The impact of GI events on persistence and adherence to osteoporosis treatment: 3-, 6-, and 12-month findings in the MUSIC-OS study.

The goal of this multinational, prospective, observational study was to examine the relationship between gastrointestinal (GI) events and self-reported levels of medication adherence and persistence in postmenopausal women. A total of 73.9% of patients remained on their osteoporosis (OP) therapy at month 12, although the presence of a GI event at baseline, month 3, and month 6 significantly reduced month 12 persistence among new users. The odds of a month-12 ADEOS score ≥ 20 were significantly lower among patients who experienced a GI event between baseline and month 6. The occurrence of GI events was observed to be associated with a lower likelihood of patient adherence and persistence to OP medication. INTRODUCTION: This study examines the relationship between gastrointestinal (GI) events and self-reported adherence and persistence with initial osteoporosis (OP) therapy over the course of the first 12 months of treatment. METHODS: The Medication Use Patterns, Treatment Satisfaction, and Inadequate Control of Osteoporosis Study was a multinational, prospective, observational study examining the impact of GI events on OP management in postmenopausal women. Information regarding GI events was collected at the time of enrollment and at months 3, 6, and 12 of follow-up. Patients reported GI events and medication persistence and completed the 12-item Adherence Evaluation of Osteoporosis treatment (ADEOS) questionnaire. Multivariate logistic and general linear models examined the association between GI events at various time points and persistence and adherence at month 12. RESULTS: The study enrolled 2943 women; 22.8% were classified as new users of OP therapy and the remainder were considered experienced users. Across all patients, 68.1% reported GI events at baseline; by month 12, over 80% of subjects who completed follow-up reported at least one GI problem. The majority of patients (86.7%) were treated only with bisphosphonates at baseline. At month 12, 73.9% of patients remained on therapy; logistic regression revealed that those with GI problems by month 6 were significantly less likely to persist with treatment, after adjusting for other factors. The odds of a month 12 ADEOS score ≥ 20 (considered predictive of adherence) were significantly lower among patients who experienced a GI event between baseline and month 6. CONCLUSIONS: The occurrence of GI events was associated with a lower likelihood of patient adherence to and persistence with OP medication.

Association of gastrointestinal events with quality of life and treatment satisfaction in osteoporosis patients: results from the Medication Use Patterns, Treatment Satisfaction, and Inadequate Control of Osteoporosis Study (MUSIC OS).

The purpose of this study was to assess the association of GI events with HRQoL and treatment satisfaction. The effect of baseline GI events persisted through 1 year of follow-up, as indicated by lower EQ-5D, OPAQ-SV, and treatment satisfaction scores among patients with vs without baseline GI events. The presence of GI events is an independent predictor of decreased HRQoL and treatment satisfaction in patients being treated for osteoporosis. INTRODUCTION: The goal of this study was to assess the association of gastrointestinal (GI) events with health-related quality of life (HRQoL) and treatment satisfaction in patients being treated for osteoporosis. METHODS: MUSIC OS was a multinational, prospective, observational study examining the impact of GI events on osteoporosis management in postmenopausal women. In this analysis, HRQoL and treatment satisfaction were assessed at baseline, 6, and 12 months and compared between patients with and without GI events. Covariate-adjusted scores were calculated using multivariate least-squares regression analysis, and differences between the mean scores of patients with and without baseline and post-baseline GI events were determined. RESULTS: Among the 2959 patients in the analysis, unadjusted scores at each time point were lower (i.e., worse) for patients with GI events than patients without GI events. In adjusted analyses, the effect of baseline GI events persisted through 1 year of follow-up, as indicated by lower EQ-5D and OPAQ-SV scores at 12 months among patients with vs without baseline GI events (-0.04 for the EQ-5D utility score, -5.07 for the EQ-5D visual analog scale, -3.35 for OPAQ physical function, -4.60 for OPAQ emotional status, and -8.50 for OPAQ back pain; P ≤ 0.001 for all values). Decrements in month 12 treatment satisfaction scores were -6.46 for patients with baseline GI events and -7.88 for patients with post-baseline GI events. CONCLUSIONS: The presence of GI events is an independent predictor of decreased HRQoL and treatment satisfaction in patients being treated for osteoporosis.

Gastrointestinal symptoms and association with medication use patterns, adherence, treatment satisfaction, quality of life, and resource use in osteoporosis: baseline results of the MUSIC-OS study.

SUMMARY: The Medication Use Patterns, Treatment Satisfaction, and Inadequate Control of Osteoporosis Study (MUSIC-OS) is a prospective, observational study of women with osteoporosis in Europe and Canada. At baseline, patients with gastrointestinal symptoms reported lower adherence to osteoporosis treatment, treatment satisfaction, and health-related quality of life, than those without gastrointestinal symptoms. INTRODUCTION: The aim of the study was to examine gastrointestinal (GI) symptoms and the association between GI symptoms and treatment adherence, treatment satisfaction, and health-related quality of life (HRQoL) among osteoporotic women in Europe and Canada. METHODS: Baseline results are reported here for a prospective study which enrolled postmenopausal, osteoporotic women who were initiating (new users) or continuing (experienced users) osteoporosis treatment at study entry (baseline). A patient survey was administered at baseline and included the occurrence of GI symptoms during 6-month pre-enrolment, treatment adherence (adherence evaluation of osteoporosis (ADEOS), score 0-22), treatment satisfaction (Osteoporosis Treatment Satisfaction Questionnaire for Medications (OPSAT-Q), score 0-100) and HRQoL (EuroQol-5 dimension (EQ-5D) utility, score 0-1; OPAQ-SV, score 0-100). The association between GI symptoms and ADEOS (experienced users), OPSAT-Q (experienced users), and HRQoL (new and experienced users) was assessed by general linear models adjusted for patient characteristics. RESULTS: A total of 2959 patients (2275 experienced and 684 new users) were included. Overall, 68.1% of patients experienced GI symptoms in the past 6 months. Compared with patients without GI symptoms, patients with GI symptoms had lower mean baseline scores on most measures. The mean adjusted differences were ADEOS, -0.43; OPSAT-Q, -5.68; EQ-5D, -0.04 (new users) and -0.06 (experienced users), all P < 0.01. GI symptoms were also associated with lower OPAQ-SV domain scores: physical function, -4.17 (experienced users); emotional status, -4.28 (new users) and -5.68 (experienced users); back pain, -5.82 (new users) and -11.33 (experienced users), all P < 0.01. CONCLUSIONS: Patients with GI symptoms have lower treatment adherence and treatment satisfaction and worse HRQoL than patients without GI symptoms.

Fracture risk in patients receiving acid-suppressant medication alone and in combination with bisphosphonates.

SUMMARY: Previous studies have found an association between acid suppressants and fracture risk. We assessed fracture risk in patients taking concomitant acid suppressant and bisphosphonates. Positive associations were observed for any hip and vertebral fracture. The effect size was modest; however, the significance lies in the widespread prescribing of acid suppressants. INTRODUCTION: Previous studies have found that acid-suppressive medication (ASM) is associated with an increased risk of fracture. Bisphosphonates can cause upper gastrointestinal problems, and patients may be prescribed ASM to minimise these effects. METHODS: A retrospective cohort study using the GPRD was conducted in patients aged 40 years and older starting proton pump inhibitors (PPI, N = 234,144), H(2) receptor antagonists (H(2)RA, N = 166,798) or bisphosphonates (N = 67,309). Fracture risk in current versus past use of ASM and concomitant use of bisphosphonate plus ASM versus bisphosphonate alone was compared using time-dependent Cox regression. RESULTS: In the 6 months before initiating bisphosphonate therapy, 20.1% of patients received a PPI and 7.5% an H(2)RA. Current PPI use was associated with an increased risk of any (adjusted relative rate (ARR) 1.15, 95% CI 1.10-1.20), hip (ARR 1.22, 95% CI 1.10-1.37), and vertebral fracture (ARR 1.40, 95% CI 1.11-1.78); and concomitant bisphosphonates and PPIs with an increased risk of any (ARR 1.08, 95% CI 1.01-1.16) and hip fracture (ARR 1.24, 95% CI 1.08-1.42). CONCLUSIONS: ASM is associated with an increased risk of fracture when taken alone or in combination with bisphosphonates. Given the frequency of coprescription of ASM and bisphosphonates, this issue requires further investigation.

Salvage of isolated vaginal recurrences in women with surgical stage I endometrial cancer: a multiinstitutional experience.

The objective of this study was to evaluate the treatment outcomes and risk factors of women with surgical stage I endometrial adenocarcinoma who were initially treated with surgery alone and subsequently developed isolated vaginal recurrences. Patients with surgical stage I endometrial adenocarcinoma diagnosed from 1975 to 2002 were identified from tumor registry databases at seven institutions. All patients were treated with surgery alone including a total hysterectomy, bilateral salpingo-oophorectomy, pelvic (+/- para-aortic) lymph node dissection, and peritoneal cytology and did not receive postoperative radiation therapy. Vaginal recurrences were documented histologically. Metastatic disease in the chest and abdomen was excluded by radiologic studies. Overall survival was calculated by the Kaplan-Meier method. Sixty-nine women with surgical stage I endometrial cancer with isolated vaginal recurrences were identified. Of the 69 patients, 10 (15%) were diagnosed with stage IA disease, 43 (62%) were diagnosed with stage IB disease, and 16 (23%) were diagnosed with stage IC disease. Patients diagnosed with grade 1 disease were 22 (32%), grade 2 disease were 26 (38%), and grade 3 disease were 21 (30%). Among women, 81% with isolated vaginal recurrences were salvaged with radiation therapy. The mean time to recurrence was 24 months, and the mean follow-up was 63 months. Among women, 18% died from subsequent recurrent disease. The 5-year overall survival was 75%. The majority of isolated vaginal recurrences in women with surgical stage I endometrial cancer can be successfully salvaged with radiation therapy, further questioning the role of adjuvant therapy for patients with uterine-confined endometrial cancer at the time of initial diagnosis.

Juxtacrine effects of IL-1 alpha precursor promote iNOS expression in vascular smooth muscle cells.

After injury to the blood vessel wall, vascular smooth muscle cells (SMC) synthesize interleukin (IL)-1 and inducible nitric oxide (NO) synthase (iNOS). The present study tested whether endogenous production of IL-1 alpha stimulates iNOS expression in vascular SMC, and assessed whether IL-1 alpha exerts autocrine effects on the cells producing IL-1 alpha or juxtacrine effects on cells that contact the IL-1 alpha producing cells. Rat aortic SMC were transiently transfected with expression plasmids encoding either IL-1 alpha precursor, which localizes to the plasma membrane, or mature IL-1 alpha, which remains cytosolic. iNOS mRNA levels, determined by RT-PCR, and production of nitrite, a stable oxidation product of NO, were markedly elevated in SMC overexpressing IL-1 alpha precursor, and modestly elevated in SMC overexpressing mature IL-1 alpha, relative to SMC transfected with vector alone. Exposure to exogenous IL-1 beta or TNF-alpha further stimulated iNOS gene expression in SMC producing IL-1 alpha; low levels of IL-1 beta (20 pg/ml) were effective in SMC transfected with IL-1 alpha precursor plasmid, whereas SMC transfected with mature IL-1 alpha plasmid or vector alone required higher concentrations of IL-1 beta (200 and 2,000 pg/ml, respectively). The increases in iNOS mRNA levels and NO production in SMC overexpressing IL-1 alpha precursor were prevented by exogenous IL-1 receptor antagonist, suggesting that these effects were mediated by the type I IL-1 receptor. Immunostaining studies indicated that IL-1 alpha precursor stimulates iNOS gene expression via cell-cell contact. Expression of iNOS was enhanced in cells that were in contact with a cell overexpressing IL-1 alpha precursor (identified by coexpression of green fluorescent protein), and in cells that were overexpressing IL-1 alpha themselves, but only when the cell contacted another cell. Together these results indicate that IL-1 alpha precursor acts by cell-cell contact as an autocrine and juxtacrine enhancer of iNOS gene expression, inducing moderate iNOS expression on its own, and markedly augmenting the responsiveness of rat aortic SMC to exogenous cytokines.

Cost-effective prescribing of proton pump inhibitor therapy: an audit in general practice.

General practitioners must prescribe cost effectively to control drug expenditure and provide optimal treatment for patients requiring long-term management. An audit was implemented in general practices to review the management of dyspepsia, improve care, rationalise therapy and reduce costs. Policy included identifying patients receiving proton pump inhibitor (PPI) therapy and changing to low-dose cost-effective therapy. If PPI therapy was not required, patients were changed to antacids, H2 receptor antagonists or no treatment. This was an audit in general practice, not a clinical trial, therefore findings reflect outcomes in normal clinical practice. This paper describes the implementation and findings of the audit between January 1997 and July 1999 in 91 general practices involving 7121 patients. Extrapolation of the results concluded that savings of up to 50,000 Pounds could be made in a practice of 10,000 patients, allowing reinvestment in health improvement plans and optimal care.

Hypoxia stimulates proliferation and interleukin-1alpha production in human vascular smooth muscle cells.

Several lines of evidence indicate that hypoxia is a stimulus to vascular smooth muscle cell (VSMC) proliferation that occurs in pulmonary hypertension. The present study tested the hypothesis that low O(2) tension directly stimulates human VSMC proliferation by inducing them to produce interleukin (IL)-1, a potent autocrine growth factor for human VSMC. Human VSMC derived from pulmonary artery, aorta, or saphenous vein were incubated in either a normal in vitro O(2) environment (20% O(2)) or in chambers containing low (approximately 1%) or moderate (5%) O(2). Levels of IL-1alpha and IL-1beta mRNA increased in human VSMC after 24-48 h of incubation in low O(2) compared with levels in normoxic cells and then decreased upon subsequent reoxygenation. Levels of cell-associated IL-1alpha also increased progressively after 24-48 h in low O(2); however, detectable IL-1alpha was not released from the cells in the media. IL-1beta was detectable in cell lysates and supernatants; however, the levels were not affected by exposure to low O(2). mRNA encoding for tumor necrosis factor-alpha (TNF-alpha), a related cytokine and VSMC mitogen, was not detectable in human VSMC exposed to either low or 20% O(2). Proliferation of human VSMC was not stimulated during exposure to low O(2), despite the fact that cells remained responsive to the mitogenic effect of exogenous IL-1. Interestingly, however, exposure to 5% O(2) enhanced proliferation of human VSMC but did not induce IL-1alpha production. Inhibition of IL-1 binding to the type I IL-1 receptor by exogenous addition of IL-1-receptor antagonist (10 microgram/ml) did not attenuate the proliferation rates of human VSMC incubated in 20%, 5%, or low O(2) or in human VSMC that were reoxygenated after exposure to low O(2). These results demonstrate two direct and distinct effects of hypoxia on VSMC. Exposure to moderately low O(2) tension induces VSMC proliferation, independent of IL-1, whereas exposure to very low O(2) tension induces production of IL-1alpha.

Constitutive expression of interleukin-1alpha precursor promotes human vascular smooth muscle cell proliferation.

Vascular smooth muscle cell (VSMC) proliferation plays a critical role in the failure of vascular surgeries and contributes to the development of atherosclerotic lesions. Evidence that interleukin-1 (IL-1) is a mitogen for cultured VSMC has implicated its release by activated macrophages in the development of atherosclerosis. VSMC also produce IL-1, including the precursor form of IL-1alpha. However, it is not known whether IL-1alpha precursor is processed to mature IL-1alpha or released from VSMC, nor is it known whether either precursor or mature IL-1alpha functions as an autocrine growth factor. The goals of the present study were to establish whether proliferation is enhanced in human VSMC transfectants producing IL-1alpha constitutively at levels comparable to those produced after activation, and to determine which domains of IL-1alpha are important for its activity. Human VSMC were stably transfected with expression vectors directing constitutive expression of either full-length IL-1alpha precursor [IL-1alpha-(1-271)], its NH2-terminal domain [IL-1alpha-(1-112)], or mature IL-1alpha [IL-1alpha-(113-271)]. Both IL-1alpha-(1-271) and IL-1alpha-(113-271) stable transfectants produced moderate levels of IL-1alpha (0.2-1.0 ng/10(6) cells) and released low levels of IL-1alpha into the supernatant (<20 pg/ml). VSMC stably transfected with either IL-1alpha-(1-271) or IL-1alpha-(113-271) expression plasmids proliferated rapidly compared with nontransfected or vector-transfected VSMC and displayed a distinct morphology characterized by elongated, spindle-shaped cells. Stable transfection with IL-1alpha-(1-271) was somewhat more effective than transfection with IL-1alpha-(113-271). Interestingly, VSMC transfected with IL-1alpha-(113-271) expression plasmids also expressed IL-1alpha-(1-271) mRNA, suggesting that IL-1alpha-(113-271) activates an IL-1-induced IL-1 autocrine loop. In contrast, neither proliferation rates nor morphology was affected by stable transfection with IL-1alpha-(1-112) expression plasmids. Exogenous IL-1 receptor antagonist partially reversed the enhanced DNA synthesis in VSMC transfected with either IL-1alpha-(1-271) or IL-1alpha-(113-271) expression plasmids, suggesting that the pro-proliferative effect of VSMC-derived IL-1alpha is at least partially mediated by signaling via the type I IL-1 receptor. These results demonstrate that IL-1alpha precursor is an autocrine growth factor for human VSMC and further indicate that amino acids 113-271 play a crucial role in its actions.

Involvement of prostaglandins in cachexia induced by T-cell leukemia in the rat.

We have previously demonstrated that experimentally induced T-cell leukemia in the rat results in a rapid and severe cachexia. This weight loss is largely due to a reduction in food intake, but is also accompanied by inappropriately high rates of energy expenditure. Increases in resting oxygen consumption (VO2) of 25% to 35% above the levels of pair-fed animals were observed over the period of weight loss. The present study investigated the possible involvement of prostaglandins in the cachexia induced by T-cell leukemia in the rat. Acute systemic injection of the cyclo-oxygenase inhibitors (indomethacin 1 mg/kg or flurbiprofen 1 mg/kg intraperitoneally [IP]) significantly reduced (by 14% and 10%, respectively) the increase in metabolic rate and also reversed the elevated body temperature of leukemic animals. Intracerebroventricular (ICV) injection of indomethacin (0.2 mg/kg) had only modest effects on the increase in temperature or hypermetabolism of leukemic animals. Long-term daily injection of indomethacin or flurbiprofen (1 mg/kg/d IP) had no significant effect on food intake or body weight of leukemic animals, and neither treatment significantly affected disease status. Indomethacin significantly reduced the decline in epididymal fat pad weight of leukemic animals. These data indicate that prostaglandins, produced peripherally, are involved in the acute hypermetabolism associated with T-cell leukemia, but have little or no effect on the hypophagia or body weight loss of leukemic rats.

Involvement of cytokines in cachexia induced by T-cell leukaemia in the rat.

The objective of this study was to investigate the involvement of cytokines (IL-1, IL-6 and TNF-alpha) in cachexia induced by T-cell leukaemia in the rat. Leukaemic rats exhibited a marked and significant increase in circulating IL-6 concentration from days 12-17 corresponding to the period of weight loss after induction of leukaemia. IL-6 plasma bioactivity correlated significantly with spleen weight and weight loss, implicating IL-6 in the cachectic response. In contrast, IL-1 and TNF-alpha plasma bioactivities were not increased compared to control rats, indicating that these cytokines are not circulating mediators of cachexia induced by T-cell leukaemia in the rat. These data suggest that IL-6 produced by the host may contribute to cachexia induced by T-cell leukaemia.

Mechanisms of cachexia induced by T-cell leukemia in the rat.

Body wasting (cachexia) is a common feature of cancer and a major cause of morbidity and mortality. The mechanisms underlying cachexia are largely unknown, and studies in experimental animals have focused mainly on solid tumors. Therefore, the objective of the present study was to quantify and investigate cachexia in experimentally induced T-cell leukemia in the rat. Induction of leukemia by serial passage (injection of cervical lymph node suspension) resulted in a rapid increase in white blood cell (WBC count, hypertrophy of the spleen (by day 11), and severe morbidity within 17 to 18 days. Body weight gain and food intake declined steadily in leukemic animals from day 12, although weight loss was significantly greater in pair-fed, nonleukemic animals. However, leukemic rats had a lower body fat content and higher water content than pair-fed animals on day 18, so the measurement of body weight significantly underestimated the severity of cachexia. Resting oxygen consumption (VO2), measured during the light phase, declined in pair-fed animals from day 13, but was elevated in leukemic rats on days 12 to 18 by 25% (P < .05, one-way ANOVA) compared with pair-fed rats and by 7% (P < .05, one-way ANOVA) relative to free-feeding controls. Hypermetabolism was associated with an increase in brown adipose tissue (BAT) activity (74% and 89%, respectively, P < .05, one-way ANOVA) in leukemic rats compared with control and pair-fed groups. Effects of leukemia on VO2 and BAT were prevented by administration of the adrenergic antagonist, propranolol. These results indicate that T-cell leukemia in the rat results in rapid and severe cachexia, which is largely due to marked hypophagia, but is also accompanied by inappropriately high rates of energy expenditure that are mediated by sympathetic activation of BAT thermogenesis.

Normal glutamate metabolism in Alzheimer's disease fibroblasts deficient in alpha-ketoglutarate dehydrogenase complex activity.

Deficient activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC) has been documented in Alzheimer disease (AD) brain and fibroblasts. We examined glutamate metabolism in intact AD fibroblasts previously shown to have reduced KGDHC activity to determine whether this enzyme deficiency leads to a metabolic deficit in extraneural tissues. After exposure to [13N]ammonia for 5 min, the ratio of [13N]glutamate to [13N]aspartate and the ratio of unlabeled glutamate to aspartate were comparable in AD and control fibroblasts. The ratio of [13N]glutamate/[13N]glutamine was 3.7 +/- 1.8 in AD and 6.8 +/- 2.8 in control cells, but the difference was not statistically significant. Unlabeled glutamate/glutamine ratios were similar in the AD and control cells. The rate of conversion of alpha-keto[1-14C]glutarate to 14CO2 was slightly but not statistically significantly less in the AD than in the control cells. The similarity in levels of glutamate and other amino acids in intact AD and control cells may be due in part to the high glutamate and glutamine content of the culture medium used. The similar incorporation of label derived from [13N]ammonia into glutamate/aspartate and the similar levels of alpha-ketoglutarate in AD and control cells may be due in part to the fact that KGDHC is not the rate-limiting enzyme for the tricarboxylic acid cycle in fibroblasts, although it does appear to be rate-limiting in brain. Cultured cells are established tools for identifying genetic and molecular defects in the host, but the studies above show the limitations in using them as a model of brain cell metabolism.

Tumor necrosis factor-alpha and fever after peripheral inflammation in the rat.

The involvement of endogenous tumor necrosis factor-alpha (TNF-alpha) in the pyrogenic [i.e., rise in colonic temperature (Tc)] and thermogenic [increase in oxygen consumption (VO2)] responses to inflammation was investigated in rats subjected to an intramuscular injection of turpentine. Turpentine administration caused a rise in Tc and VO2 within 2 h (0.9 +/- 0.1 degrees C, 27 +/- 2%, respectively). Eighteen to twenty hours after turpentine, the magnitude of these responses had increased (2.3 degrees C fever and a 28% increase in metabolic rate compared with control animals) and was associated with marked inflammation in the injected limb. A rapid (by 4 h) and sustained rise in the plasma concentration of the endogenous pyrogen IL-6, but not TNF-alpha, was also observed. Intravenous pretreatment with a TNF-alpha antiserum attenuated the rise in Tc observed 2, 8, and 18 h after turpentine injection and almost abolished the hypermetabolic response observed at 18 h. In addition, the TNF-alpha antiserum inhibited the peak rise (8 h) in plasma IL-6 by 76%. These findings indicate that endogenous TNF-alpha is involved in fever and hypermetabolism during inflammation and that it may exert these effects by inducing the release of IL-6 into circulation.

Dietary n-3 Fatty Acids Inhibit Fever Induced by Inflammation in the Rat.

Modification of endogenous eicosanoid synthesis by dietary n-3 fatty acid supplementation reduces febrile responses, but the mechanisms underlying these effects in vivo have not been determined. In the present study, local inflammation was induced by intramuscular injection ofturpentine in rats fed control or n-3 supplemented diets for 8-9 weeks. In animals fed the control diet, turpentine induced fever, hypermetabolism, marked local inflammation (oedema), increased plasma IL-6 concentrations and raised cerebrospinal fluid (CSF) concentrations of PGE2. N-3 fatty acid supplementation significantly inhibited the rise in CSF PGE2, fever and hypermetaboHsm induced by turpentine. Local inflammation and increased plasma IL-6 concentrations were not affected by n-3 supplementation. These findings suggest that modification of dietary fat intake inhibits fever via reduced release of prostaglandins, probably within the brain, but does not affect the local or afferent signals involved in fever generation.

Effect of dietary fish oil supplementation on fever and cytokine production in human volunteers.

The effect of dietary fish oil supplementation on acute phase responses to intramuscular injection of typhoid vaccine, and in vitro cytokine production, was investigated in human volunteers. Half of the subjects supplemented their normal diet with 4.5 g/day of fish oil for 6-8 weeks. Injection of typhoid vaccine in unsupplemented subjects caused an increase in white cell count, resting heart rate, metabolic rate, oxygen consumption, and oral temperature. Fish oil supplementation inhibited the tachycardia and attenuated the maximal increases in oral temperature and metabolic rate following typhoid vaccine. However, interpretation of these latter results were complicated by similarly attenuated responses in saline-injected subjects. The in vitro production of interleukin-1 and interleukin-6 from whole blood was suppressed by fish oil supplementation, however, production of tumor necrosis factor alpha was not significantly altered. Fish oil supplementation may therefore provide a non-pharmacological approach of attenuating several of the responses associated with injury and infection and this may be related to reduced cytokine (IL-1 and IL-6) production.

Inhibition of the thermogenic and pyrogenic responses to interleukin-1 beta in the rat by dietary N-3 fatty acid supplementation.

The thermogenic (increase in oxygen consumption, VO2) and pyrogenic (Tc) responses to the cytokine interleukin-1 beta (IL-1 beta) were studied in rats fed a n-3 fatty acid supplemented diet (8.75% n-3 fatty acids/kg diet). 4-6 weeks after commencing the diets, the n-3 supplemented rats exhibited reduced pyrogenic (0.5 +/- 0.1 degrees C versus 1.1 +/- 0.2 degrees C in control animals) and thermogenic (9 +/- 3% versus 22 +/- 6% in control animals) responses to intraperitoneal (i.p.) injection of IL-1 beta (1 micrograms/rat). However, responses to centrally administered IL-1 beta (5ng intracerebroventricular (i.c.v.)) were similar in both groups at this time. After 8-9 weeks of supplementation, n-3 supplemented animals exhibited attenuated responses to both ip IL-1 beta (VO2 responses reduced by 68% and Tc by 0.8 degrees C) and also i.c.v. IL-1 beta (VO2 responses reduced by 56% and Tc by 0.7 degrees C). N-3 supplementation did not, however, influence the thermogenic capacity of these animals since responses to noradrenaline were similar in control and n-3 fed animals (50% increase in VO2). These findings demonstrate that n-3 supplementation modifies the pyrogenic and thermogenic responses to IL-1 beta, probably via changes in eicosanoid metabolism. Modification of central responses to IL-1 are delayed compared to the effects of peripheral administration indicating separate mechanisms of IL-1 on fever and thermogenesis in the brain and the periphery.

Dietary N-3 fatty acids inhibit ischaemic and excitotoxic brain damage in the rat.

Arachidonic acid [20:4(N-6)] has been implicated in neurological damage induced by cerebral ischaemia. Membrane arachidonate concentrations can be reduced by changes in dietary fat intake. Therefore, in the present study, we have investigated the effects of N-3 fatty acid supplementation on neuronal damage induced by permanent focal cerebral ischaemia or pharmacological activation of striatal NMDA receptors. Weanling rats were fed either a control diet or an N-3 supplemented diet (1.75% by weight as N-3 fatty acids) for 6 weeks. N-3-supplemented animals reduced ischaemic damage following middle cerebral artery occlusion (36%, p < 0.05), and excitotoxic damage induced by infusion of the selective NMDA agonist (1-aminocyclobutane-cis-1,3-dicarboxylic acid, 43%, p < 0.001) compared to the control-fed group. These data are consistent with the proposed role of arachidonic acid in ischaemic and excitotoxic brain damage, and suggest that modest dietary supplementation with N-3 fatty acids may offer benefit to populations at high risk of stroke.

IgE antibodies specific for cartilage collagens type II, IX and XI in rheumatic diseases.

Serum samples from 149 patients with RA and other rheumatological diseases, and 57 non-arthritic controls have been assayed for IgE antibodies to the cartilage collagen types II, IX and XI in their native and denatured state. Using an improved ELISA technique together with antigen-binding inhibition studies to confirm specificity, 10 of the 149 (7%) patients showed IgE antibodies to human collagen type II and bovine collagen types II, IX or XI. Some patients responded to only one collagen type whereas others had IgE positive responses to two or all three collagen species. Most of the IgE responses detected were directed towards the denatured collagens. Those sera showing an IgE response to bovine type II collagen produced a similar response to the human equivalent, including two patients with SLE. None of 57 control subjects demonstrated IgE specificity for any of the cartilage collagens. Patients with IgE specificity for the cartilage collagens did not demonstrate IgM or IgA specificity for these antigens, but two of these patients showed IgG responses to type II and XI collagens. Whereas eight patients were exclusively IgE-positive for the cartilage collagens, others expressed specificities for IgG, IgM or IgA. It therefore appears that the specific autoimmune profile for each patient is often different from others, both in terms of the class of immunoglobulin expressed and the collagen antigens recognised. At present no correlations were observed between the IgE-positive patients and their clinical assessment and/or prognosis.

Metabolic and febrile responses to typhoid vaccine in humans: effect of beta-adrenergic blockade.

Fever and activation of acute phase responses were induced in human volunteers by intramuscular injection of typhoid vaccine. Vaccine injection caused a rapid (within 1 h) and sustained rise in metabolic rate (peak response 16%, 6-8 h), followed by later increases in white blood cell count (3-4 h), skin temperature (4-5 h), oral temperature (5-6 h), heart rate (6-8 h), and plasma cortisol (5-8 h). A peak fever [1.2 +/- 0.2 degree C (SE) rise] was recorded 12 h after vaccine injection. The involvement of the sympathetic nervous system in the development of these responses was investigated by the oral administration of propranolol before (80 mg) and 3 h after (40 mg) vaccine injection. Propranolol prevented the increases in metabolic rate, heart rate, and skin temperature but did not inhibit the rise in oral temperature or white cell count after vaccine administration. These data indicate that the sympathetic nervous system is responsible for the rise in energy expenditure associated with fever in humans. However, the rise in body temperature can develop in the absence of this increase in metabolic rate possibly by changes in heat loss.