Association between vitamin D and zoledronate-induced acute-phase response fever risk in osteoporotic patients.

Objectives: To elucidate the independent correlation between vitamin D content and zoledronate (ZOL)-triggered acute-phase response (APR) fever risk in osteoporotic (OP) patients, and to examine the potential threshold for optimal vitamin D concentrations that prevent the occurrence of ZOL-induced fever. Methods: This retrospective investigation was based on a prospectively documented database compiled at the Affiliated Kunshan Hospital of Jiangsu University between January 2015 and March 2022. In total, 2095 OP patients, who received ZOL during hospitalization, were selected for analysis. The primary endpoint was the presence (>37.3°C) or absence (≤37.3°C) of fever, quantified by the maximum body temperature, measured within 3 days of ZOL infusion. The exposure variable was the baseline serum 25-hydroxyvitamin D (25[OH]D) levels. Results: The OP patients with fever exhibited markedly reduced 25(OH)D content than those without fever. Upon adjusting for age, gender, order of infusion of ZOL, main diagnosis, season of blood collection, year of blood collection, calcitonin usage, and beta-C-terminal telopeptide of type I collagen (ß-CTX) levels, a 10 ng/mL rise in serum 25(OH)D content was correlated with a 14% (OR, 0.86; 95% CI, 0.76 to 0.98, P-value = 0.0188) decrease in the odds of ZOL-induced fever. In addition, a non-linear relationship was also observed between 25(OH)D levels and fever risk, and the turning point of the adjusted smoothed curve was 35 ng/mL of serum 25(OH)D content. Conclusions: Herein, we demonstrated the independent negative relationship between serum 25(OH)D content and ZOL-induced fever risk. According to our analysis, 25(OH)D above 35 ng/mL may be more effective in preventing ZOL-induced APR. If this is confirmed, a "vitamin D supplemental period" is warranted prior to ZOL infusion, particularly the first ZOL infusion, to ensure appropriate 25(OH)D levels that protect against ZOL-induced fever.

Preventive Role of Vitamin D Supplementation for Acute Phase Reaction after Bisphosphonate Infusion in Paget's Disease.

CONTEXT: Intravenous aminobisphosphonates (N-BPs) can induce an acute phase reaction (APR) in up to 40% to 70% of first infusions, causing discomfort and often requiring intervention with analgesics or antipyretics. OBJECTIVE: Our aim was to explore the risk factors of APR in a large sample of patients with Paget's disease of bone (PDB) and to assess the possible preventive effects of vitamin D administration. METHODS: An observational analysis was performed in 330 patients with PDB at the time of N-BP infusion. Then, an interventional study was performed in 66 patients with active, untreated PDB to evaluate if vitamin D administration (oral cholecalciferol 50 000 IU/weekly for 8 weeks before infusion) may prevent APR. RESULTS: In a retrospective study, APR occurred in 47.6% and 18.3% of naive or previously treated patients, respectively. Its prevalence progressively increased in relation to the severity of vitamin D deficiency, reaching 80.0% in patients with 25-hydroxyvitamin D (25OHD) levels below 10 ng/mL (relative risk (RR) = 3.7; 95% confidence interval (CI) 2.8-4.7, P < .0001), even in cases previously treated with N-BPs. Moreover, APR occurred more frequently in patients who experienced a previous APR (RR = 2.8; 95% CI 1.5-5.2; P < .001) or in carriers of SQSTM1 mutation (RR = 2.3; 95% CI 1.3-4.2; P = .005). In the interventional study, vitamin D supplementation prevented APR in most cases, equivalent to a RR of 0.31 (95% CI 0.14-0.67; P < .005) with respect to prevalence rates of the observational cohort. A similar trend was observed concerning the occurrence of hypocalcemia. CONCLUSIONS: The achievement of adequate 25OHD levels is recommended before N-BP infusion in order to minimize the risk of APR or hypocalcemia in PDB.

Fracture Prevention with Zoledronate in Older Women with Osteopenia.

BACKGROUND: Bisphosphonates prevent fractures in patients with osteoporosis, but their efficacy in women with osteopenia is unknown. Most fractures in postmenopausal women occur in those with osteopenia, so therapies that are effective in women with osteopenia are needed. METHODS: We conducted a 6-year, double-blind trial involving 2000 women with osteopenia (defined by a T score of -1.0 to -2.5 at either the total hip or the femoral neck on either side) who were 65 years of age or older. Participants were randomly assigned to receive four infusions of either zoledronate at a dose of 5 mg (zoledronate group) or normal saline (placebo group) at 18-month intervals. A dietary calcium intake of 1 g per day was advised, but calcium supplements were not provided. Participants who were not already taking vitamin D supplements received cholecalciferol before the trial began (a single dose of 2.5 mg) and during the trial (1.25 mg per month). The primary end point was the time to first occurrence of a nonvertebral or vertebral fragility fracture. RESULTS: At baseline, the mean (±SD) age was 71±5 years, the T score at the femoral neck was -1.6±0.5, and the median 10-year risk of hip fracture was 2.3%. A fragility fracture occurred in 190 women in the placebo group and in 122 women in the zoledronate group (hazard ratio with zoledronate, 0.63; 95% confidence interval, 0.50 to 0.79; P<0.001). The number of women that would need to be treated to prevent the occurrence of a fracture in 1 woman was 15. As compared with the placebo group, women who received zoledronate had a lower risk of nonvertebral fragility fractures (hazard ratio, 0.66; P=0.001), symptomatic fractures (hazard ratio, 0.73; P=0.003), vertebral fractures (odds ratio, 0.45; P=0.002), and height loss (P<0.001). CONCLUSIONS: The risk of nonvertebral or vertebral fragility fractures was significantly lower in women with osteopenia who received zoledronate than in women who received placebo. (Funded by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12609000593235 .).

Dose-dependent acute phase response of aqueous leaf decoction of Nerium oleander in Wistar rats.

Many studies have been carried out in order to determine the toxicity of medicinal plants. The objective of this study was to compare and analyze the hepatic response against two doses of Nerium oleander, (N. oleander) “kaner” leaf decoction. Aqueous leaf decoction was injected intramuscularly into both hind limbs of male rats (200∓10g), assigned into three categories (n=4): control group with no treatment; group I, injected with 5 ml/ kg; and group II injected with 10 ml/ kg of leaf decoction, respectively. Animals were sacrificed 6 h after administration and hepato-histological changes were then observed. The decoction induced an acute phase reaction reflected by a more significant recruitment of inflammatory cells in group II than in group I and controls, as observed by histological studies. These results indicated that both doses can induce an acute-phase condition. Hence, traditional practice of medicinal plants without preliminary dose assessment must not be administered.

Short-Term Safety of Zoledronic Acid in Young Patients With Bone Disorders: An Extensive Institutional Experience.

CONTEXT: Zoledronic acid (ZA) is increasingly used in young patients with bone disorders. However, data related to the safety of ZA administration in this population are limited. OBJECTIVE: The study aimed to characterize the short-term safety profile of ZA and identify risk factors for ZA-related adverse events (AEs) in young patients. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective chart review of inpatients and outpatients less than 21 years old who received at least one ZA infusion between July 2010 and January 2014 at The Children's Hospital of Philadelphia. RESULTS: Eighty-one patients (56% male; median age, 12 y; age at first infusion, 0.5 to 20 y) with diverse skeletal disorders received a total of 204 infusions. The most common indications were osteoporosis (33% of cohort) and osteogenesis imperfecta (27.2%). The median ZA dose was 0.025 mg/kg (interquartile range, 0.025-0.05); the median dosing interval was 6 months (range, 1 to 25.6 mo). AEs were mild and more common after the first ZA infusion in patients with no previous bisphosphonate exposure: hypophosphatemia (25.2% of infusions), acute phase reactions (19.1%), and hypocalcemia (16.4%). Symptomatic hypocalcemia requiring iv calcium occurred after two infusions. ZA dose was significantly associated with hypophosphatemia, but not other AEs. Hypocalcemia was more common in patients with high bone turnover as assessed by preinfusion alkaline phosphatase levels. AEs were not associated with diagnosis, baseline serum calcium, or calcium/calcitriol supplementation. CONCLUSION: Acute AEs related to ZA infusion in youths are common, occur principally after the first ZA infusion in bisphosphonate-naive patients, and are typically mild and easily managed. Future prospective studies are needed to determine the potential long-term risks, as well as benefits, of ZA therapy in the pediatric population.

Osteoporosis treatment: focus on safety.

Osteoporosis results in approximately one-half of older white women and one-third of men sustaining fractures, which cause significant disability and increased mortality. Interventions are now available which reduce fracture risk by about one-half, and there is evidence that they also reduce mortality in frail elderly by about 10%. The mechanism of this reduced mortality is unclear but it has the potential to substantially impact on the cost-benefit of osteoporosis treatment. Available treatments are generally well-tolerated. Bisphosphonates cause gastrointestinal side-effects when administered orally, and acute phase responses when given intravenously. Osteonecrosis of the jaw is overwhelmingly a problem of cancer sufferers rather than those with osteoporosis, but atypical patterns of fracture in the upper femoral shaft sometimes occur in users of these drugs, though they are very rare in comparison with the other osteoporotic fractures which these drugs prevent. Thus, the cost-benefit of bisphosphonate use is clearly positive in those with osteoporosis. In contrast, calcium supplements probably increase the risk of myocardial infarction, admissions to hospital with acute gastrointestinal complaints and risk of renal calculi, whereas their impact on fracture is marginal (about a 10% reduction). Thus, they are not cost-effective, and a balanced diet is a safer way of obtaining one's calcium requirements.

The impact of dietary calcium intake and vitamin D status on the effects of zoledronate.

UNLABELLED: We investigated whether baseline dietary calcium intake or vitamin D status modified the effects of zoledronate. Neither variable influenced the effect of zoledronate on bone mineral density, bone turnover, or risk of acute phase reaction, suggesting that co-administration of calcium and vitamin D supplements with zoledronate may not always be necessary. INTRODUCTION: Calcium and vitamin D supplements are often co-administered with bisphosphonates, but it is unclear whether they are necessary for therapeutic efficacy or minimizing side effects of bisphosphonates. We investigated whether baseline dietary calcium intake or vitamin D status modified the effect of zoledronate on bone mineral density (BMD) or bone turnover at 1 year, or the risk of acute phase reactions (APR). METHODS: Data were pooled from two trials of zoledronate in postmenopausal women without vitamin D deficiency in which calcium and vitamin D were not routinely administered. The cohort (zoledronate n = 154, placebo n = 68) was divided into subgroups by baseline dietary calcium intake (<800 vs. ≥800 mg/day) and vitamin D status [25-hydroxyvitamin D (25OHD) <50 vs. ≥50 nmol/L, and <75 nmol/L vs. ≥75 nmol/L] and treatment × subgroup interactions tested. RESULTS: There were 52, 86, and 36 % of the zoledronate group and 64, 94, and 46 % of the placebo group that had dietary calcium intake ≥800 mg/day, 25OHD ≥50 nmol/L, and 25OHD ≥75 nmol/L, respectively. There were no significant interactions between treatment and either baseline dietary calcium or baseline vitamin D status for lumbar spine BMD, total hip BMD, the bone turnover markers P1NP and ß-CTx, or the risk of an APR. There was also no three-way interaction between baseline dietary calcium intake, baseline vitamin D status, and treatment for any of these variables. CONCLUSIONS: Baseline dietary calcium intake and vitamin D status did not alter the effects of zoledronate, suggesting that co-administration of calcium and vitamin D with zoledronate may not be necessary for individuals not at risk of marked vitamin D deficiency.

Net effect of an acute phase response--partial alleviation with probiotic supplementation.

The acute phase response (APR) is characterized by inflammation, fever, and altered organ metabolism resulting in muscle catabolism and anorexia. Lipopolysaccharide (LPS)-induced APR may reflect depressed growth and appetite loss. Therefore, a 1-wk growth experiment was conducted to examine whether dietary supplementation of a multispecies probiotic (PoultryStar) would alleviate growth suppression and anorexia caused by LPS-induced APR. The experiment was designed with 4 treatments (n = 8 cages/treatment; 6 birds/cage) starting at 14 d of age. Before (0 to 14 d of age) and for the experiment (14 to 21 d of age), male broiler chicks were fed diets devoid of probiotic or were supplemented with 1.7 x 10(8) cfu/kg of probiotic. At 14 d of age, birds fed the diet devoid of probiotic were further divided into 3 treatments: an unchallenged positive control, LPS-challenged negative control (LPS-NC), and a treatment that was pair-fed to LPS-NC. The probiotic-fed birds were also then challenged with LPS. The LPS (Escherichia coli 055:B5) was injected intraperitoneally 4 times at 48-h intervals at 1 mg/kg of BW. The LPS challenge dramatically depressed BW gain from 14 to 21 d of age by 22% (P < 0.001). However, 41% of growth depression was attributable to factors other than feed intake reduction when compared with the pair-fed treatment. Probiotic supplementation recovered 17% of depressed growth (vs. LPS-NC; P = 0.068), but this improved growth was not due to improvements in feed intake (P = 0.47). However, recovery of feed intake of the probiotic + LPS birds occurred 48-h earlier than the LPS-NC birds. Growth depression induced by LPS administration resulted in an overall relative feed intake (vs. positive control) of 0.83 and also decreased net energy and protein accretion. Probiotic supplementation did not alleviate the reduction in net energy or protein accretion induced by LPS. In conclusion, APR (induced by LPS administration) diverted a large portion of consumed nutrients from tissue accretion. Probiotic supplementation lessened the anorexic effects of LPS resulting in a trend toward BW gain improvement versus the LPS-NC.

Nadroparine blunts lipopolysaccharide-induced hypothermia and behavioral depression in mice.

INTRODUCTION: Despite the use of appropriate antimicrobial therapy and intensive care support, sepsis remains a major cause of morbidity and mortality in surgical clinics. Low-molecular weight heparin treatment may reduce mortality and end-organ failure in sepsis. The purpose of this study was to compare the effects of low-molecular weight heparins such as nadroparine, enoxaparine, and dalteparine on lipopolysaccharide-induced acute phase reaction in mice. METHODS: Lipopolysaccharide was injected intraperitoneally to produce a systemic inflammatory response and septic shock-like effects in adult male BALB/c mice. Mices were treated with low-molecular weight heparins (nadroparine, enoxaparine, dalteparine) and unfractioned heparin in different doses and times. Rectal temperature and spontaneous locomotor activity of the mice were evaluated. RESULTS: Lipopolysaccharide (1 mg/kg, intraperitoneal) produced a hypothermia that occurred 20 minutes after injection. Nadroparine pretreatment (23.75 U/kg, sc) 2 hours before lipopolysaccharide challenge, but not synchronous injection, inhibited the hypothermic response. Pretreatment with equivalent doses of enoxaparine or dalteparine had no effect on the hypothermia. The high dose of lipopolysaccharide (60 mg/kg, intraperitoneal) caused more profound hypothermia and also inhibited spontaneous locomotor activity 24 hours after injection. Synchronous nadroparine administration partially attenuated the hypothermia and significantly abolished the depression of spontaneous locomotor activity. CONCLUSIONS: The results suggest that some low-molecular weight heparins such as nadroparine might be beneficial in high-risk surgical patients because of their potential anti-inflammatory action, in addition to their efficiency in preventing thrombo-embolic complications.

Dietary L-carnitine supplementation enhances the lipopolysaccharide-induced acute phase protein response in broiler chickens.

The objective of the present study was to evaluate the potential effects of dietary L-carnitine supplementation on acute phase protein response upon a lipopolysaccharide (LPS) challenge of male broiler chickens receiving a commercial broiler diet supplemented with 15 or 100 mg L-carnitine/kg or an unsupplemented (control) diet from 14 days of age onwards. At 28 days of age, eight chickens per dietary treatment were weighed and subcutaneously injected with 300 microg LPS from E. coli (100 microg LPS/ml saline) or 3 ml saline (unsupplemented group only). During the next 10 days, blood samples were taken repeatedly and analysed for their hemopexin (HX) and alpha-1 acid glycoprotein (AGP) levels. Extra dietary L-carnitine did not affect broiler performance. At day 1 postinjection, plasma HX and AGP levels were significantly increased in all treatment groups. However, the elevations in circulating HX and AGP levels were more pronounced in the L-carnitine supplemented chickens, especially in the 100mg L-carnitine group. It is concluded that extra L-carnitine in the diet of broiler chickens enhances or advances the acute phase protein response. The exact mode of action needs to be elucidated but seems to be consistent with a glucocorticoid mimicking effect.

Rat models of acute inflammation: a randomized controlled study on the effects of homeopathic remedies.

BACKGROUND: One of the cardinal principles of homeopathy is the "law of similarities", according to which patients can be treated by administering substances which, when tested in healthy subjects, cause symptoms that are similar to those presented by the patients themselves. Over the last few years, there has been an increase in the number of pre-clinical (in vitro and animal) studies aimed at evaluating the pharmacological activity or efficacy of some homeopathic remedies under potentially reproducible conditions. However, in addition to some contradictory results, these studies have also highlighted a series of methodological difficulties.The present study was designed to explore the possibility to test in a controlled way the effects of homeopathic remedies on two known experimental models of acute inflammation in the rat. To this aim, the study considered six different remedies indicated by homeopathic practice for this type of symptom in two experimental edema models (carrageenan- and autologous blood-induced edema), using two treatment administration routes (sub-plantar injection and oral administration). METHODS: In a first phase, the different remedies were tested in the four experimental conditions, following a single-blind (measurement) procedure. In a second phase, some of the remedies (in the same and in different dilutions) were tested by oral administration in the carrageenan-induced edema, under double-blind (treatment administration and measurement) and fully randomized conditions. Seven-hundred-twenty male Sprague Dawley rats weighing 170-180 g were used. Six homeopathic remedies (Arnica montana D4, Apis mellifica D4, D30, Atropa belladonna D4, Hamamelis virginiana D4, Lachesis D6, D30, Phosphorus D6, D30), saline and indomethacin were tested. Edema was measured using a water-based plethysmometer, before and at different times after edema induction. Data were analyzed by ANOVA and Student t test. RESULTS: In the first phase of experiments, some statistically significant effects of homeopathic remedies (Apis, Lachesis and Phosporus) were observed (the reduction in paw volume increase ranging from 10% to 28% at different times since edema induction). In the second phase of experiments, the effects of homeopathic remedies were not confirmed. On the contrary, the unblinded standard allopathic drug indomethacin exhibited its anti-inflammatory effect in both experimental phases (the reduction in paw volume increase ranging from 14% to 40% in the first phase, and from 18% to 38% in the second phase of experiments). CONCLUSION: The discrepancies between single-blind and double-blind methods in animal pharmacological research are noteworthy and should be better investigated, also in non-homeopathic research.

The embryolethality of lipopolysaccharide in CD-1 and metallothionein I-II null mice: lack of a role for induced zinc deficiency or metallothionein induction.

Lipopolysaccharide (LPS) is embryolethal in CD-1 mice. LPS induces metallothionein (MT) via cytokines, including TNF-alpha, IL-1, and IL-6, which initiate and maintain the acute phase response. Maternal hepatic MT induction in pregnant rats, by diverse toxicants, can result in maternal hypozincemia and subsequent embryonal zinc (Zn) deficiency. We examined the hypothesis that LPS causes embryo toxicity in CD-1 mice via MT induction and subsequent embryo Zn deficiency by (1) determining whether LPS induces maternal hepatic MT and causes Zn redistribution, (2) assessing the effects of maternal Zn supplementation on LPS developmental toxicity, and (3) assessing the role of MT with MT I-II null mice (MTKO). Timed pregnant CD-1 mice were dosed i.p. with LPS (S. typhimurium) (0.05 mg/kg) on gestation day (gd) 9. Zn supplementation was administered on gd 8 (10 mg/kg, pretreatment) or on gd 9 as a cotreatment (5 or 10 mg/kg). MTKO and wild type (WT) mice were dosed with LPS (0.05 or 0.1 mg/kg) on gd 9, and maternal liver MT and Zn and plasma Zn were measured. In CD-1 mice, maternal hepatic MT was elevated 24 h after LPS treatment, and cotreatment with Zn caused further elevation of MT. Maternal hepatic Zn concentrations paralleled hepatic MT concentrations. Maternal plasma Zn on gd 10 showed no consistent effect of LPS treatment or Zn cotreatment on gd 9. Zn pretreatment (10 mg/kg) on gd 8 did not ameliorate LPS embryolethality, while Zn cotreatment (5 or 10 mg/kg) on gd 9 exacerbated the toxicity of LPS. LPS produced a similar incidence of embryolethality in MTKO and WT strains on gd10. Plasma Zn concentrations were similar in both strains, while hepatic Zn concentrations were significantly higher in WT than in the MTKO strain. In conclusion, while LPS can induce maternal hepatic MT and Zn redistribution in CD-1 mice, this does not appear to be a key mechanism leading to LPS embryotoxicity.

Nonregenerative stimulation of hepatocyte proliferation in the rat: variable effects in relation to spontaneous liver growth; a possible link with metabolic induction.

Three procedures were used to stimulate hepatocyte proliferation in the rat without reducing liver mass, resulting in a supplementary growth which differs from the regenerative growth observed after loss of liver mass by hepatectomy or toxic necrosis. They were: (a) the ingestion of cyproterone, a cytochrome P450 inducing drug (b) the injection of an irritant which provokes glycogenesis and synthesis of acute-phase proteins (c) the injection of albumin-bound bilirubin leading to elimination of glucuronated bilirubin in bile. This ensuing supplementary growth was studied in the rat under several conditions of hepatic proliferation: 1. In normal adult rats, in which hepatocyte proliferation is very low, the effect on proliferation was either weak or undetectable. 2. In suckling rats, with a rapid body and liver growth, all the stimulants provoked a synchronized wave of proliferation with a steep increase of the percentage of S-phase hepatocytes from 4.5% in controls to 15-30% in treated rats. This increase was followed by a compensatory period of low proliferation during which a treatment with a second stimulant was much less effective. 3. In 2/3 hepatectomized adult rats, the proliferation induced by cyproterone was higher than the spontaneous regenerative proliferation alone and additional to it during all of the regenerative process. The proliferation induced by acute inflammation was competitive with the synchronous spontaneous proliferation during the early period of synchronized proliferation following surgery, suggesting that both are similar acute responses. Differently, during the late period of lower and unsynchronized regenerative proliferation, the proliferation provoked by acute inflammation was additional to the spontaneous one. A stimulation of proliferation by injection of the albumin-bilirubin complex was observed during the late period after 2/3 hepatectomy. The highest level of stimulation occurred when the liver growth and the hepatocyte proliferation were already high. This suggests that these stimulants are not complete mitogenic stimuli and need cofactors which are present during the spontaneous growth or, alternatively, that the effect of stimulants is opposed by an inhibitory mechanism present in the adult rat.

Reduced inflammatory response in rats fed fat-rich diets: role of leukotrienes.

The effect of fat-rich diets on the acute inflammatory response was examined. Male Wistar rats aged 21 days were fed, for 6 weeks, with a control diet (4% fat content), or a control diet supplemented with coconut or soybean oils (15% fat content). Carrageenan-induced paw oedema and pleurisy were evaluated. Prostaglandin (PG) E2 and leukotriene (LT) C4/D4 concentrations were determined in the pleural exudate (ELISA). Pleural samples were tested for their effect on cutaneous vascular permeability of control rats and the effect of a LTD4 receptor antagonist (L660-711; 10 mg/kg; i.v.) examined. Relative to controls, rats fed both fat-rich diets presented a significant reduction in protein leakage and oedema formation without affecting the number of migrating leukocytes. Production of LTC4/D4 in pleural exudate was significantly increased from 1.8 +/- 0.2 ng/ml in controls to 2.8 +/- 0.2 and 3.0 +/- 0.3 ng/ml in animals fed coconut and soybean oil enriched diets, respectively, without changes in PGE2 production. The activity of these samples on cutaneous vascular permeability was 50% reduced, returning to control values after treatment of testing animals with a LTD4 receptor antagonist. Rats fed fat-rich diets presented a reduced inflammatory response due, at least in part, to the LTC4/D4 mediated vasoconstrictor effect.

Toxic damage to the respiratory epithelium induces acute phase changes in vitamin A metabolism without depleting retinol stores of South African children.

Whereas there is much information concerning the effects of vitamin A status on response to infectious challenge, the effects of infection or trauma on vitamin A metabolism and status are less well documented. These relationships need to be understood to optimize clinical and public health programs to improve vitamin A status and health of children in less-developed countries. We measured acute changes in retinol and retinol-binding protein in 57 young South African children hospitalized following respiratory epithelial damage resulting from accidental ingestion of kerosene. In addition, vitamin A status, as measured by the modified relative dose response test, of these children 3 mo later was compared with that of neighborhood control children to determine whether their illness had depleted retinol stores. Plasma retinol was already significantly below control levels when children were admitted [geometric mean (95% CI): 0.57 micromol/L (0.48-0.67) compared with 1.15 micromol/L (1.02-1.30) for controls] and decreased further the following morning [0.38 micromol/L (0.31-0.46)]. Significant differences in retinol-binding protein were not detected until the next morning [5.99 mg/L (4.70-7.63) compared with 14.0 mg/L (11.8-16.6) for controls] and were not as large as the relative differences in retinol. This dissociation between changes in retinol and its binding protein suggests that there may be increased retinol uptake by certain tissues during the acute phase response. The proportion of case children (37/46, 80%) with inadequate liver retinol stores 3 mo after the illness was slightly, but not significantly (chi2 = 2.16, P = 0.14), greater than the proportion of control children (28/42, 67%). Acute respiratory illness therefore did not further deplete retinol stores in this population in which stores were already frequently inadequate.

The effect of factor Xa/phospholipid infusion on the acute phase response in baboons.

Disseminated intravascular coagulation (DIC) is a frequent complication of septicemia or tissue injury and may be accompanied by elevations of interleukin-6, a mediator of the acute phase response. It is not known whether thrombin or fibrin deposition may directly induce an acute phase response. To study this, we employed a baboon model of in vivo thrombin generation, induced by the administration of purified bovine Factor Xa and phospholipid vesicles. Two Xa/phospholipid dosages were used, a low dosage (2 animals) leading to a rapid 49% decrease in fibrinogen and a high dosage (two injections at 5h interval; 3 animals) leading to complete fibrinogen depletion. Thereafter, fibrinogen levels increased in both treatment groups, reached a maximum of 2.52 +/- 0.23 g/l (mean +/- SE, n = 5; p < 0.01 with respect to basal levels) at day 2, and returned to normal by day seven. In five control (injection of 0.15% NaCl) baboons no significant changes of fibrinogen were observed (maximal values: 1.88 +/- 0.12 g/l). Serum concentrations of C-reactive protein, an acute phase protein, increased from 3.7 +/- 0.4 mg/l to a maximum of 33.0 +/- 7.3 at day one, which was five-fold higher (p < 0.01) than in control animals at day one (6.2 +/- 0.5 mg/l). Transient increases were observed within 6h for interleukin-6 from basal values of 6.2 +/- 1.7 ng/l to peak plasma levels of 42.9 +/- 21.4 ng/l, a value three-fold higher (p = 0.07) than in control animals (14.8 +/- 4.0 ng/l). The preliminary results of this observational study suggest that factor Xa/phospholipid infusion is followed by an acute phase response, leading after one day to significant increases of fibrinogen and of C-reactive protein.

Brain regions involved in the development of acute phase responses accompanying fever in rabbits.

1. The effects of microinjection of rabbit endogenous pyrogen and human recombinant interleukin-1 alpha on rectal temperature and acute phase responses were extensively examined in forty different brain regions of rabbits. The acute phase responses that were investigated were the changes in plasma levels of iron, zinc and copper concentration and the changes in circulating leucocyte count. 2. The rostral hypothalamic regions, such as nucleus broca ventralis, preoptic area and anterior hypothalamic region, responded to the microinjection of endogenous pyrogen or interleukin-1 by producing both fever and acute phase responses. 3. The microinjection of endogenous pyrogen or interleukin-1 into the rostral hypothalamic regions significantly decreased the plasma levels of iron and zinc concentration 8 and 24 h after injection. The circulating leucocyte count increased 8 h after injection. However, neither the injections of endogenous pyrogen nor interleukin-1 affected the number of red blood cells. 4. The present results show that the rostral hypothalamic regions respond directly to endogenous pyrogen or interleukin-1 with the consequent development of fever and acute phase responses.

Suppression of acute and chronic inflammation by dietary gamma linolenic acid.

We examined the effect of diets enriched in gamma linolenic acid (GLA) on acute inflammation induced by monosodium urate crystals, and on subacute and chronic inflammation induced by complete Freund's adjuvant in the rat subcutaneous air pouch and in rats with adjuvant induced arthritis. Diets were enriched (15% fat) with borage seed oil (23% GLA) or safflower oil (less than 1% GLA). Diets enriched with GLA suppressed inflammation markedly in all models, whereas the safflower oil diet did not influence the inflammatory response. The degree of inflammation was quantified by measuring pouch exudate cell concentration, lysosomal enzyme activity, volume, protein concentration and prostaglandin E2 and leukotriene B4 concentrations. In the chronic air pouch model, the pouch lining was thickened, invaded by mononuclear cells and exhibited proliferation of lining cells 14 days after adjuvant injection. The lesion was far less severe and usual pouch lining architecture was maintained in animals given dietary GLA. Livers of rats fed borage seed oil were enriched in GLA and dihomo gamma linolenic acid (DGLA), and the DGLA/arachidonate ratio was increased 5-fold compared with animals fed safflower oil. Enrichment of diet with plant seed oils rich in GLA may provide a way to alter generation of prostaglandins and leukotrienes and to influence acute and chronic inflammatory responses.