and remained present through 48 hours. The total number of labeled and unlabeled mononuclear cells present in the C5f-treated RCL lavage at 48 hours was significantly increased above controls. The signal for this monocyte migration (as for lung retention) was shown to be transient in that radiolabeled monocytes did not migrate when infused 16 hours after the induction of the inflammatory response. C5f did not induce monocyte lung retention nor monocyte migration into the alveolar space of animals rendered neutropenic.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Effects of cell isolation procedures and radioligand selection on the characterization of human leukocyte beta-adrenergic receptors.

Radioligand binding techniques are commonly used in the characterization of beta-adrenergic receptors on human peripheral leukocytes. Accurate interpretation of receptor binding parameters necessitates appropriate radioligand selection. In addition, cell isolation techniques should have minimal effect on the binding parameters of receptors. Our observation of curvilinear Scatchard plots with (-)-[125I]iodocyanopindolol (ICYP) resulted in a re-evaluation of this radioligand and the influence of cell isolation techniques on leukocyte beta-adrenergic receptor binding parameters. Membranes from mononuclear (MN) and polymorphonuclear (PMN) cells isolated by a standard procedure (Ficoll-Hypaque) resulted in biphasic Scatchard plots with ICYP in three of four subjects. In contrast, linear Scatchard plots were observed for ICYP binding to membranes from MN and PMN cells isolated from the same four subjects with an alternative procedure utilizing plasma Percoll. Competition and saturation binding assays with ICYP identified a high degree of nonspecific binding. Decreased stereoselectivity with (-)- and (+)-propranolol was observed with membranes from Ficoll-Hypaque cells as compared to plasma Percoll cells. Kinetic analysis with ICYP demonstrated apparent irreversible binding whether displacement was initiated with a beta-adrenergic receptor antagonist or agonist. These problems with ICYP prompted evaluation of an alternative radioligand, (-)-[125I]iodopindolol (IPIN); this radioligand demonstrated rapid and completely reversible binding, improved stereoselectivity, and low nonspecific binding. Using IPIN, Scatchard plots from three additional subjects were linear for both cell isolation procedures. Based on these observations, the preferred method of human leukocyte beta-adrenergic receptor analysis incorporates the plasma Percoll cell isolation technique and the radioligand IPIN.

Binding, Competitive↗
PubMed1987

Human monocyte adherence: a primary effect of chemotactic factors on the monocyte to stimulate adherence to human endothelium.

Monocyte emigration into areas of inflammation is initiated by monocyte adherence to the microvascular endothelium which may be induced by the local production of chemotactic factors at the inflammatory site. However, it is not clear whether such stimuli act on the monocyte and/or the endothelial cell to promote this effect. Accordingly, the effect of the chemotactic peptides C5a des arg and formyl-methionyl-leucyl-phenylalanine (FMLP) on human monocyte adherence to human microvascular endothelial cell monolayers was investigated in vitro. Monocytes (92 to 98% pure) were isolated by discontinuous plasma-Percoll density gradients and cell elutriation, methods designed to minimize monocyte exposure to endotoxin. Mean spontaneous (unstimulated) adherence of 111Indium-tropolonate-radiolabeled monocytes to microvascular endothelial cell monolayers was 19.7% +/- 1.3. Monocyte adherence to microvascular endothelial cell monolayers was stimulated in a dose-response fashion in the presence of C5a des arg or FMLP to a maximum mean adherence of 47.2% +/- 2.9 or 43.8% +/- 2.2, respectively. C5a des arg or FMLP stimulated monocytes to adhere to monolayers of human vascular smooth muscle cells, human dermal fibroblasts, or serum-coated plastic wells in a comparable fashion as to endothelial cells. The simultaneous presence of both chemotactic peptides C5a des arg and FMLP in the assay system stimulated monocyte adherence to the same degree as either stimulus alone. This finding suggested that those monocytes stimulated to adhere by C5a des arg were the same subpopulation responding to FMLP. Spontaneous monocyte adherence (in the absence of chemotactic peptides) to both endothelial cell monolayers and serum-coated plastic wells was reduced in the presence of plasma, but chemotactic peptides induced a significant, albeit reduced, adhesion of monocytes in this circumstance. The pretreatment of monocytes with either C5a des arg or FMLP prior to the adherence assay induced stimulus-specific desensitization of monocyte adherence. Neither a desensitization nor stimulated monocyte adherence occurred when endothelial cell monolayers or serum-coated plastic wells were pretreated with either of the chemotactic peptides. The fixation of endothelial cell monolayers prior to the adherence assay did not alter the degree of spontaneous, C5a des arg-stimulated, or FMLP-stimulated monocyte adherence. These data suggest that the stimulated adhesion of monocytes to endothelial cells by C5a des arg or FMLP represents primarily an effect of these chemotactic peptides on the monocyte.

Cell Adhesion↗
PubMed1987

Physiological neutrophil sequestration in the lung: visual evidence for localization in capillaries.

Although the lung is known to be a major site of neutrophil margination, the anatomic location of these sequestered cells within the lung is controversial. To determine the site of margination and the kinetics of neutrophil transit through the pulmonary microvasculature, we infused fluorescein isothiocyanate-labeled canine neutrophils into the pulmonary arteries of 10 anesthetized normal dogs and made fluorescence videomicroscopic observations of the subpleural pulmonary microcirculation through a window inserted into the chest wall. The site of fluorescent neutrophil sequestration was exclusively in the pulmonary capillaries with a total of 951 labeled cells impeded in the capillary bed for a minimum of 2 s. No cells were delayed in the arterioles or venules. Transit times of individual neutrophils varied over a wide range from less than 2 s to greater than 20 min with an exponential distribution skewed toward rapid transit times. These observations indicate that neutrophil margination occurs in the pulmonary capillaries with neutrophils impeded for variable periods of time on each pass through the lung. The resulting wide distribution of transit times may determine the dynamic equilibrium between circulating and marginated neutrophils.

Animals↗
PubMed1987

Neutrophil-mediated pulmonary vascular injury. Synergistic effect of trace amounts of lipopolysaccharide and neutrophil stimuli on vascular permeability and neutrophil sequestration in the lung.

The pathogenesis of acute lung injury in humans is obscure, but lipopolysaccharide (LPS), complement activation, and neutrophils have been implicated. We investigated in rabbits the interaction of small amounts of intravascularly administered LPS (100 ng) with neutrophil chemotactic factors, the synthetic chemotactic peptide formyl-norleucyl-leucyl-phenylalanine (FNLP), and the biologically relevant chemotactic fragments of C5 (C5f). These neutrophil stimuli produce neutropenia when injected intravascularly in rabbits, reflecting neutrophil adherence to vascular endothelium. When LPS was injected with FNLP, the duration of neutropenia was enhanced. Studies with radiolabeled neutrophils infused in vivo demonstrated prolonged neutrophil sequestration within the lung in rabbits that were given FNLP plus LPS, an effect that was visible for 4 h after injection. Morphometric analysis of tissue sections 4 h after infusion confirmed the presence of greater numbers of neutrophils in the lungs of animals receiving LPS and FNLP. When a combination of LPS and chemotactic factors was infused at both zero and 6 h, we found a marked enhancement of lung vascular permeability at 24 h (as assessed by radiolabeled albumin accumulation), an effect not seen with either LPS or chemotactic factor alone. Ultrastructural studies revealed neutrophil sequestration and alteration in endothelial cells in the animals that received the combination of LPS and chemotactic factors. Neutrophil depletion with nitrogen mustard completely abolished the increased vascular permeability seen in animals that received LPS and chemotactic factors. This study suggests that small amounts of intravascularly administered LPS enhance the sequestration of neutrophils within the lung and increase lung vascular permeability and endothelial injury caused by neutrophils stimulated by intravascularly administered chemotactic factors. This mechanism may be relevant to the production of acute lung injury in human beings.

Albumins↗
PubMed1987

The pulmonary vascular sequestration of neutrophils in endotoxemia is initiated by an effect of endotoxin on the neutrophil in the rabbit.

Endotoxemia causes neutrophil sequestration in the pulmonary vascular bed. Such sequestration may be a critical initiating event in the generation of microvascular injury, although the mechanisms that lead to this localization are not understood. To investigate these phenomena, the following study employed intravenous pulses of 111Indium-tropolonate-labeled neutrophils (111In-neutrophils), which circulated in the rabbit with normal kinetics and responded in a manner indistinguishable from unlabeled, circulating neutrophils in response to an intravenous injection of purified endotoxic lipopolysaccharide (LPS) or epinephrine. Pulmonary sequestration of 111In-neutrophils was assessed by quantitative external gamma camera scintigraphy of a lung suprahilar region of interest. Noninvasive assessment of radioactivity by this method accurately reflected total lung radioactivity, which was shown by autoradiography to be confined to the injected 111In-neutrophils. Intravenously administered LPS caused a marked, dose-dependent sequestration of 111In-neutrophils in the pulmonary vasculature, and exhaustive ultrastructural autoradiography showed discretely radiolabeled neutrophils located within pulmonary capillaries. A distinct effect was seen with an intravenous injection of as little as 100 ng per rabbit (i.e., 500 pg/ml blood). A 5-min ex vivo pretreatment of 111In-neutrophils with 10 ng to 10 micrograms/ml LPS in heat-inactivated plasma (which resulted in retention of as little as 500 pg LPS per 10(7) neutrophils) also caused dose-dependent pulmonary sequestration of the pretreated 111In-neutrophils but did not cause generalized neutropenia in recipient rabbits. There was no evidence of complement activation on the surface of pretreated neutrophils.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

The requirement for polymorphonuclear leukocytes in the late asthmatic response and heightened airways reactivity in an animal model.

The antigen-induced late asthmatic response (LAR) and subsequent heightened airways reactivity after this response have been associated with increased airways inflammation. Employing an animal model of the LAR in rabbits previously developed in our laboratory, 3 phases of experiments were performed to investigate the role of polymorphonuclear leukocytes (PML) in the LAR and heightened reactivity. In all 3 phases, airways reactivity to histamine and bronchoalveolar lavage analysis were performed 3 days before and 3 days after bronchial challenge with ragweed extract. In Phase 1, 2 groups of rabbits receiving nitrogen mustard were studied: an immune group received immune serum containing antiragweed IgE, and a control group received nonimmune serum. In Phase II, nitrogen mustard was administered to immune rabbits during aortic occlusion to allow the lungs to be exposed to nitrogen mustard while limiting exposure of the bone marrow to this drug, preventing depletion of PML. In Phase III, both an immune and a nonimmune group of rabbits received nitrogen mustard as in Phase I; however, prior to antigen challenge, they were repleted with a neutrophil-rich population of PML. In all experiments, no group of control (nonimmune) rabbits, whether depleted or repleted of PML, developed an immediate asthmatic response (IAR) or a LAR. In addition, no significant increases in lavage cells or airways reactivity occurred after ragweed challenge. In contrast, those animals receiving immune serum and nitrogen mustard developed an IAR; however, no LAR occurred, and no significant change in airways reactivity was observed. Rabbits receiving immune serum and nitrogen mustard with aortic occlusion developed an IAR and LAR, and airways reactivity increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Neutrophil-mediated injury to endothelial cells. Enhancement by endotoxin and essential role of neutrophil elastase.

The neutrophil has been implicated as an important mediator of vascular injury, especially after endotoxemia. This study examines neutrophil-mediated injury to human microvascular endothelial cells in vitro. We found that neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine (FMLP), the complement fragment C5a, or lipopolysaccharide (LPS) (1-1,000 ng/ml) alone produced minimal endothelial injury over a 4-h assay. In contrast, neutrophils incubated with endothelial cells in the presence of low concentrations of LPS (1-10 ng/ml) could then be stimulated by FMLP or C5a to produce marked endothelial injury. Injury was maximal at concentrations of 100 ng/ml LPS and 10(-7) M FMLP. Pretreatment of neutrophils with LPS resulted in a similar degree of injury, suggesting that LPS effects were largely on the neutrophil. Endothelial cell injury produced by LPS-exposed, FMLP-stimulated neutrophils had a time course similar to that induced by the addition of purified human neutrophil elastase, and different from that induced by hydrogen peroxide (H2O2). Further, neutrophil-mediated injury was not inhibited by scavengers of a variety of oxygen radical species, and occurred with neutrophils from a patient with chronic granulomatous disease, which produced no H2O2. In contrast, the specific serine elastase inhibitor methoxy-succinyl-alanyl-alanyl-prolyl-valyl-chloromethyl ketone inhibited 63% of the neutrophil-mediated injury and 64% of the neutrophil elastase-induced injury. However, neutrophil-mediated injury was not inhibited significantly by 50% serum, 50% plasma, or purified alpha 1 proteinase inhibitor. These results suggest that, in this system, chemotactic factor-stimulated human neutrophil injury of microvascular endothelial cells is enhanced by small amounts of LPS and may be mediated in large part by the action of neutrophil elastase.

Amino Acid Chloromethyl Ketones↗
PubMed1985

Modulation of multiple neutrophil functions by preparative methods or trace concentrations of bacterial lipopolysaccharide.

Human neutrophils were isolated from peripheral blood by four methods: 1) Ficoll-Hypaque gradients and erythrocyte lysis, 2) plasma-Percoll gradients, 3) a "lipopolysaccharide (LPS)-free" method yielding 85% neutrophils, and 4) by centrifugation of cells prepared by Method 3 through a plasma-Percoll gradient to produce pure neutrophils. The use of the Ficoll-Hypaque method resulted in spontaneous change of cell shape, enhanced formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated release of superoxide anion, increased release of lysosomal enzymes upon subsequent FMLP stimulation, and reduced chemotactic responsiveness, by comparison with the other methods. These effects were not due to erythrocyte lysis by NH4C1 but were reproduced by exposure of neutrophils prepared by the "LPS-free" method or the use of plasma-Percoll gradients to 10-100 ng/ml LPS. Neutrophil change of shape and stimulated O-2 production were particularly sensitive markers of these effects. The effects of trace concentrations of LPS in the modulation of neutrophil function may have relevance to the pathophysiology of endotoxemia and its resultant tissue injury.

Ammonium Chloride↗
PubMed1983

Long-term efficacy of fenfluramine in treatment of obesity.

42 obese women who lost at least 6 kg after 26 weeks on fenfluramine tablets had their treatment changed to either an equivalent dose of a sustained-release preparation of fenfluramine or matching placebo in double-blind fashion. Of the 21 given placebo all but 2 regained weight over the following year. Of the 21 crossed over to fenfluramine, 8 maintained their weight loss, 7 regained weight, and 6 had to be withdrawn for reasons other than weight gain. Plasma concentrations of fenfluramine and norfenfluramine taken before and 4 weeks after the crossover were similar in both responders and non-responders, but non-responders did not maintain their drug levels for as long as did the responders. Longer controlled administration of fenfluramine will prevent weight regain in some obese women but the hazards of prolonged use remain to be evaluated.

Body Weight↗