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The effect of pre-immunization with soluble haptenated serum proteins or haptenated carbohydrates on the subsequent responses to the hapten in thymus-dependent or thymus-independent form was investigated. In certain cases both thymus-dependent and -independent responses were suppressed whilst in others a differential suppression of thymus-independent responsiveness was observed. These results are discussed in terms of B-cell sub-populations and mechanisms of tolerance induction. [ABSTRACT FROM AUTHOR]

Hypoglycaemia in falciparum malaria is associated with a poor prognosis and is correlated with mortality. High levels of serum TNF are also correlated with disease severity and mortality, and it has been suggested that TNF may cause the hypoglycaemia. However Hypoglycaemia in mice infected with Plasmodium chabaudi or the lethal strain of P. yoelii YM is related to hyperinsulinaemia. Its development was not prevented by treatments which diminished TNF activity or production without affecting levels of plasma insulin. Conversely, it was inhibited by diazoxide, which inhibited insulin secretion but did not affect TNF production. Furthermore, in mice exhibiting neurological symptoms during infection with P. berghei, blood glucose concentrations were significantly raised when TNF levels were high, and TNF levels in the spleen were highest of all in non-lethal P. yoelii infections in which hypoglycaemia does not occur. Administration of human rTNF to normal animals caused an increase rather than a drop in blood glucose levels. Mice transgenic for human TNF did not develop hypoglycaemia when infected with P. yoelii YM, but showed signs of insulin resistance. In this with current views on the role of TNF in obesity and the control of glucose homeostasis, we conclude that the hypoglycaemia of malaria is not caused by increased levels of TNF, which may in fact be beneficial, but is secondary to a hyperinsulinaemia that is probably stimulated directly by products of the parasite. [ABSTRACT FROM AUTHOR]

We investigated the development of cell-mediated immunity in lethal and non-lethal malarial infections by assaying the cytotoxic activity of spleen cells for L929 tumour cells at different times after infection of mice with the lethal P. berghei. a lethal variant of Ptasmodium yoelii and the non-lethal P. yoelii and P. chahaudi. In all cases the cytotoxicity increased lo a peak during the first week and then diminished but the time of the peak varied with the infection; its activity was lowest with P. berghei. A second peak occurred in the non-lethal infections at the time of recovery. A protective vaccine accelerated and enhanced the early peak of cytotoxicity. The activity was mediated by adherent phagocytic cells, probably through the release of tumour necrosis factor (TNF) by macrophages since it was inhibited by antiserum against recombinant mouse TNF and did not destroy TNF-resistant L929 cells. Its induction was not dependent on T cells since it occurred in T cell-deficient mice infected with non-lethal P. yoelii. However, the accelerated increase associated with vaccination could be adoptively transferred by spleen lymphocytes from vaccinated mice. [ABSTRACT FROM AUTHOR]

Heat-stable soluble products of rodent malarial parasites induce activated peritoneal macrophages to secrete tumour necrosis factor (TNF) in vitro. Since heat-stable parasite antigens are known to be present in the circulation of patients with malaria and it has been suggested that much of the pathology of malaria is due to TNF, we investigated the ability of such antigens to induce the production of TNF in vivo and to be toxic to mice. Injection of antigens obtained from Plasmodium yoelii or from P. berghei into mice which had previously received the macrophage-activating agent Propionibacterium acnes induced the release of TNF into the serum in amounts equivalent to the maximum release induced by bacterial lipopolysaccharide (LPS). Specific antiserum blocked the ability of the boiled soluble antigens, but not of LPS, to induce release of TNF. Similarly, vaccination specifically inhibited the release of TNF into the serum in response to subsequent stimulation with the antigens, but not with LPS. Mice made hypersensitive to the lethal action of TNF by pretreatment with D-galactosamine were killed in a dose-related fashion by administration of antigen preparations; addition of specific antiserum or prior vaccination with the antigens protected such mice, but not those given LPS, from death. We conclude that, in malaria, soluble antigens derived from the parasites may act like a toxin by stimulating the production of TNF, an important mediator of endotoxic shock, and that immunization with such antigens may diminish TNF secretion and consequently many of the clinical manifestations of the disease. [ABSTRACT FROM AUTHOR]

Objective: To determine the within-trial cost-efficacy of surgical therapy relative to conventional therapy for achieving remission of recently diagnosed type 2 diabetes in class I and II obese patients.Research Design and Methods: Efficacy results were derived from a 2-year randomized controlled trial. A health sector perspective was adopted, and within-trial intervention costs included gastric banding surgery, mitigation of complications, outpatient medical consultations, medical investigations, pathology, weight loss therapies, and medication. Resource use was measured based on data drawn from a trial database and patient medical records and valued based on private hospital costs and government schedules in 2006 Australian dollars (AUD). An incremental cost-effectiveness analysis was undertaken.Results: Mean 2-year intervention costs per patient were 13,400 AUD for surgical therapy and 3,400 AUD for conventional therapy, with laparoscopic adjustable gastric band (LAGB) surgery accounting for 85% of the difference. Outpatient medical consultation costs were three times higher for surgical patients, whereas medication costs were 1.5 times higher for conventional patients. The cost differences were primarily in the first 6 months of the trial. Relative to conventional therapy, the incremental cost-effectiveness ratio for surgical therapy was 16,600 AUD per case of diabetes remitted (currency exchange: 1 AUD = 0.74 USD).Conclusions: Surgical therapy appears to be a cost-effective option for managing type 2 diabetes in class I and II obese patients. [ABSTRACT FROM AUTHOR]

Tumour necrosis serum (TNS), from animals primed with macrophage activating agents and challenged with endotoxin, causes necrosis of some tumours and can kill certain tumour lines in vitro and malarial parasites in vitro and in vivo. We have tested the possibility that the same factor is responsible for killing both tumour cells and malarial parasites. In competitive inhibition experiments, parasitized erythrocytes, but not normal erythrocytes, inhibited the cytotoxicity of TNS against a tumour cell line. Conversely, the tumour cells inhibited the killing of Plasmodium yoelii in vitro by TNS. When rabbit TNS was fractionated by ion exchange chromatography followed by gel filtration and the fractions at each step were pooled according to their ability to kill the tumour cells, in vitro parasite killing activity was found to correlate with tumour cell cytotoxicity, to a final sample which was purified more than 600-fold. Our results suggest that in terms of function, at least, the same component of TNS is responsible for the killing of both tumour cells and malarial parasites. [ABSTRACT FROM AUTHOR]

The molecular characteristics of a serum IL-2 inhibitor were determined by fractionating active sera from normal and malaria-infected mice, and assaying inhibitory activity in blocking production and expression of IL-2 activity. Using isoelectric focusing and ion exchange chromatography, the activity resolved in a single peak (pI = 6.2). HPLC gel filtration resolved two peaks of activity (50,000 and 25,000 MW) which are proabably related. The molecule is precipitated by 50% saturated ammonium sulphate, and is destroyed by heating above 56° or by acidification below pH 4. [ABSTRACT FROM AUTHOR]

The faster degradation of antigen by macrophages in Biozzi low (L) responder mice, compared to Biozzi high (H) responder mice, is thought to be responsible for their lower antibody response. We have measured four functions associated with macro- phages to see whether macrophages from L mice were generally more active than those from H mice. Peritoneal macrophages obtained from normal mice were compared with those from groups of mice given Mycobacterium boris BCG or Propionibacteriumacnes. Cells from normal H mice gave a stronger oxidative burst when triggered with phorbol myristate acetate, and were more cytotoxic for tumour cells than cells from L mice. Cells from all mice injected with 8CC or P. acnes gave a stronger oxidative burst, and were more cytotoxic for tumour cells; again, both responses were higher in H mice than in L mice. By contrast, when groups of mice that had received P. aenes were given endotoxin and bled, higher titres of tumour necrosis factor were found in the sera of L mice. Spleen cells from both lines of mice released similar levels of interleukin-1, both spontaneously and in response to lipopolysaccharide. Our results suggest that these various macrophage responses are expressed independently in H and L mice. [ABSTRACT FROM AUTHOR]

A single dose of a formalin-fixed malaria vaccine which normally protects mice against challenge with the live parasite, is ineffective in mice born to immune mothers. This inhibition of protection, which is due to maternally-derived IgG, can be overcome if a second dose of vaccine is given 10 or more days after the first. We show that this is related to the production of specific IgM antibody in response to the first dose of vaccine, which competitively blocks the inhibitory effect of the IgG. The implications of this finding in relation to immune regulation and immunization regimes are discussed. [ABSTRACT FROM AUTHOR]

The isoelectric heterogeneity of both IgM and IgG murine anti-sheep red cell serum antibodies has been examined using an adaptation of published methods. It was found that the IgM spectra were restricted in a characteristic manner, implying oligoclonality. In cell transfer experiments, the T cell dependency of the IgM responses was confirmed. Further, helper cells appeared to switch on IgG antibody production and, simultaneously, recruit many novel IgG-forming clones into the response. The pattern of the IgM oligoclonality was attributed in part t o the inheritance of genes at, or closely linked to, the Ig1 heavy chain locus. These findings are discussed in relation to current research on the regulation of diversity. [ABSTRACT FROM AUTHOR]

Anaemia during blood-stage plasmodial infections is known to be due to at least three mechanisms: direct destruction of erythrocytes by the intra-erythrocytes parasite, inhibition of erythropoiesis, and premature removal of uninfected erythrocytes. The removal of the uninfected erythrocytes is considered by many to be dependent on an antibody-mediated mechanism. Our investigations involving normal, severe combined immunodeficient (SCID) and nude BALB/c mice and the murine malaria parasite Plasmodium yoelii. indicate that this mechanism is unlikely. The process of removal of uninfected erythrocytes was reduced in SCID mice but could not be enhanced by the passive transfer of serum from infected immunocompetent mice. Macrophage activation, as judged by the removal of xenogeneic erythrocytes, did not differ in the three strains of mice. Changes in the erythrocytes themselves may be responsible for their shortened lifespan. [ABSTRACT FROM AUTHOR]

Hypoglycaemia is associated with severe malaria and is an important prognostic indicator. Molecules liberated during overnight incubation of erythrocytes infected with Plasmodium yoelii induce marked hypoglycaemia in normal mice, with a delayed time course compared with insulin; some, though weaker, activity could also be obtained by overnight incubation of uninfected erythrocytes. The active component shares many properties with the phospholipid-containing molecules which we have previously shown to be toxic and to induce the release of tumour necrosis factor (TNF) from macrophages. However a MoAb which neutralize the cytotoxicity of tumour necrosis factor in vitro did not prevent this induction of hypoglycaemia, whereas antiserum against the toxic antigens did, as did immunization of normal (but not the immunoglobulin-deficient SCID) mice with the same material. Furthermore, normal mice injected with the antigens after immunization with phosphatidyl inositol or inositol monophosphate did not develop hypoglycaemia; the latter compound was also inhibitory when mixed with the antigens before injection. These compounds were previously shown to block the induction of TNF by the antigens and to induce the production of inhibitory antibodies. The role of these molecules in the etiology of the hypoglycaemia of malaria is discussed. [ABSTRACT FROM AUTHOR]

We show here that purified lipoarabinomannan (LAM) from Mycobacterium tuberculosis can cause the release of tumour necrosis factor (TNF) in vitro from human blood monocytes and activated mouse peritoneal macrophages, and the production of TNF in vivo in mice pretreated with Propionibacterium acnes, with a potency comparable to that of lipopolysaccharide (LPS) from Gram negative bacteria. Like LPS, LAM binds to polymyxin B. We confirmed that its activity was distinct from any contaminating LPS and was associated with the antigenic activity by affinity chromatography, using a monoclonal antibody specific for LAM. Treatment with dilute alkali greatly diminished the TNF-inducing activity, suggesting that o-acyl groups may be involved. When LAM was fractionated by electrophoresis on SDS-Page and blotted on nitrocellulose, most TNF-inducing capacity coincided with the bulk of the LAM, as estimated by molecular weight and antigenic activity. This modification of the Western blotting technique may be generally useful for the study of macrophage-triggering molecules. The ability of LAM to cause the release of TNF may be responsible for some of the characteristics of tuberculosis, such as fever, weight loss, raised acute phase reactants and necrosis that can be mediated by this cytokine. [ABSTRACT FROM AUTHOR]

As tumour necrosis serum kills malarial parasites in vitro and inhibits the multiplication of some species of Plasmodium in mice, we examined the effect of recombinant mouse tumour necrosis factor (rTNF) on P. yoelii both in vitro and in vivo. Parasites incubated overnight with rTNF showed no loss of viability, but repeated injection of rTNF into infected mice reduced parasitaemia and significantly prolonged survival of mice infected with a lethal variant of the parasite. We conclude that TNF acts on blood-stage malaria in vivo via a host cell and that another molecule in tumour necrosis serum is involved in killing the parasite in vitro. [ABSTRACT FROM AUTHOR]

The excessive production of tumour necrosis factor (TNF) is associated with the pathology of blood-stage malaria and phosphatidylinositol-containing phospholipid antigens from parasitized erythrocytes stimulate its secretion by macrophages, thus acting as toxins. This brief report describes some properties of an inhibitor present in lysates from erythrocytes infected with malarial parasites that blocked the detection of recombinant TNF in an enzyme-linked immunosorbent assay and diminished or abolished the cytotoxicity of TNF. It was not found in control lysates of normal erythrocytes. Its addition to macrophage cultures stimulated by toxic malarial preparations or by bacterial lipopolysaccharide also blocked the detection of TNF. These findings may explain the contradictory results obtained from different assays for TNF, and emphasize the need for caution when interpreting the results of a single assay system. If released when parasitized erythrocytes rupture in vivo, the inhibitor could help protect both parasite and host from the damaging effects of TNF. [ABSTRACT FROM AUTHOR]

In patients with malaria, the clinical manifestations of the disease are associated with the presence of high concentrations of tumour necrosis factor (TNF) in the serum. Blood-stage parasites of human and rodent malarial parasites release serologically related exoantigens which induce the production of TNF in vitro and in vivo and which can kill mice made hypersensitive to TNF by pretreatment with D-galactosamine. They also elicit the production of T-independent antibody, which blocks these effects. The capacity of the exoantigens to stimulate macrophages to secrete TNF does not require the presence of protein or carbohydrate, but is associated with a lipid whose activity can be abolished by treatment with phospholipase C. Treatments of the exoantigens which destroyed their activity in vitro also abrogated their immunogenicity and their toxicity for mice. No TNF-inducing activity could be detected in preparations of parasitized erythrocytes that was not associated with phospholipid, and the TNF-inducing properties of the malarial phospholipids are quite distinct from those of bacterial lipopolysaccharide. We conclude that release of potentially toxic phospholipids by parasites may be responsible for some of the pathology of malaria. [ABSTRACT FROM AUTHOR]

Much of the pathology of malaria may be due to the interactions of cytokines, especially tumour necrosis factor (TNF), with various cell types, including endothelial cells, with consequent widespread systemic effects. It has been shown previously that heat-stable exoantigens in the supernatants of blood-stage parasite cultures induced the release of TNF in vitro from activated macrophages and behaved like toxins in vivo, that mice immunized with the antigens are protected from the toxic effect and that their serum specifically blocks the ability of the antigens to stimulate the induction of TNF. It is reported here that the inhibitory antibody is mainly IgM and that it appears to be T-independent, as the litres of antisera from T-deficient and immunologically intact mice were similar. Antisera raised against exoantigens from two species of rodent parasite inhibited TNF production by those of the human parasite Plasmodium falciparum, and vice versa, indicating that the TNF-inducing moieties of the exoantigens cross-react and therefore presumably contain common epitopes. Thus vaccination with these exoantigens might provide a means of protection against the clinical effects of malaria and of generating anti-disease immunity by reducing cytokine production. However, these findings imply that it will be necessary to confer on these antigens the ability to stimulate T cells and generate memory before they can provide a useful basis for an anti-disease vaccine. The results obtained are discussed in relation to some of the epidemiological features of malaria. [ABSTRACT FROM AUTHOR]

Purpose: There are significant alterations in gastro-intestinal function, food tolerance, and symptoms following sleeve gastrectomy (SG). These substantially change over the first year, but it is unclear what the underlying physiological basis for these changes is. We examined changes in oesophageal transit and gastric emptying and how these correlate with changes in gastro-intestinal symptoms and food tolerance., Material and Methods: Post-SG patients undertook protocolised nuclear scintigraphy imaging along with a clinical questionnaire at 6 weeks, 6 months, and 12 months., Results: Thirteen patients were studied: mean age (44.8 ± 8.5 years), 76.9% females, pre-operative BMI (46.9 ± 6.7 kg/m2). Post-operative %TWL was 11.9 ± 5.1% (6 weeks) and 32.2 ± 10.1% (12 months), p-value < 0.0001. There was a substantial increase of meal within the proximal stomach; 22.3% (IQR 12%) (6 weeks) vs. 34.2% (IQR 19.7%) (12 months), p = 0.038. Hyper-accelerated transit into the small bowel decreased from 6 weeks 49.6% (IQR 10.8%) to 42.7% (IQR 20.5%) 12 months, p = 0.022. Gastric emptying half-time increased from 6 weeks 19 (IQR 8.5) to 12 months 27 (IQR 11.5) min, p = 0.027. The incidence of deglutitive reflux of semi-solids decreased over time; 46.2% (6 weeks) vs. 18.2% (12 months), p-value < 0.0001. Reflux score of 10.6 ± 7.6 at 6 weeks vs. 3.5 ± 4.4 at 12 months, (p = 0.049) and regurgitation score of 9.9 ± 3.3 at 6 weeks vs. 6.5 ± 1.7, p = 0.021 significantly reduced., Conclusions: These data demonstrate that there is an increase in the capacity of the proximal gastric sleeve to accommodate substrate over the first year. Gastric emptying remains rapid but reduce over time, correlating with improved food tolerance and reduced reflux symptoms. This is likely the physiological basis for the changes in symptoms and food tolerance observed early post-SG., (© 2023. The Author(s).)