Effects of in-feed clinoptilolite treatment on serum metabolic and antioxidative biomarkers and acute phase response in dairy cows during pregnancy and early lactation.

The objective of this study was to evaluate the effects of in-feed clinoptilolite (CPL) on serum metabolic and antioxidative biomarkers, acute phase proteins and reproductive performance in cows during pregnancy and lactation. A total of 78 Holstein-Friesian cows were randomly assigned into two groups: the treatment group, cows fed CPL (n = 38) which received 50 g of powdered CPL twice a day from day 180 before parturition to day 60 postpartum; and the control group (n = 40). Blood samples were taken on days 180, 90, 60, 30 and 10 before parturition, on day of calving and on days 5, 12, 19, 26, 33, 40 and 60 postpartum, and were analysed for metabolic biomarkers: glucose, triglycerides, total cholesterol, high density lipoprotein cholesterol, non-esterified fatty acids, beta-hydroxybutyrate (BHB), antioxidative biomarkers and acute phase proteins: paraoxonase-1 (PON1), apolipoprotein A-I, haptoglobin (Hp) and serum amyloid A (SAA). CPL supplementation increased concentration of glucose and significantly decreased (P < .05) level of BHB during puerperium. The SAA concentration in CPL-fed cows was significantly decreased (P < .05) on days 33, 40 and 60 postpartum as well as Hp concentration on days 0 and 12 postpartum. The results of this study suggest that the CPL-fed cows may have improved metabolic status due to the tendency of greater glucose levels and decreased BHB values during early lactation. In addition, acute phase response was lower (P < .05) in CPL-fed cows. Such an outcome might be attributed to the effect of dietary CPL on intensity and severity of the negative energy balance and inflammatory response in dairy cows.

Supplementation of a Lactobacillus acidophilus fermentation product can attenuate the acute phase response following a lipopolysaccharide challenge in weaned pigs.

Lactobacillus acidophilus fermentation products have been used to improve the performance of nursery pigs. However, research on the influence of this supplement on health is lacking. This study was designed to determine if feeding a Lactobacillus acidophilus fermentation product to weaned pigs would reduce stress and acute phase responses (APR) following a lipopolysaccharide (LPS) challenge. Pigs (n=30; 6.4±0.1 kg) were individually housed in stainless steel pens with ad libitum access to feed and water. Pigs were weighed upon arrival, assigned to one of three groups (n=10/treatment), and fed for 18 days: (1) Control, fed a non-medicated starter diet; (2) Control diet with the inclusion of a Lactobacillus acidophilus fermentation product at 1 kg/metric ton (SGX1) and (3) Control diet with the inclusion of a Lactobacillus acidophilus fermentation product at 2 kg/metric ton (SGX2). On day 7 pigs were anesthetized for insertion of an i.p. temperature device, and similarly on day 14 for insertion of a jugular catheter. Pigs were challenged i.v. with LPS (25 µg/kg BW) on day 15. Blood samples were collected at 0.5 h (serum) and 1 h (complete blood cell counts) intervals from -2 to 8 h and at 24 h relative to LPS administration at 0 h. Pigs and feeders were weighed on days 7, 14 and 18. The supplemented pigs had increased BW and average daily gain before the challenge. In response to LPS, there was a greater increase in i.p. temperature in Control pigs compared with supplemented pigs. In addition, cortisol was reduced in SGX2 pigs while cortisol was elevated in SGX1 pigs at several time points post-challenge. White blood cells, neutrophils and lymphocytes were decreased in SGX1 and SGX2 compared with Control pigs. Furthermore, the pro-inflammatory cytokine response varied by treatment and dose of treatment. Specifically, serum TNF-α was greatest in SGX2, intermediate in Control, and least in SGX1 pigs, while the magnitude and temporal pattern of IFN-γ in SGX2 pigs was delayed and reduced. In contrast, IL-6 concentrations were reduced in both SGX treatment groups compared with Control pigs. These data demonstrate that different supplementation feed inclusion rates produced differential responses, and that feeding SynGenX to weaned pigs attenuated the APR to an LPS challenge.

Preclinical safety, pharmacokinetics, and pharmacodynamics of recombinant human interleukin-21 in cynomolgus macaques (Macaca fascicularis).

Interleukin-21 (IL-21), a pleiotropic immunostimulatory type I cytokine, has anticancer effects in animal models. Preclinical studies designed to assess the safety of recombinant human IL-21 (rIL-21) for use in phase I oncology studies are described. The rIL-21 (≤3.0 mg/kg per dose) was given intravenously to cynomolgus monkeys (Macaca fascicularis) once daily for 5 days, followed by 9 nondosing days (1 cycle) for ≤4 cycles. The rIL-21 pharmacokinetics was dose-dependent. Accumulation was not observed after repeated dosing, consistent with the short elimination half-life (t (1/2,λz); 0.4-0.8 hours). Safety findings included cyclical anemia and thrombocytopenia, clinical pathology changes consistent with acute-phase response, leukocyte infiltrates in hepatic sinusoids, and sporadic serum transaminase elevations (typically <3 times upper-limit of normal); all were reversible upon cessation of treatment. Decreased pharmacodynamic responses with time corresponded to the development of anti-rIL-21 antibodies; effects varied among individuals and were dose-dependent. These studies demonstrated rIL-21 to be generally well-tolerated when administered to cynomolgus monkeys, and all adverse effects were reversible upon treatment cessation. However, development of anti-rIL-21 antibodies may limit the use of this species in long-term studies.

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.

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.

Omega-3 fatty acid effects on biochemical indices following cancer surgery.

Epidemiological studies have indicated that a high intake of saturated fat and/or animal fat increases the risk of colon and breast cancer. Laboratory and clinical investigations have shown a reduced risk of colon carcinogenesis after alimentation with omega-3 fatty acids, as found in fish oil. Mechanisms accounting for these anti-tumor effects are reduced levels of PGE(2) and inducible NO synthase as well as an increased lipid peroxidation, or translation inhibition with subsequent cell cycle arrest. Further, omega-3 eicosapentaenoic acid is capable of down-regulating the production and effect of a number of mediators of cachexia, such as IL-1, IL-6, TNF-alpha and proteolysis-inducing factor. In patients with advanced cancer, it is possible to increase energy and protein intake via an enteral or parenteral route, but this seems to have little impact on progressive weight loss. Fish oil administration improved patients' conditions in cancer cachexia and during radio- and chemotherapy. In patients undergoing tumor resection surgery we observed improvement of liver and pancreas biochemical indices when omega-3 fatty acids were administered. This paper is a review of recent developments in the field of nutrition in cancer patients with emphasis on the acute phase response following cancer surgery and the beneficial aspects of fish oil administration.

[Comparative study of the healing process of gastrographies with and without the use of Jatropha gossypiifolia L. (bellyache bush) extract in rats]. / Estudo comparativo da cicatrização de gastrorrafias com e sem o uso do extrato de Jatropha gossypiifolia L. (pião roxo) em ratos.

INTRODUCTION: The healing process of the gastrointestinal tract is of huge importance in the surgical field history, as well as the search for appropriate types of threads and suture techniques and the many factors that influence it. The use of phytotherapic drugs as accelerators of the healing process has been done for many years and is one of the current objectives of scientific researches trying to prove its therapeutic properties. PURPOSE: To evaluate the use of Jatropha gossypiifolia L. extract on the healing process of gastrographies in rats. METHODS: Forty wistar male rats were divided in 2 groups of 20 rats, named control and Jatropha groups. Ten animals of each group were killed in the third day post-surgery and were named control and Jatropha groups of the 3rd day. The remaining 10 animals of each group were killed in the seventh day and were named accordingly for the 7th day. In each animal, gastrostomy and gastrography were performed in a single plane using polypropylene thread 6-0 (Prolene). The animals from the Jatropha group were given a single dose of 200 mg/kg of the Jatropha gossypiifolia L. extract intraperitoneally on the same day of the procedure and the ones from the control group were given the same quantity in milliliters (ml), but of saline solution (sodium chloride 0.9%). The following parameters were evaluated: 1) macroscopic alterations; 2) the suture's resistance to atmospheric air insufflation (pressure of rupture); 3) histologic characteristics. RESULTS: No animal died during the clinical follow-up and optimal healing of the abdominal wall was seen without any signs of infection, dehiscence, abscesses or peritonitis. Healing of the serous surface was considered good in all animals, without occurrence of fistulas; however, intraperitoneal adhesions occurred in 7 rats of the sub-group control and 9 of the sub-group Jatropha on the 3rd day post-operative and in 9 of the sub-group control and 8 of the sub-group Jatropha on the 7th day, but the differences were not statistically significant between the groups. Healing of the mucous surface was classified as good in all the animals. The resistance of the gastrographies to the atmospheric air insufflation showed statistically significant increase of the rupture pressure in the Jatropha group during the 3rd day of observation. Histologic evaluation showed differences that were statistically significant, considered the criteria, as well as reduced acute inflammatory reaction and better coaptation of the edges in the sub-group Jatropha of 7th post-surgery, when compared to the sub-group control of the same period. CONCLUSION: The raw extract of Jatropha gossypiifolia L. aids the healing on the 3rd day post-surgery, concerning the enhanced resistance of the gastrographies to pressure of rupture, and on the 7th day, presenting better coaptation of the edges and reducing acute inflammatory reaction by microscopic analyses.

Estudo comparativo da cicatrização de gastrorrafias com e sem o uso do extrato de Jatropha gossypiifolia L. (pião roxo) em ratos / Comparative study of the healing process of gastrorrhaphies with and without the use of Jatropha gossypiifolia L. (bellyache bush) extract in rats

INTRODUÇÃO:A cicatrização do trato gastrintestinal é de grande importância na história da cirurgia, buscando-se tipos de fios e pontos apropriados e os diversos fatores que a influenciam. O uso de fitoterápicos como aceleradores da cicatrização tem sido feito por muitos anos sendo objetivo atual de pesquisas para a comprovação científica dessas propriedades terapêuticas. OBJETIVO: Avaliar o uso do extrato bruto de Jatropha gossypiifolia L. na cicatrização de gastrorrafias em ratos. MÉTODOS: Foram utilizados 40 ratos Wistar, machos, divididos em dois grupos de 20, denominados de grupos controle e Jatropha. Dez animais de cada grupo foram mortos no 3º dia pós-operatório e denominados subgrupos controle e Jatropha do 3º dia e os 10 restantes de cada grupo foram mortos no 7º dia com a mesma denominação do 7º dia. Em cada animal foi realizado gastrotomia e gastrorrafia em plano único com fio polipropileno 6-0 (Prolene®, Ethicon). Os animais do grupo Jatropha receberam dose única de 200mg/Kg do extrato bruto de Jatropha gossypiifolia L via intraperitoneal no dia do procedimento e os do grupo controle a mesma quantidade em mililitros de solução salina (cloreto de sódio à 0,9%). Foram avaliados os seguintes parâmetros: 1) alterações macroscópicas; 2) a resistência à insuflação de ar atmosférico (pressão de ruptura) da sutura; 3) características histológicas. RESULTADOS: Não houve morte dos animais na evolução clínica, ocorrendo boa cicatrização da parede abdominal, com ausência de sinais de infecção, deiscência, abscessos ou peritonites. A cicatrização da superfície serosa foi considerada boa em todos os animais, não ocorrendo fístulas, porém, as aderências intra-peritoneais ocorreram em sete ratos do subgrupo controle e nove do subgrupo Jatropha do 3º dia pós-operatório e em nove do subgrupo controle e oito do subgrupo Jatropha do 7º dia, não havendo diferenças estatisticamente significantes entre os grupos. A cicatrização da superfície mucosa foi classificada como boa em todos os animais. A resistência das gastrorrafias à insuflação de ar atmosférico demonstrou aumento estatisticamente significante da pressão de ruptura no grupo Jatropha do 3º dia de observação. A avaliação histológica demonstrou diferenças estatisticamente significantes, quanto aos critérios, reação inflamatória aguda menor e coaptação das bordas maior no subgrupo Jatropha do 7º dia pós-operatório em relação ao grupo controle do mesmo período. CONCLUSÃO: O extrato bruto de Jatropha gossypiifolia L. favorece a cicatrização no 3º dia pós-operatório em relação à maior resistência das gastrorrafias à pressão de ruptura, e no 7º dia com melhor coaptação das bordas e reduzindo reação inflamatória aguda à microscopia.

INTRODUCTION: The healing process of the gastrointestinal tract is of huge importance in the surgical field history, as well as the search for appropriate types of threads and suture techniques and the many factors that influence it. The use of phytotherapic drugs as accelerators of the healing process has been done for many years and is one of the current objectives of scientific researches trying to prove its therapeutic properties. PURPOSE: To evaluate the use of Jatropha gossypiifolia L. extract on the healing process of gastrorraphies in rats. METHODS: Forty wistar male rats were divided in 2 groups of 20 rats, named control and Jatropha groups. Ten animals of each group were killed in the third day post-surgery and were named control and Jatropha groups of the 3rd day. The remaining 10 animals of each group were killed in the seventh day and were named accordingly for the 7th day. In each animal, gastrostomy and gastrorraphy were performed in a single plane using polypropylene thread 6-0 (Prolene). The animals from the Jatropha group were given a single dose of 200 mg/kg of the Jatropha gossypiifolia L. extract intraperitoneally on the same day of the procedure and the ones from the control group were given the same quantity in milliliters (ml), but of saline solution (sodium chloride 0.9%). The following parameters were evaluated: 1) macroscopic alterations; 2) the suture's resistance to atmospheric air insufflation (pressure of rupture); 3) histologic characteristics. RESULTS: No animal died during the clinical follow-up and optimal healing of the abdominal wall was seen without any signs of infection, dehiscence, abscesses or peritonitis. Healing of the serous surface was considered good in all animals, without occurrence of fistulas; however, intraperitoneal adhesions occurred in 7 rats of the sub-group control and 9 of the sub-group Jatropha on the 3rd day post-operative and in 9 of the sub-group control and 8 of the sub-group Jatropha on the 7th day, but the differences were not statistically significant between the groups. Healing of the mucous surface was classified as good in all the animals. The resistance of the gastrorraphies to the atmospheric air insufflation showed statistically significant increase of the rupture pressure in the Jatropha group during the 3rd day of observation. Histologic evaluation showed differences that were statistically significant, considered the criteria, as well as reduced acute inflammatory reaction and better coaptation of the edges in the sub-group Jatropha of 7th post-surgery, when comparet to the sub-group control of the same period. CONCLUSION: The raw extract of Jatropha gossypiifolia L. aids the healing on the 3rd day post-surgery, concerning the enhanced resistance of the gastrorraphies to pressure of rupture, and on the 7th day, presenting better coaptation of the edges and reducing acute inflammatory reaction by microscopic analyses.

Effects of blood pressure lowering in the acute phase of total anterior circulation infarcts and other stroke subtypes.

BACKGROUND: Lowering of blood pressure (BP) in the acute phase of stroke is reported both to worsen and to improve the outcome. To investigate whether heterogeneity exists between stroke subtypes in the response to BP lowering, we analysed data from the Intravenous Nimodipine West European Stroke Trial (INWEST). METHODS: INWEST enrolled acute ischaemic stroke patients within 24 h (n = 295) to the following groups: placebo (n = 100), 1 mg/h nimodipine (n = 101) or 2 mg/h nimodipine (n = 94). Patients were retrospectively classified as total anterior circulation infarct (TACI) (i.e. hemiparesis + hemianopia + dysphasia) and non-TACI (exclusion of any one of these). Main outcome measures were neurological (Orgogozo) and functional (Barthel) scores at day 21. RESULTS: 106 patients were labelled as TACI and 62 as non-TACI. No significant difference in BP was observed between the TACI and non-TACI subtypes at baseline, nor did the subtypes differ in BP course within the treatment groups. A higher proportion of non-TACI patients received postrandomisation antihypertensive agents in addition to the study drug compared with TACI patients (55% non-TACI vs. 26% TACI, p < 0.005). For TACI patients, there was no outcome difference between the placebo- and nimodipine-treated groups. For non-TACI patients, placebo had a significantly better neurological (p = 0.004) and functional (p = 0.04) outcome than the high-dose nimodipine group. In multivariate analysis for TACI patients, BP reduction and nimodipine treatment had no relation with outcome. Baseline stroke severity (p < 0.005) was the only significant predictor of the outcome at day 21. For non-TACI patients, diastolic BP (DBP) reduction (p = 0.03) and nimodipine treatment (p = 0.001) were related to neurological deterioration and nimodipine treatment (p = 0.01) to functional deterioration. Systolic BP reduction was associated with neurological (p < 0.005) and functional improvement (p = 0.01). Baseline stroke severity (p < 0.005) was related to both neurological and functional outcome. CONCLUSION: BP lowering and nimodipine treatment had no significant effect on outcome for TACI patients. For non-TACI patients, DBP lowering worsened the neurological outcome and high-dose nimodipine worsened both the neurological and functional outcome.

Modulation of the inflammatory response in the rat TMJ with increasing doses of complete Freund's adjuvant.

OBJECTIVES: Acute inflammation stresses the physiological system, which must respond in order to reestablish homeostasis. The purpose of this study was to determine whether bilateral temporomandibular joint (TMJ) injections of different doses of Complete Freund's Adjuvant (CFA) produced dose-dependent changes in biologic markers of acute inflammation. The ability to establish an animal model with varying degrees of joint inflammation would allow evaluation of agents or conditions that could modulate the severity of the disease. DESIGN: The TMJs of three groups of male Sprague-Dawley rats were injected with CFA containing varying doses of Mycobacterium tuberculosis (MT). A group of non-injected and a group of saline injected rats were used as controls. Food intake, body weights, swelling and chromodacryorrhea were recorded daily. Interleukin-1 beta (IL-1 beta) and corticosterone levels were assayed and condylar cartilage thickness was measured 48 h after injections. RESULTS: Twenty-four hours post-injection, bilateral TMJ swelling and chromodacryorrhea were significantly (P< 0.05) increased following 10 microg of MT and further increased with elevated MT dose. In the CFA groups food intake was attenuated (P< 0.01) 24 and 48 h post-injection and negatively correlated with dose at 24 h. Body weight was also negatively correlated with dose. TMJ retrodiscal tissues IL-1 beta was increased (P< 0.05) in a dose-dependent manner. CFA increased corticosterone (P< 0.05), but this elevation was not dose dependent. Condylar cartilage thickness was decreased in a dose-dependent manner. CONCLUSIONS: These data suggest that an intermediate dose of CFA can be used to effect submaximal levels of TMJ inflammation that will allow experimental modulation in future studies.

Hepatocyte growth factor modulates the hepatic acute-phase response in thermally injured rats.

OBJECTIVE: Hepatocyte growth factor (HGF) has been shown to modulate the acute-phase response in vitro. The specific in vivo role of HGF in this multifactorial response, however, remains unknown. This study examines the effects of exogenous HGF on the acute-phase response in thermally injured rats. DESIGN: Prospective, randomized, laboratory study. SETTINGS: Shriners Hospital for Children and University of Texas Medical Branch laboratories. SUBJECTS: Fifty-six male Sprague-Dawley rats (weight range, 300-325 g). INTERVENTION: Animals received a 60% total body surface area third-degree scald burn and were randomly divided to receive either 400 microg/kg/day i.v. HGF or saline (control). MEASUREMENTS AND MAIN RESULTS: Serum acute-phase proteins, cytokines, and insulin-like growth factor (IGF)-I concentrations, as well as liver weight, protein and triglyceride content, IGF-I concentrations, and cytokine gene expression were measured 1, 2, 5, or 7 days after burn. Serum albumin was increased on days 2, 5, and 7 after burn, and transferrin was increased on day 7 after burn in HGF-treated rats compared with controls (p<.05). HGF increased alpha2-macroglobulin concentrations on postburn days 2, 5, and 7 compared with controls (p<.05). Serum interleukin-6 and tumor necrosis factor-alpha were significantly higher within 2 days of burn in rats treated with HGF (p<.05). HGF increased the hepatic gene expression of tumor necrosis factor-alpha compared with controls (p<.05). Serum IGF-I decreased in rats receiving HGF 1, 2, and 5 days after burn, whereas liver IGF-I concentrations were higher on days 1 and 7 after burn compared with controls (p<.05). Hepatic protein concentrations were higher in the HGF group compared with controls on postburn days 1, 2, and 7, with a concomitant increase in total liver weight (p<.05). HGF exerted a strong mitogenic effect on hepatocytes 1 and 2 days after thermal injury compared with controls (p<.05). CONCLUSIONS: These findings suggest that HGF modulates the acute-phase response in vivo after burn and causes changes in liver morphology.

Insulin-like growth factor I in combination with insulin-like growth factor binding protein 3 affects the hepatic acute phase response and hepatic morphology in thermally injured rats.

OBJECTIVE: To modulate the hepatic acute phase response after a thermal injury by the administration of insulin-like growth factor I (IGF-I) in combination with its principal binding protein 3 (IGFBP-3). SUMMARY BACKGROUND DATA: The hepatic acute phase response is a cascade of events initiated to restore homeostasis after trauma; however, a prolonged response contributes to multiorgan failure, hypermetabolism, complications, and death. Although IGF-1 has been shown to improve cell recovery and play a major role in liver regeneration, its effect on the hepatic acute phase response is not known. METHODS: Sprague-Dawley rats (56 males) received a 60% total body surface area third-degree scald burn and were randomly divided to receive either rhIGF-I/BP-3 (10 mg/kg/day given subcutaneously) or saline (control). Rats were killed on postburn days 1, 2, 5, and 7 and serum glucose, electrolytes, acute phase reactant proteins, tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and rat and human serum IGF-I and IGFBP-3 were measured. Hepatic protein concentrations, hepatocyte proliferation, and hepatocyte apoptosis were determined. RESULTS: No hypoglycemia or electrolyte imbalance could be shown in rats receiving the growth factor complex compared with saline. rhIGF-I/BP-3 increased serum protein on postburn days 2 and 7, albumin on days 5 and 7, and transferrin on days 1, 5, and 7, and decreased haptoglobin and alpha1-acid glycoprotein on postburn days 5 and 7 compared with controls. IGF-I/ BP-3 had no effect on type II acute phase proteins. Rats receiving IGF-I/BP-3 had lower serum levels of interleukin 1 beta and tumor necrosis factor alpha on the first day after burn compared with controls, whereas serum levels of interleukin 6 did not change. rhIGF-I/BP-3 significantly increased total liver protein content on postburn days 1, 2, 5, and 7 compared with controls. IGF-I/BP-3 increased hepatocyte proliferation and decreased hepatocyte apoptosis versus controls. CONCLUSION: In combination with its principal binding protein, rhIGF-I decreases the proinflammatory cytokines interleukin 1 beta and tumor necrosis factor alpha, followed by a decrease in type I acute phase proteins. IGF-I/BP-3 had no effect on interleukin 6 and type II acute phase proteins. Decreases in acute phase protein and proinflammatory cytokine synthesis were associated with increases in constitutive hepatic proteins, total liver protein content, and hepatocyte proliferation. IGF-I/BP-3 attenuates the hypermetabolic response after thermal injury and may improve the clinical outcome.

The combination of growth hormone with hepatocyte growth factor alters the acute phase response.

Recombinant human growth hormone (rhGH) and hepatocyte growth factor (HGF) have both been shown to individually modulate hepatic acute phase reactant proteins and cytokine expression following trauma through different pathways. Recombinant hGH has also been shown to decrease serum and hepatic HGF concentrations after a thermal injury. We hypothesized that the combination of rhGH plus HGF improves the burn-induced acute phase response. Fifty-six male Sprague-Dawley rats received a 60% TBSA third-degree scald burn and were randomly divided to receive either rhGH (2.5 mg/kg/day sc.) plus HGF (200 microg/kg i.v. every 12 h) or placebo (saline). Rats were sacrificed on post-burn days 1, 2, 5, or 7 and serum constitutive and acute phase proteins, TNF-alpha, IL-1beta, IL-6 and liver total protein measured. Hepatic cytokine gene expression, triglyceride concentration, and hepatocyte proliferation were also measured. In rats receiving rhGH/HGF, serum albumin increased on days 5 and 7 and transferrin on day 7 after burn compared to placebo (P<0.05). Haptoglobin decreased 5 days after burn compared to placebo (P<0.05). RhGH/HGF increased serum TNF-alpha on day 2 after burn, while it decreased serum IL-1beta on day 1 after burn compared with placebo (P<0.05). RhGH/HGF had no effect on hepatic cytokine gene expression compared with placebo. Liver total protein content and hepatocyte proliferation increased on days 1, 2, 5, and 7 after burn with rhGH/HGF treatment (P<0.05). These findings indicate that rhGH in combination with HGF exert additive effects on constitutive hepatic proteins and partial inhibitory effects on acute phase protein and cytokine expression. RhGH/HGF has a strong mitogenic effect on hepatocytes.

Fish oil-enriched nutritional supplement attenuates progression of the acute-phase response in weight-losing patients with advanced pancreatic cancer.

The presence of an acute-phase protein response (APPR) has been suggested to shorten survival and contribute to weight loss in patients with pancreatic cancer. Fatty acids derived from fish oil have been shown to alter proinflammatory cytokine production and acute-phase protein synthesis in vitro. The present study was designed to determine the effects of a fish oil-enriched nutritional supplement on the concentrations of a range of individual acute-phase proteins (APP) in patients with advanced pancreatic cancer. In a sequential series, 18 patients with pancreatic cancer received the supplement (providing 2 g eicosapentaenoic acid and 1 g docosahexaenoic acid/d) for 3 wk while another 18 received full supportive care alone. Six healthy subjects served as additional controls. Acute-phase proteins were measured before and after the 3-wk intervention period in cancer patients. At baseline, albumin, transferrin and pre-albumin were significantly reduced and fibrinogen, haptoglobin, alpha-1-acid glycoprotein, alpha-1-antitrypsin, ceruloplasmin and C-reactive protein (CRP) were significantly elevated in the cancer patients compared with healthy controls, reflecting their roles as negative and positive acute phase proteins, respectively. In the supplemented cancer group, the only significant change in APP concentrations over the 4-wk study period was an increase in transferrin. In the control cancer group there were further significant reductions in albumin, transferrin and pre-albumin, and a significant increase in CRP concentration. These results suggest that many positive and negative APP are altered in advanced pancreatic cancer. The APPR tends to progress in untreated patients but may be stabilized by the administration of a fish oil-enriched nutritional supplement. This may have implications for reducing wasting in such patients.

Immune-endocrine interactions in agricultural species: chromium and its effect on health and performance.

The purported performance-enhancing effects of supplemental Cr, as elaborated in studies focusing on beef and dairy cattle models of agricultural stress, affect both immune and endocrine pathways. Furthermore, interactions between the immune and endocrine systems, associated with the actions of insulin and cortisol, may be coordinated through the production of regulatory cytokines. Unlocking the mechanism of action of Cr as a useful farm animal management tool may provide further understanding of the health and performance ramifications of immune-endocrine interactions in agricultural species.

Parenteral zinc supplementation in adult humans during the acute phase response increases the febrile response.

The acute phase response (APR) that follows injury or infection is characterized by a decrease in serum zinc concentrations, which we hypothesized benefits the host. Additionally, we proposed that preventing this decline by supplementing zinc would result in an exaggerated APR as indicated by elevated temperatures, increased serum cytokine concentrations, interleukin 6 and the acute phase protein (ceruloplasmin). A prospective, randomized, double-blinded, clinical trial was conducted. Patients on home parenteral nutrition with a diagnosis of catheter sepsis and patients with a diagnosis of pancreatitis, also on total parenteral nutrition (TPN), were recruited for the study. Following enrollment, block randomization was used to assign patients to receive 0 mg (n = 23) or 30 mg (n = 21) of zinc per day for the first 3 d of TPN. Blood samples for measurement of serum zinc, copper, ceruloplasmin and interleukin-6 were obtained upon enrollment and on d 1 through 3 of TPN. The highest temperatures reported on these days in the medical record were also recorded. Repeated measures ANOVA was used to determine differences in the primary outcome variables over time. No significant differences between groups were observed in serum interleukin-6 or ceruloplasmin concentrations. A significantly higher (P = 0.035) temperature was observed in the zinc-supplemented group compared with the control group on d 3 of parenteral nutrition. We conclude that parenteral zinc supplementation in patients experiencing a mild APR resulted in an exaggerated APR as evidenced by a significantly higher febrile response.

Topical ocular levocabastine reduces ICAM-1 expression on epithelial cells both in vivo and in vitro.

BACKGROUND: Levocabastine is a selective topical H1 antagonist, effective in the treatment of seasonal allergic rhinitis and conjunctivitis. OBJECTIVE: We evaluated the possible effects of levocabastine eye drops on early (EPR) and late phase (LPR) inflammatory changes induced by allergen-specific conjunctival challenge (ASCC). We focused our attention on the possible effect of levocabastine on expression of the intracellular adhesion molecule-1 (ICAM-1) on epithelial cells. Such a phenomenon is likely to play an important role in allergic inflammation. METHODS: The study was a double-blind, placebo-controlled, randomized trial, performed in cross-over, outside the pollen season. Ten out-patients suffering from allergic rhinoconjunctivitis due to parietaria judaica (wall parietary) were enrolled. Patients randomly received levocabastine eye drops (0.5 mg/mL) or placebo eyedrops, one drop in the left eye (right eye as control), 30 min before ASCC. Clinical evaluation (hyperaemia, burning-itching, lacrimation and eyelid swelling) and cytological assessment (number of neutrophils, eosinophils and lymphocytes, and ICAM-1 expression on conjunctival epithelium) were evaluated at baseline, 30 min and 6 h after ASCC. In parallel, we evaluated the in vitro effect of levocabastine at concentrations ranging from 2 x 10(-9) M to 2 x 10(-5) M on ICAM-1 expression and shedding by a continuously cultured differentiated epithelial cell line (WK). RESULTS: Levocabastine reduced symptom scores during EPR (15 min and 30 min, P < 0.002), inflammatory cell infiltration during EPR (P < 0.002 for neutrophils, eosinophils and lymphocytes) and ICAM-1 expression on epithelium both during EPR (P < 0.002) and LPR (P < 0.02). LPR symptom scores and inflammatory cell infiltration were only slightly modified by levocabastine treatment. In vitro levocabastine at 2 x 10(-5) M concentration was able to down-regulate basal ICAM-1 expression, although it exerted no effect on ICAM-1 release by epithelium. CONCLUSION: Levocabastine exerts anti-allergic activity, in that it reduces in vivo inflammatory cell infiltration due to ASCC, and also adhesion molecule expression on conjunctival epithelium. The latter phenomenon may be due, at least in part, to a direct effect of levocabastine on epithelial cells.

[Study on extravascular lung water and polymorphonuclear leukocyte elastase during acute phase following radical treatment of lung cancer: effect of ulinastatin on respiratory functions].

We studied respiratory functions, extravascular lung water (EVLW) as measured by a thermodilution method using double Na indicators, and variations in polymorphonuclear leukocyte elastase (PMNE) during the acute phase following radical treatment of lung cancer, as well as to investigate clinical effect of ulinastatin. Using 16 patients with lung cancer who had undergone surgery of R 2 a or more, 10 patients without ulinastatin therapy were compared with six patients given 300,000 U/day of this drug by drip infusion from Day 0 and 4 of disease. It was found that EVLW value decreased most on Day 1, and gradually increased thereafter but did not return to the preoperative level. PMNE value increased from immediately after surgery and peaked on Day 3, but returned nearly to the preoperative level by Day 5. Although this was different from the variations in EVLW value, there was a correlation between these two parameters on Day 3 when PMNE peaked. Further, ulinastatin tended to inhibit PMNE and improve oxygenation index. Respiratory and circulatory parameters vary in complex manners during the acute phase following radical treatment of lung cancer, and could not be accurately evaluated by means of thermodilution using Na. PMNE is considered a contributing factor to pulmonary tissue disorders following radical treatment of lung cancer, and ulinastatin appeared to be effective in the postoperative management of patients undergoing radical treatment of lung cancer.