Improving management of needle distress during the journey to dialysis through psychological education and training-the INJECT study feasibility pilot protocol.

BACKGROUND: Needle-related distress is a common yet poorly recognised and managed problem among haemodialysis (HD) patients. The aim of this pilot study is to test the feasibility and acceptability of the INJECT Intervention-an innovative psychology-based intervention to empower patients to self-manage needle distress with the support of dialysis nurses. METHODS: This investigator-initiated, single-arm, non-randomised feasibility study will take place in a large dialysis service in Adelaide, Australia. Participants will include patients aged ≥ 18 years, commencing or already receiving maintenance HD, recruited through dialysis physicians and nursing staff as individuals believed to be at risk of needle distress. They will be screened for inclusion using the Dialysis Fear of Injection Questionnaire (DFIQ) and enrolled into the study if the score is ≥ 2. The multi-pronged intervention encompasses (i) psychologist review, (ii) patient self-management program and (iii) nursing education program. The primary aim is to evaluate feasibility and acceptability of the intervention from patient and dialysis nurse perspectives, including recruitment, retention, engagement with the intervention and completion. Secondary exploratory outcomes will assess suitability of various tools for measuring needle distress, evaluate acceptability of the nursing education program and measure cannulation-related trauma and vascular access outcomes. CONCLUSION: The results will inform the protocol for larger trials addressing needle distress in HD patients. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000229875, approved 4 April 2021, https://www.anzctr.org.au/ .

Novel characterization of bEnd.3 cells that express lymphatic vessel endothelial hyaluronan receptor-1.

Murine bEnd.3 endothelioma cell line has been widely used in vascular research and here we report the novel finding that bEnd.3 cells express lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and vascular endothelial growth factor receptor-3 (VEGFR-3). Moreover, these cells express progenitor cell markers of Sca-1 and CD133. Upon stimulation with tumor necrosis factor-alpha (TNF-alpha), the bEnd.3 cells demonstrate enhanced formation of capillary-type tubes, which express LYVE-1. As the bEnd.3 cell line is derived from murine endothelioma, we further examined human tissues of endothelioma and identified lymphatic vessels in the tumor samples which express both LYVE-1 and podoplanin. Moreover, a significantly higher number of lymphatic vessels were detected in the endothelioma samples compared with normal control. Taken together, this study not only redefines bEnd.3 cells for vascular research, but also indicates a broader category of human diseases that are associated with lymphatics, such as endothelioma.

DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer.

There are two major molecular pathways to sporadic colorectal cancer, the chromosomal instability (CIN) and the CpG island methylator phenotype (CIMP) pathways. This study recruited 166 patients undergoing colonoscopy. Biopsy samples were collected from the cecum, transverse colon, sigmoid colon and rectum. DNA methylation was quantified at 'type A' (ESR1, GATA5, HIC1, HPP1, SFRP1) and 'type C' markers (MGMT, MLH1, CDKN2A, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. 'Type A' genes are frequently methylated in normal and neoplastic tissues, proportional to tissue age. 'Type C' methylation is more specific for neoplasia. The last five 'type C' markers comprise a CIMP panel. The mean 'type A' and CIMP-panel methylation Z-scores were calculated. In all, 88 patients had adenomatous lesions, 32 had proximal serrated polyps (PSPs) and 50 were normal. Most 'type A' genes showed direct correlations between methylation and age (ESR1, rho=0.66, P<0.0001), with higher methylation distally (ESR1, P<0.0001). On multivariate analysis, 'type A' methylation was inversely associated with colorectal adenomas (odds ratio=0.23, P<0.001), the precursor to CIN cancers. CIMP-panel methylation was significantly associated with advanced PSPs (odds ratio=5.1, P=0.009), the precursor to CIMP cancers. DNA methylation in normal mucosa varied with age and region and was associated with pathway-specific pathology. In the future, the colorectal field could yield important information and potentially inform clinical practice.

The colonic response to genotoxic carcinogens in the rat: regulation by dietary fibre.

The apoptotic response to DNA damage appears to be an innate biological mechanism for protection against tumourigenesis. It is possible that agents that protect against colorectal cancer act by enhancing the apoptotic deletion of cells suffering DNA damage, with consequent removal of those with tumourigenic mutations. We examined the acute apoptotic response to genotoxic carcinogens ("AARGC") in colonic epithelium and the possibility that dietary fibres of different fermentability might regulate AARGC. To fully define the time-course and nature of AARGC in response to the carcinogen azoxymethane (AOM), a single injection of AOM (10 mg/kg) was given to rats and apoptosis monitored in the colon by light microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling staining over a 72 h period. Having defined the site and time of maximum response, two groups of eight rats were fed diets containing 10% wheat bran fibre (WB; fermentable) or 10% methylcellulose (MC; poorly fermentable) for 4 weeks. Colonic AARGC was compared by light microscopy; lumenal short chain fatty acids (SCFAs) and pH were measured as indicators of the fermentative environment. AOM-induced AARGC was maximal at 8 h and greater in distal compared with proximal colon. Apoptotic cells were situated predominantly in the lower half of the crypt, with the median at position 9 indicating involvement of daughter as well as stem cells. There was no "second wave" of apoptosis within 72 h as follows irradiation in small intestine. Distal colonic AARGC in rats fed WB was twice that in rats fed MC (P < 0.01). Compared with MC, WB significantly lowered lumenal pH and increased all SCFAs including butyrate, while proliferation did not differ between the fibres. Certainly, dietary fibres can regulate AARGC and further studies are warranted to determine if this biological effect is the way in which dietary factors regulate tumourigenesis. Lumenal generation of butyrate may enhance AARGC as butyrate is proapoptotic in vitro.

Effects of resistant starch and nonstarch polysaccharides on colonic luminal environment and genotoxin-induced apoptosis in the rat.

Fermentation of polysaccharides in the colon seems likely to regulate tumorigenesis but the mechanisms are unclear. A possible mechanism may be through facilitation of the acute apoptotic response to genotoxin-induced DNA damage. This study evaluated the effects of selected dietary polysaccharides, resistant starch (supplied as Hi-maize) and nonstarch polysaccharides (supplied as wheat bran and cellulose) on certain biological events relevant to protection against colon cancer (fecal bulk, pH, butyrate and apoptosis). Male Sprague-Dawley rats were fed the different experimental diets for a period of 4 weeks, after which a single azoxymethane injection was given to induce DNA damage; 6 h later the acute apoptotic response was measured. Other measures included short chain fatty acid (SCFA) levels, fecal bulk and pH. All wheat bran treatments significantly (P < 0.05) enhanced carcinogen-induced apoptosis in the distal colon, increased fecal bulk and butyrate levels and reduced fecal pH, when compared with rats fed NF or Cellulose diets. Total SCFA (P < 0.001, r = 0.496) and butyrate levels (P < 0.001, r = 0.353) in the feces correlated positively with the acute apoptotic response in distal colonic crypts. Resistant starch supplementation by this modest amount did not enhance carcinogen-induced apoptosis. While it did significantly increase bulk, SCFA and butyrate levels and lower pH, the magnitude of these effects was not as great as with wheat bran. These findings indicate that wheat bran is the most effective regulator of these biological events of relevance to protection against colon cancer. Assuming that the acute apoptotic response to genotoxic carcinogens acts to remove genetically damaged cells that might otherwise form mutated clones that progress to malignancy, we have identified an additional biological mechanism by which dietary polysaccharides provide protection.

The influence of dietary proteins on colon cancer risk.

Experimental evidence is accumulating from animal models and in vitro data which shows that dietary proteins can influence cancer expression, some having a promotional influence, others a preventative effect relative to an arbitrarily established standard diet. This result will to a degree be determined by the nature of the cancer model under study. Dairy proteins have been shown to be relatively protective when compared with defatted soybean meal and cooked red meat in the rat dimethylhydrazine-induced (DMH) colon cancer model. Some epidemiological evidence supports these experimental observations. Both protein and fat appear to be influencing outcome, with potential for interactive effects. A number of possible mechanisms have been postulated as to how these proteins and closely associated factors could be influencing colon cancer risk, an area that deserves more investigation. Combinations of foods such as dairy foods with cereals and/or probiotic bacteria provide potentially interesting alliances in reducing colon cancer risk. The combining of relatively protective agents deserves more investigation as to its potential, in devising functional foods and diets worthy of further evaluation, in animal models of cancer, and human intervention studies using relevant endpoint markers.

Folate deficiency diminishes the occurrence of aberrant crypt foci in the rat colon but does not alter global DNA methylation status.

BACKGROUND AND AIMS: It has been suggested that a diminished folate status may enhance colorectal carcinogenesis by causing DNA hypomethylation. The aims of the present study were to assess the impact of different levels of folate depletion on azoxymethane (AOM)-induced aberrant crypt foci (ACF) formation and DNA hypomethylation in the colon of male Sprague-Dawley rats. METHODS: Rats, aged 4 weeks, were divided into four groups and were fed semipurified diets either containing adequate folate (control), devoid of folate (FD) or FD + 1% succinylsulfathiazole before AOM treatment (FD1) or during the last 4 weeks of the study (FD2). At 8 weeks of age, all animals received subcutaneous injections of AOM once weekly for 3 weeks at a dose rate of 15 mg/kg bodyweight. Animals were necropsied 6 weeks after the last AOM injection and the ACF were visualized under light microscopy in formalin-fixed, methylene blue-stained colons. RESULTS: Blood folate concentrations were significantly depleted (P < 0.001) in the treatment groups consuming folate deplete diets, with the FD2 treatment group having significantly lower folate levels compared with all other groups. Higher plasma homocysteine concentrations (P < 0.001) were observed in the groups that exhibited diminished blood folate levels. There were no significant differences in global DNA methylation in the liver or colonic mucosa between the four groups, despite some groups exhibiting marked folate depletion. Animals with the most severe folate deficiency (FD2) had a lower final bodyweight and had significantly fewer ACF in their colon (P < 0.05) compared with control animals. Total (mean +/- SEM) ACF counts were as follows: control 286+/-24; FD 290+/-25; FD1 218+/-32; and FD2 205+/-27. CONCLUSIONS: In this model, folate deficiency diminished the occurrence of ACF but did not alter global DNA methylation status in the colon.

A randomized trial of in-home visits for disability prevention in community-dwelling older people at low and high risk for nursing home admission.

BACKGROUND: In-home preventive visits with multidimensional geriatric assessments can delay the onset of disabilities in older people. METHODS: This was a stratified randomized trial. There were 791 participants, community-dwelling people in Bern, Switzerland, older than 75 years. The participants' risk status was based on 6 baseline predictors of functional deterioration. The intervention consisted of annual multidimensional assessments and quarterly follow-up in-home visits by 3 public health nurses (nurses A, B, and C), who, in collaboration with geriatricians, evaluated problems, gave recommendations, facilitated adherence with recommendations, and provided health education. Each nurse was responsible for conducting the home visits in 1 ZIP code area. RESULTS: After 3 years, surviving participants at low baseline risk in the intervention group were less dependent in instrumental activities of daily living (ADL) compared with controls (odds ratio, 0.6; 95% confidence interval, 0.3-1.0; P = .04). Among subjects at high baseline risk, there were no favorable intervention effects on ADL and an unfavorable increase in nursing home admissions (P= .02). Despite the similar health status of subjects, nurse C identified fewer problems in the subjects who were visited compared with those assessed by nurses A and B. Subgroup analysis revealed that among low-risk subjects visited by nurses A and B, the intervention had favorable effects on instrumental ADL (P = .005) and basic ADL (P = .009), reduced nursing home admissions (P = .004), and resulted in net cost savings in the third year (US $1403 per person per year). Among low-risk subjects visited by nurse C, the intervention had no favorable effects. CONCLUSIONS: These data suggest that this intervention can reduce disabilities among elderly people at low risk but not among those at high risk for functional impairment, and that these effects are likely related to the home visitor's performance in conducting the visits.

Equity in the delivery of health care in Europe and the US.

This paper presents a comparison of horizontal equity in health care utilization in 10 European countries and the US. It does not only extend previous work by using more recent data from a larger set of countries, but also uses new methods and presents disaggregated results by various types of care. In all countries, the lower-income groups are more intensive users of the health care system. But after indirect standardization for need differences, there is little or no evidence of significant inequity in the delivery of health care overall, though in half of the countries, significant pro-rich inequity emerges for physician contacts. This seems to be due mainly to a higher use of medical specialist services by higher-income groups and a higher use of GP care among lower-income groups. These findings appear to be fairly general and emerge in countries with very diverse characteristics regarding access and provider incentives.

Folate deficiency reduces the development of colorectal cancer in rats.

Alterations in folate status may play an important role in carcinogenesis. The aim of this study was to examine the effect of a diminished folate status on azoxymethane (AOM)-induced intestinal tumours in Sprague-Dawley rats. A total of 125 weanling male rats were divided into five equal groups and fed semi-purified diets containing either 8 mg/kg folate or no folate. After 4 weeks on experimental diets, all animals received three weekly subcutaneous injections of AOM at a dose rate of 15 mg/kg bodyweight. The animals were necropsied after 26 weeks. Rats with a diminished folate status, evident by significantly reduced blood and colonic folate concentrations and elevated plasma homocysteine levels, had significantly (P < 0.01) lower incidence and number of small intestinal and colonic tumours compared with rats displaying an adequate folate status. There was a significant decrease in the incidence of colonic adenocarcinomas (P < 0.01) and size of colonic tumours observed in the rats displaying a diminished folate status. This study shows that a diminished folate status was associated with a decrease in the development of AOM-induced colorectal cancers. The decrease in risk may be attributed to the known role of folate in cell multiplication.

Equity in the finance of health care: some further international comparisons.

This paper presents further international comparisons of progressivity of health care financing systems. The paper builds on the work of Wagstaff et al. [Wagstaff, A., van Doorslaer E., et al., 1992. Equity in the finance of health care: some international comparisons, Journal of Health Economics 11, pp. 361-387] but extends it in a number of directions: we modify the methodology used there and achieve a higher degree of cross-country comparability in variable definitions; we update and extend the cross-section of countries; and we present evidence on trends in financing mixes and progressivity.

The redistributive effect of health care finance in twelve OECD countries.

The OECD countries finance their health care through a mixture of taxes, social insurance contributions, private insurance premiums and out-of-pocket payments. The various payment sources have very different implications for both vertical and horizontal equity and on redistributive effect which is a function of both. This paper presents results on the income redistribution consequences of the health care financing mixes adopted in twelve OECD countries by decomposing the overall income redistributive effect into a progressivity, horizontal inequity and reranking component. The general finding of this study is that the vertical effect is much more important than horizontal inequity and reranking in determining the overall redistributive effect but that their relative importance varies by source of payment. Public finance sources tend to have small positive redistributive effects and less differential treatment while private financing sources generally have (larger) negative redistributive effects which are to a substantial degree caused by differential treatment.

Ability of endogenous folate from soy protein isolate to maintain plasma homocysteine and hepatic DNA methylation during methyl group depletion in rats.

We investigated different means of achieving methyl depletion by feeding weanling rats modified AIN diets depleted of folate (FD), folate + choline (FCD), and folate + choline + methionine (FCMD), and examined the consequent effects on folate status, homocysteine levels, and methylation status. Control rats were fed a 12% protein diet consisting of either casein or soy protein isolate (SPI) and containing 2 mg/kg folate, 0.2% choline, and 0.4% methionine. After the rats had been on the diets for 4 and 8 weeks, whole blood folate concentration was measured and found to be significantly depleted in the folate deficient treatments compared with controls at 4 weeks (p < 0.001), this reduction being significantly greater (p < 0.03) in casein-fed rats (60%) than in SPI-fed rats (32%). The omission of choline and methionine from the diet had no further influence on whole blood folate. A significant inverse correlation was observed in the casein-fed rats after 8 weeks between mean plasma homocysteine concentration and decreasing methyl content of the diet (r2 = 0.978, p < 0.002), an effect not seen in the corresponding SPI-fed rats. Hypomethylation of hepatic DNA evidenced by a reduction in 5-methylcytosine content was present in the casein rats fed FCD and FCMD relative to control (p < 0.05). No hepatic DNA methylation changes were observed in the SPI-fed rats. The results obtained in the present work demonstrate that a soy-based diet can compensate against methyl group depletion by maintaining plasma homocysteine levels and an adequate level of DNA methylation, a result we attribute to endogenous folate content.

Income-related inequalities in health: some international comparisons.

This paper presents evidence on income-related inequalities in self-assessed health in nine industrialized countries. Health interview survey data were used to construct concentration curves of self-assessed health, measured as a latent variable. Inequalities in health favoured the higher income groups and were statistically significant in all countries. Inequalities were particularly high in the United States and the United Kingdom. Amongst other European countries, Sweden, Finland and the former East Germany had the lowest inequality. Across countries, a strong association was found between inequalities in health and inequalities in income.

Effect of high-amylose starch and oat bran on metabolic variables and bowel function in subjects with hypertriglyceridemia.

We compared the effects of a diet in which approximately 25% of the carbohydrate was replaced by high-amylose starch with those of a similar diet high in oat bran or low-amylose starch in 23 hypertriglyceridemic subjects who were overweight mostly because of abdominal adiposity. Each diet was consumed for 4 wk in random order and in a crossover fashion. Overall, the diets were high in carbohydrate (> 55% of energy) and low in fat (< 30% of energy); the amount of resistant starch in the foods containing high-amylose starch was 17 g in women and 25 g in men. The metabolic effects of specific starches on plasma lipids, fasting and postprandial glucose and insulin profiles, and bowel function were assessed at the end of each intervention. Plasma triacylglycerols (triglycerides) were significantly lower after the oat bran diet than after the other two diets (P < 0.02). No other effects on fasting plasma lipids, glucose, or insulin were noted. However, when the high-amylose starch comprised 33% of the carbohydrate content in a test meal, there was a significant but biologically small reduction in the overall postprandial plasma insulin concentration by 17% relative to the low-amylose diet (P < 0.01). Both the oat bran and the high-amylose diet resulted in an increased frequency of bowel actions and lower fecal pH (P < 0.02) relative to the low-amylose diet. However, unlike the oat bran diet, the high-amylose diet increased short-chain fatty acid concentrations in fecal water by 32% (P < 0.001).

Complement subcomponent C1q modulation of TNF-alpha binding to L929 cells for enhanced TNF-mediated cytotoxicity.

Complement subcomponent C1q has been recently implicated in the modulation of autocrine binding of TNF-alpha to murine macrophages for induction of nitric oxide synthase. In the present study, the putative role of C1q in increasing TNF-alpha binding to L929 cells to mediate cytotoxicity was explored. TNF-sensitive L929 cells (L929-S) had higher total endogenous cellular and surface C1q levels and bound correspondingly more phycoerythrin-labelled rTNF-alpha (PE-TNF) than did a TNF-resistant L929 variant (L929-R). Pretreatment of L929-S with soluble C1q increased their sensitivity to TNF-mediated cytotoxicity coincident with increased binding of PE-TNF, but similar treatment of L929-R had no effect. Pretreatment of L929-S with an inhibitor of C1q secretion, 3,4 dehydro-D,L-proline (DHP), resulted in a decrease in their TNF-mediated cytotoxicity, as well as reduced binding of PE-TNF. Subsequent exposure of DHP-treated L929-S with exogenous soluble C1q restored their TNF-mediated cytotoxicity and binding of PE-TNF. These results provide evidence for the modulation of TNF-alpha binding to TNF sensitive tumour targets L929 by either endogenously synthesized or exogenously added C1q to promote TNF-mediated cytotoxicity by mechanisms which remain to be elucidated.

Tumor-derived recognition factor (TDRF) induces production of TNF-alpha by murine macrophages, but requires synergy with IFN-gamma alone or in combination with IL-2 to induce nitric oxide synthase.

A constitutively produced soluble activity, designated tumor-derived recognition factor (TDRF), from L1210, P815 and EL4 tumor targets, was previously shown to synergize with interferon-gamma (IFN-gamma) and subactivating concentrations of interleukin-2 (IL-2) to induce murine macrophage production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) for cytotoxicity of the target of origin. Another study had suggested that TDRF upregulated both TNF-alpha receptor (TNF-alpha R) and IFN-gamma receptor (IFN-gamma R) mRNA synthesis, as well as increased TNF-alpha and IFN-gamma binding to their receptors. In the present study, we have further characterized the concentration-dependent macrophage activating potential of TDRF alone and in synergy with IFN-gamma or IFN-gamma and subactivating concentrations of IL-2. Higher concentrations of TDRF acted independently on inflammatory C3H FeJ mouse macrophage to induce expression of TNF-alpha mRNA and release of TNF-alpha, but failed to induce nitric oxide synthase (NOS) mRNA expression and NO generation. At lower concentrations, TDRF synergized with either IFN-gamma alone or in combination with IL-2 to stimulate a dose-related increase in the expression of TNF-alpha mRNA and secretion of TNF-alpha, as well as increased induction of NOS mRNA and cytotoxic NO generation by macrophage. MCA tumor targets which did not produce TDRF activity were killed by macrophage that had been activated by exogenously added L1210-derived TDRF in synergy with IFN-gamma or in combination with subactivating concentrations of IL-2, but not by TDRF alone. Taken together, our results indicate that TDRF acted independently in a dose-dependent fashion to induce macrophage synthesis and release of TNF-alpha, but in the absence of IFN-gamma or in combination with IL-2 failed to induce the NOS enzyme which was necessary for cytotoxic NO generation. Thus TDRF appears to be a sufficient second signal for IFN-gamma-primed macrophage or alternatively a sufficient third signal for IFN-gamma and IL-2 treated macrophage to culminate the activation process for NOS mRNA synthesis and NO-mediated tumor cytotoxicity.

IFN-alpha beta reconstitutes the deficiency in lipid A-activated AKR macrophages for nitric oxide synthase.

AKR mouse peritoneal macrophages (PM) were previously found to have a defect in their response to lipid A for nitric oxide (NO)-mediated tumor cytotoxicity, which was related to a lower level of C1q synthesis and reconstituted by exogenous IFN-gamma or C1q. We used AKR-PM as a model to further define the role of IFN-alpha beta in modulation of induction of macrophage nitric oxide synthase (NOS) in response to lipid A. Studies have revealed that AKR-PM produced a significantly lower level of IFN-alpha beta than responsive C3H-PM in response to lipid A. AKR-PM failed to increase NOS mRNA synthesis and NO generation when exposed to lipid A, although they had normal levels of TNF-alpha bioactivity and mRNA expression. This partial deficiency of AKR-PM to lipid A stimulation was reconstituted completely by exogenous IFN-alpha beta for both synthesis of NOS mRNA and release of NO. The failure of AKR-PM to produce NOS to lipid A stimulation appears to be related to reduced secretion of IFN-alpha beta and the resultant failure to express TNF-alpha type II receptor (TNF-RII) mRNA, which in turn decreases TNF-alpha binding to its receptor for autocrine induction of NOS. Insufficient synthesis and secretion of endogenous IFN-alpha beta may be the primary reason for AKR-PM refractoriness to induction of NOS in response to lipid A. furthermore, the close correlation between lack of IFN-alpha beta secretion and decreased TNF-RII mRNA synthesis may implicate a critical role for IFN-alpha beta in the upregulation of macrophage TNF-RII receptor expression for autocrine induction of NOS during lipid A stimulation.

Evidence for endogenous C1q modulates TNF-alpha receptor synthesis and autocrine binding of TNF-alpha associated with lipid A activation of murine macrophages for nitric oxide production.

The role of endogenously synthesized complement subcomponent C1q on autocrine binding of tumor necrosis factors (TNF-alpha) and on TNF-alpha receptor (TNF-R) mRNA synthesis by mouse macrophages was investigated. Activation of C3H mouse peritoneal macrophages (C3H-PM phi) by Lipid A induced TNF-alpha and nitric oxide (NO) to kill tumor targets. Such activation also increased macrophage-endogenous C1q synthesis and secretion in a dose-dependent fashion. Antibody for C1q markedly inhibited C3H-PM phi NO production in response to Lipid A, but had no effect on TNF-alpha production. C3H-PM phi treated with C1q or Lipid A displayed increased TNF-R mRNA synthesis and in combination with Lipid A and anti-C1q antibody inhibited TNF-R and nitric oxide synthase (NOS) mRNA synthesis compared with Lipid A only, but had no effect on TNF mRNA synthesis. In vitro treatment of C3H-PM phi with C1q also increased TNF-alpha binding to their surfaces. Taken together, the data indicate that endogenously synthesized C1q is operative in promoting TNF-R mRNA synthesis and resultant autocrine binding of TNF-alpha for induction of NOS in the process of NO-mediated tumor cytotoxicity by Lipid A-activated macrophages.

Autocrine induction of macrophage synthesis of complement subcomponent C1q by endogenous interferon-alpha/beta.

Peritoneal macrophages (M phi) constitutively synthesize and secrete interferon-alpha (IFN-alpha) and IFN-beta, as well as complement subcomponent C1q. Because exogenous interferon-gamma (IFN-gamma) stimulates Mø synthesis of C1q, our purpose was to determine if endogenous secretion of IFN-alpha/beta regulated the constitutive level of endogenous C1q mRNA synthesis in an autocrine fashion. Both exogenous IFN-alpha and IFN-beta effectively substituted for IFN-gamma in stimulating M phi C1q mRNA expression in a dose-dependent fashion by northern blot analysis. Neutralizing anti-INF-alpha/beta antibodies inhibited M phi constitutive C1q mRNA synthesis by approximately twofold and abrogated the feedback stimulatory effects of exogenous C1q on C1q mRNA expression. Paraffin oil-elicited inflammatory M phi displayed distinctively different constitutive levels of C1q mRNA expression from thioglycollate brothelicited M phi, which was correlated with their relative levels of secretory IFN-alpha/beta by ELISA. Exogenous IFN-alpha/beta also restored C1q mRNA synthesis of AKR mouse M phi with low constitutive C1q mRNA expression. The cumulative results support the concept that constitutive synthesis of C1q by M phi is regulated by the endogenous synthesis and secretion of IFN-alpha/beta, which appears to act in an autocrine fashion.