臺灣博碩士論文加值系統

足墊皮膚炎(Foot pad dermatitis, FPD) 會造成肉雞產業經濟損失及福祉問題，FPD轉變成潰瘍時可能造成雞隻疼痛及不適，因此，本研究之目的在於探討飼養密度、墊料厚度及更換墊料對台灣紅羽土雞足墊皮膚炎發生率之影響及探尋血清中與發炎相關之蛋白質。試驗共使用480隻商用台灣紅羽土雞，逢機分配至兩種飼養密度(25及35隻雞/欄)及墊料厚度(5及10 cm)，於11週齡時將一半處理組更換新墊料；試驗期間記錄雞隻體重、飼料效率、足墊外觀評分及墊料濕度，並取不同病變等級之雞隻足墊組織供組織切片分析及採血供蛋白質分析。結果顯示，較高的飼養密度及較薄的墊料厚度會降低雞隻最終體重、增加墊料濕度，導致較高之FPD發生率；更換新墊料可顯著使足墊有恢復的狀況。雞隻血清蛋白質二維電泳分析共偵測到103個蛋白質點，其中28個蛋白質點在不同病變等級雞隻間有顯著差異且具有1.5倍以上之改變，經蛋白質胜肽質量指紋分析後成功鑑定其中22個蛋白質點身分，其分屬14個不同蛋白質。基因功能分析結果顯示此等差異表現蛋白質在細胞組成方面，主要位於胞外囊泡，其分子功能主要與蛋白質結合及離子結合有關，並參與運輸及免疫反應等生物過程。不同病變等級雞隻血清iTRAQ蛋白質分析共鑑定出1146個蛋白質，其中135個蛋白質有顯著組間差異且具有1.5倍以上之改變。基因功能分析結果顯示此等差異表現蛋白質主要位於細胞膜(34%)、細胞質(30%)及胞外囊泡(19%)，主要與蛋白質結合(44%)、抗原結合(27%)及離子結合(10%)等分子功能相關，並參與調節免疫反應(33%)、運輸(11%)及訊息傳遞(11%)等生物過程。Heat shock protein 70 (HSP70)、Tenascin、Protein kinase C (PKC)、Ovotransferrin (OVT)、PIT 54, Hemopexin (HX), α-2-macroglobulin (A2M)及α-1-acid glycoprotein (AGP)在患有FPD雞隻血清中表現量較高；Chain B, transthyretin (TTR) 及 preproalbumin (serum albumin) 則在患有FPD雞隻血清中表現量較低。其中HSP70及Tenascin可能做為危險訊息，因而啟動免疫反應，PKC在訊息傳遞過程中扮演活化的角色，OVT、PIT 54、HX、A2M、AGP、TTR及serum albumin為急性期蛋白質，可能有助於清除細胞外血紅素及螯合鐵離子，因此有清除潛在有毒物質、維持鐵離子恆定、抗氧化及抗菌之功能，亦有抑制蛋白酶活性之功能。綜合本研究結果可知，較高的飼養密度及較薄的墊料厚度會造成較高的FPD發生率，且FPD會影響血清中蛋白質的表現，而此等差異表現蛋白質可能與參與啟動免疫反應、訊息傳遞及急性期反應。

Foot pad dermatitis (FPD) is one of the most important welfare problems in meat-type chickens and also causes economic impact on the chicken industry in Taiwan. The FPD may result in pain and discomfort to the chickens when transformed into deep ulcers. The purpose of this study was to investigate the effects of stocking density, litter depth and replacement of wet litter on the prevalence of FPD and to explore proteins associated with inflammation caused by FPD. A total of 480 commercial red-feathered Taiwan country chickens were randomly allocated to two stocking densities (25 and 35 chickens/pen) and two litter thicknesses (5 and 10 cm). At 11 weeks of age, half of the same groups were replaced with new litter. Body weight, feed conversion rate, external score of footpad and litter moisture were recorded. Footpad tissue were collected for histopathological analysis and blood samples were collected for two-dimensional gel electrophoresis (2DE) and isobaric tags for relative and absolute quantification (iTRAQ) analysis. Results indicated that higher stocking density and the thinner litter depth lowered the final body weight, increased litter moisture and induced higher prevalence of FPD. Replacing wet litter with new litter significantly recorvered the FPD. The 2DE analysis revealed that there were 28 out of 103 quantified protein spots differentially expressed among groups and with a minimum of 1.5-fold change. A total of 22 protein spots were identified by mass spectrometry and belonged to 14 different proteins. Gene ontology analysis indicated that most of the differentially expressed proteins located in extracellular exosome. The majority of these proteins involved in transport and immune response and associated with molecular function of protein binding and ion binding. The iTRAQ analysis revealed that there were 135 out of 1146 identified proteins differentially expressed with a minimum of 1.5-fold change. Gene ontology analysis indicated that most of the differentially expressed proteins located in plasma membrane (34%), cytoplasm (30%) and extracellular exosome (19%). The majority of these proteins involved in regulation of immune response (33%), transport (11%) and signal transduction (11%) and associated with molecular function of protein binding (44%), antigen binding (27%) and ion binding (10%). Heat shock protein 70 (HSP70), Tenascin, Protein kinase C (PKC), Ovotransferrin (OVT), PIT 54, Hemopexin (HX), α-2-macroglobulin (A2M) and α-1-acid glycoprotein (AGP) upregulated in the serum of red-feathered Taiwan country chickens with FPD. Transthyretin (TTR) chain B and preproalbumin (serum albumin) downregulated in the serum of red-feathered Taiwan country chickens with FPD. HSP70, Tenascin may act as a danger signal and induced immune reaction. PKC is related to signal transduction. OVT, PIT 54, HX, A2M, AGP, TTR and serum albumin were acute phase proteins that associated with antioxidant, antibacterial and antiprotease activity properties, and also help maintaining homeostasis of iron and scavenging of heme and hemoglobin. In conclusion, higher stocking density and thinner litter depth induce higher prevalence of FPD. FPD changes the expression of serum proteins and the differentially expressed proteins may associated with induced immune reaction, signal transduction and acute phase response.

中文摘要 i
Abstract ii
目錄 iii
表次 v
圖次 vi
壹、前言 1
貳、文獻探討 2
一、台灣土雞之生產概況 2
(一) 台灣土雞產值 2
(二) 足墊皮膚炎對肉雞產業之影響 2
二、家禽之足墊皮膚炎 2
(一) 外觀特徵 2
(二) 組織病理學特徵 5
三、動物福祉 6
(一) 動物福祉之定義與評估 6
(二) 疼痛之定義與評估 8
(三) 足墊皮膚炎在動物福祉之重要性 10
四、影響足墊皮膚炎發生率之因素 11
(一) 墊料品質 11
(二) 飼養密度 12
(三) 季節 12
(四) 營養 12
五、急性期反應 13
(一) 急性期反應機制 13
(二) 急性期蛋白質之功能 14
六、血清蛋白質體之研究與應用 16
(一) 定量蛋白質體學分析 16
(二) 血清蛋白質體應用 17
七、研究目的 18
參、材料與方法 19
一、試驗雞隻之品種、來源、飼養管理及試驗設計 19
二、檢測項目 19
(一) 生長性狀 19
(二) 病理檢查 19
(三) 墊料濕度 20
(四) 血清樣品採集 20
四、以二維電泳分析雞隻血清蛋白質體 21
(一) 血清蛋白質樣品製備 21
(二) 蛋白質二維電泳分析 21
(三) 蛋白質點定量分析 22
(四) 差異表現血清蛋白質點之身分鑑定 22
五、以同重元素相對和絕對定量(iTRAQ)分析雞隻血清蛋白質體 23
(一) 蛋白質樣品製備 23
(二) 蛋白質還原、烷基化及消化(Reduction, alkylation and digestion) 25
(三) iTRAQTM試劑標定 25
(四) 固相萃取(Solid phase extraction, SPE)純化 25
(五) 胜肽樣品分離(Fractionation) 25
(六) 奈米高解析液相層析-電噴灑四極棒飛行時間式串聯質譜儀(nanoUHPLC-ESI-Q-TOF-MS) 26
(七) 資料庫搜尋與蛋白質身分比對 27
六、差異表現血清蛋白質之生物資訊分析 27
七、統計分析 27
肆、結果 28
一、不同墊料厚度、飼養密度及更換墊料對台灣紅羽土雞墊料濕度之影響 28
二、不同墊料厚度、飼養密度及更換墊料對台灣紅羽土雞生長性狀之影響 30
三、不同墊料厚度、飼養密度及更換墊料對台灣紅羽土雞足墊病變之效應 32
四、不同FPD病變等級台灣紅羽土雞血清蛋白質之二維電泳分析結果及蛋白質功能註解 35
五、不同FPD病變等級台灣紅羽土雞血清蛋白質之iTRAQ分析結果及蛋白質功能註解 43
伍、討論 57
一、 飼養密度、墊料厚度及更換墊料對墊料濕度、台灣紅羽土雞生長性狀及足墊病變之影響 57
(一) 飼養密度及墊料厚度對紅羽土雞生長性狀之影響 57
(二) 飼養密度、墊料厚度及更換墊料對雞欄內墊料濕度及足墊病變之影響 58
二、 正常與FPD台灣紅羽土雞血清差異表現蛋白質之功能探討 59
(一) DAMPs激活TLRs signaling pathway誘導發炎基因表現 60
(二) APPs於發炎反應中之相關功能 61
(三) FPD恢復等級雞隻血清差異表現蛋白質之功能 67
陸、結論 69
柒、參考文獻 70

邱芷葳、陳頌方。2015。利用液相多維分離技術進行蛋白質體學之胜肽分餾分析。化學 73:57-66。
陳玉如。2003。質譜技術與蛋白質體學。醫藥基因生物技術教學資源中心。台北，台灣。
陳頌方、黎培鈺、沈蕙如。2007。找尋生物指標的利器: 差異蛋白質體學分析平台之簡介。化學 65:211-224。
行政院農業委員會。2014。農業統計資料。http://agrstat.coa.gov.tw/sdweb/public/inquiry/InquireAdvance.aspx
Abbott, W. W., J. R. Couch, and R. L. Atkinson. 1969. The incidence of foot-pad dermatitis in young turkeys fed high levels of soybean meal. Poult. Sci. 48:2186-2188.
Abd El-Wahab, A., C. F. Visscher, A. Beineke, M. Beyerbach, and J. Kamphues. 2012. Experimental studies on the effects of different litter moisture contents and exposure time to wet litter on development and severity of foot pad dermatitis in young fattening turkeys. Arch. Geflügelk. 76:55-62.
Abudabos, A. M., E. M. Samara, E. O. S. Hussein, M. Q. Al-Ghadi, and R. M. Al-Atiyat. 2013. Impacts of stocking density on the performance and welfare of broiler chickens. Ital. J. Anim. Sci. 12:e11. doi: 10.4081/ijas.2013.e11
Adler, K. L., P. H. Peng, R. K. Peng, and K. C. Klasing. 2001. The kinetics of hemopexin and alpha1-acid glycoprotein levels induced by injection of inflammatory agents in chickens. Avian Dis. 45:289-296.
Aguilera, O., L. M. Quiros, and J. F. Fierro. 2003. Transferrins selectively cause ion efflux through bacterial and artificial membranes. FEBS Lett. 548:5-10.
Alayash, A. I. 1999. Hemoglobin-based blood substitutes: oxygen carriers, pressor agents, or oxidants? Nat. Biotechnol. 17:545-549.
Allain, V., L. Mirabito, C. Arnould, M. Colas, S. Le Bouquin, C. Lupo, and V. Michel. 2009. Skin lesions in broiler chickens measured at the slaughterhouse: relationships between lesions and between their prevalence and rearing factors. Br. Poult. Sci. 50:407-417.
Allison, A. C., and W. Rees. 1957. The binding of haemoglobin by plasma proteins (haptoglobins) — its bearing on the renal threshold for haemoglobin and the aetiology of haemoglobinuria. Br. Med. J. 2:1137-1143.
Andersen, J. D., K. L. Boylan, F. S. Xue, L. B. Anderson, B. A. Witthuhn, T. W. Markowski, L. Higgins, and A. P. Skubitz. 2010. Identification of candidate biomarkers in ovarian cancer serum by depletion of highly abundant proteins and differential in-gel electrophoresis. Electrophoresis 31:599-610.
Anil, S., S. L. Anil, and J. Deen. 2002. Challenges of pain assessment in domestic animals. J. Am. Vet. Med. Assoc. 220:313-319.
Armstrong, P.B. 2010. Role of a2-macroglobulin in the immune responses of invertebrates. Invertebr. Surviv. J. 7:165-180.
Arredouani, M. S., A. Kasran, J. A. Vanoirbeek, F. G. Berger, H. Baumann, and J. L. Ceuppens. 2005. Haptoglobin dampens endotoxin-induced inflammatory effects both in vitro and in vivo. Immunology 114:263-271.
Arredouani, M., P. Matthijs, E. Van Hoeyveld, A. Kasran, H. Baumann, J. L. Ceuppens, and E. Stevens. 2003. Haptoglobin directly affects T cells and suppresses T helper cell type 2 cytokine release. Immunology 108:144-151.
Arroyo, V., R. García-Martinez, and X. Salvatella. 2014. Human serum albumin, systemic inflammation, and cirrhosis. J. Hepatol. 61:396-407.
Asea, A., M. Rehli, E. Kabingu, J. A. Boch, O. Bare, P. E. Auron, M. A. Stevenson, and S. K. Calderwood. 2002. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J. Biol. Chem. 277:15028-15034.
Asea, A., S. K. Kraeft, E. A. Kurt-Jones, M. A. Stevenson, L. B. Chen, R. W. Finberg, G. C. Koo, and S. K. Calderwood. 2000. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat. Med. 6:435-442.
Asehnoune, K., D. Strassheim, S. Mitra, K. J. Yeol, and E. Abraham. 2005. Involvement of PKC alpha/beta in TLR4 and TLR2 dependent activation of NF-kappaB. Cell. Signal 17:385-394.
Athippozhy, A., L. Huang, C. R. Wooton-Kee, T. Zhao, P. Jungsuwadee, A. J. Stromberg, and M. Vore. 2011. Differential gene expression in liver and small intestine from lactating rats compared to age-matched virgin controls detects increased mRNA of cholesterol biosynthetic genes. BMC Genomics 12:95-111.
Badolato, R., J. M. Wang, W. J. Murphy, A. R. Lloyd, D. F. Michiel, L. L. Bausserman, D. J. Kelvin, and J. J. Oppenheim. 1994. Serumamyloid-Ais a chemoattractant— induction of migration, adhesion, and tissue infiltration of monocytes and polymorphonuclear leukocytes. J. Exp. Med. 180:203-209.
Bartlett, J. R., and M. O. Smith. 2003. Effects of different levels of zinc on the performance and immune competence of broilers under heat stress. Poult. Sci. 82:1580-1588.
Baseler, M. W., and R. Burrell. 1983. Purification of haptoglobin and its effects on lymphocyte and alveolar macrophage responses. Inflammation 7:387-400.
Batal, A. B., T. M. Parr, and D. H. Baker. 2001. Zinc bioavailability in tetrabasic zinc chloride and the dietary zinc requirements of young chicks fed a soy concentrate diet. Poult. Sci. 80:87-90.
Baumann, H., and J. Gauldie. 1994. The acute phase response. Immunol. Today 15:74-80.
Bessei, W. 2006. Welfare of broilers: A review. World’s Poult. Sci. J. 62:455-466.
Bell, L. N., J. L. Theodorakis, R. Vuppalanchi, R. Saxena, K. G. Bemis, M. Wang, and N. Chalasani. 2010. Serum proteomics and biomarker discovery across the spectrum of nonalcoholic fatty liver disease. Hepatology 51:111-120.
Bianchi, M. E. 2007. DAMPs, PAMPs and alarmins: all we need to know about danger. J. Leukoc. Biol. 81:1-5.
Bienvenu, J., J. O. Jeppson, and Y. Ingenbleek. 1996 Transthyretin & retinol-binding protein. In Serum Proteins in Clinical Medicine, Ritchie RF, Navolotskaia O, eds. Foundation for Blood Research, Scarborough, pp. 9.011-9.018.
Bilgili, S. F., and J. B. Hess. 1995. Placement density influences broiler carcass grade and meat yields. J. Appl. Poult. Res. 4:384-389.
Bilgili, S. F., J. B. Hess, J. P. Blake, K. S. Macklin, B. Saenmahayak, and J. L. Sibley. 2009. Influence of bedding material on footpad dermatitis in broiler chickens. J. Appl. Poult. Res. 18:583-589.
Blomkalns, A. L., L. L. Stoll, W. Shaheen, S. A. Romig-Martin, E. W. Dickson, N. L. Weintraub, and G. M. Denning. 2011. Low level bacterial endotoxin activates two distinct signaling pathways in human peripheral blood mononuclear cells. J Inflamm 8:4. DOI: 10.1186/1476-9255-8-4
Bode, J. G., U. Albrecht, D. Haussinger, P. C. Heinrich, and F. Schaper. 2012. Hepatic acute phase proteins—Regulation by IL- and IL-1-type cytokines involving STAT3 and its crosstalk with NFkappaB-dependent signaling. Eur. J. Cell Biol. 91:6496-6505.
Boncela, J., I. Papiewska, I. Fijalkowska, B. Walkowiak, and C. S. Cierniewski. 2001. Acute phase protein alpha (1)-acid glycoprotein interacts with plasminogen activator inhibitor type 1 and stabilizes its inhibitory activity. J. Biol. Chem. 276:35305-35311.
Bond, J. E., G. J. Cianciolo, and S. V. Pizzo. 2007. Incorporation of low molecular weight molecules into a2-macroglobulin by nucleophilic exchange. Biochem. Biophys. Res. Commun. 357:433-438.
Borish, L., M. S. King, J. J. Mascali, S. Johnson, B. Coll, and L. J. Rosenwasser. 1992. Transthyretin is an inhibitor of monocyte and endothelial cell interleukin-1 production. Inflammation 16:471-484.
Bowers, E. V., J. J. Horvath, J. E. Bond, G. J. Cianciolo, and S. V. Pizzo. 2009. Antigen delivery by a2-macroglobulin enhances the cytotoxic T lymphocyte response. J. Leukocyte Biol. 86:1259-1268.
Bradshaw, R. H., R. D. Kirkden, and D. M. Broom. 2002. A review of the aetiology and pathology of leg weakness in broilers in relation to welfare. Avian Poult. Bio. Rev. 13:45-103.
Bramanti, V., A. Campisi, D. Tomassoni, A. Costa, A. Fisichella, V. Mazzone, L. Denaro, M. Avitabile, F. Amenta, and R. Avola. 2007. Astroglial-conditioned media and growth factors modulate proliferation and differentiation of astrocytes in primary culture. Neurochem. Res. 32:49-56.
Brodsky, F. M., C. Y. Chen, C. Knuehl, M. C. Towler, and D. E. Wakeham. 2001. Biological basket weaving: formation and function of clathrin-coated vesicles. Annu. Rev. Cell Dev. Biol. 17:517-568.
Bruce, D. W., S. G. Mcilroy, and E. A. Goodall. 1990. Epidemiology of a contact-dermatitis of broilers. Avian Pathol. 19:523-537.
Bruschi, M., G. Candiano, L. Santucci, and G. M. Ghiggeri. 2013. Oxidized albumin. The long way of a protein of uncertain function. Biochim. Biophys. Acta. 1830:5473-5479.
Buda, S. 2000a. Foot pad lesions and the influence of biotin in turkeys. In: H. M. Hafez (ed.), Proceedings of the German Veterinary Medical Society, Institute of Poultry Diseases. Free University, Berlin, Germany, pp. 88-91.
Buda, S. 2000b. Effects of biotin on the skin of turkey foot pads. World Poultry 16:47-48.
Buehler, P. W., B. Abraham, F. Vallelian, C. Linnemayr, C. P. Pereira, J. F. Cipollo, Y. Jia, M. Mikolajczyk, F. S. Boretti, G. Schoedon, A. I. Alayash, and D. J. Schaer. 2009. Haptoglobin preserves the CD163 hemoglobin scavenger pathway by shielding hemoglobin from peroxidative modification. Blood 113:2578-2586.
Buijs, S., E. Van Poucke, F. A. M. Tuyttens, L. Keeling, and S. Rettenbacher. 2009. Stocking density effects on broiler welfare: Identifying sensitive ranges for different indicators. Poult. Sci. 88:1536-1543.
Buresova, V., O. Hajdusek, Z. Franta, D. Sojka, and P. Kopacek. 2009. IrAM—An a2-macroglobulin from the hard tick Ixodes ricinus: Characterizationand function in phagocytosis of a potential pathogen Chryseobacterium indologenes. Dev. Comp. Immunol. 33:489-498.
Cairoli, F., M. Battocchio, M. C. Veronesi, D. Brambilla, F. Conserva, I. Eberini, R. Wait, and E. Gianazza. 2006. Serum protein pattern during cow pregnancy: Acute-phase proteins increase in the peripartum period. Electrophoresis 27:1617-1625.
Campo, J. L., and M. T. Prieto. 2009. Effects of moist litter, perches, and droppings pit on fluctuating asymmetry, tonic immobility duration, and heterophil to lymphocyte ratio of laying hens. Poult. Sci. 88:708-713.
Cantin, A. M., B. Paquette, M. Richter, and P. Larivée. 2000. Albumin-mediated regulation of cellular glutathione and nuclear factor kappa B activation. Am. J. Respir. Crit. Care Med. 162:1539-1546.
Catley, M. C., L. M. Cambridge, Y. Nasuhara, K. Ito, J. E. Chivers, A. Beaton, N. S. Holden, M. W. Bergmann, P. J. Barnes, and R. Newton. 2004. Inhibitors of protein kinase C (PKC) prevent activated transcription: role of events downstream of NF-kappaB DNA binding. J. Biol. Chem. 279:18457-18466.
Ceciliani, F., J. J. Ceron, P. D. Eckersall, and H. Sauerwein. 2012. Acute phase proteins in ruminants. J. Proteomics 75:4207-4231.
Ceciliani, F., V. Pocacqua, A. Miranda-Ribera, V. Bronzo, C. Lecchi, and P. Sartorelli. 2007. A1-acid glycoprotein modulates apoptosis in bovine monocytes. Vet. Immunol. Immunopathol. 116:145-152.
Cengiz, Ö., J. B. Hess, and S. F. Bilgili. 2011. Effect of bedding type and transient wetness on footpad dermatitis in broiler chickens. J. Appl. Poult. Res. 20:554-560.
Ceron, J. J., P. D. Eckersall, and S. Martýnez-Subiela. 2005. Acute phase proteins in dogs and cats: Current knowledge and future perspectives. Vet. Clin. Pathol. 34:85-99.
Chachaj, W., Z. Bartecka, and J. Malolepszy. 1980. Histamine binding-proteins separated from human-sera by the chromatographic method. Arch. Immunol. Ther. Exp. 28:947-951.
Chen, J., G. Tellez, and J. Escobar. 2016. Identification of Biomarkers for Footpad Dermatitis Development and Wound Healing. Front. Cell. Infect. Microbiol. 6:26. doi: 10.3389/fcimb.2016.00026
Chen, W., U. Syldath, K. Bellmann, V. Burkart, and H. Kolb. 1999. Human 60-kDa heat-shock protein: a danger signal to the innate immune system. J. Immunol. 162:3212-3219.
Chevalier, X., N. Groult, B. Larget-Piet, L. Zardi, and W. Hornebeck. 1994. Tenascin distribution in articular cartilage from normal subjects and from patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum. 37:1013-1022.
Chiquet‐Ehrismann, R., and M. Chiquet. 2003. Tenascins: regulation and putative functions during pathological stress. J. pathol. 200:488-499.
Chiquet-Ehrismann, R., and R. P. Tucker. 2004. Connective tissues: signalling by tenascins. Int. J. Biochem. Cell Biol. 36:1085-1089.
Christensen, H. 1996. An insatiable market in southern China and Hong Kong changes a chicken by-product into a snack food. Poult. Market. Technol. May/June:38-41.
Clark, S., G. Hansen, P. McLean, Jr. P. Bond, W. Wakeman, R. Meadows, and S. Buda. 2002. Pododermatitis in turkeys. Avian Dis. 46:1038-1044.
Craig-Barnes, H. A., B. S. Doumouras, and N. Palaniyar. 2010. Surfactant protein D interacts with a2-Macroglobulin and increases its innate immune potential. J. Biol. Chem. 285:13461-13470.
Cravener, T. L., W. B. Roush, and M. M. Mashaly. 1992. Broiler production under varying population-densities. Poult. Sci. 71:427-433.
David, S. A., P. Balaram, and V. I. Mathan. 1995. Characterization of the interaction of lipid A and lipopolysaccharide with human serum albumin: implications for an endotoxin carrier function for albumin. J. Endotoxin Res. 2:99-106.
Dawkins, M. S., C. A. Donnelly, and T. A. Jones. 2004. Chicken welfare is influenced more by housing conditions than by stocking density. Nature 427:342-344.
Debut, M., C. Berri, C. Arneould, D. Guemene, V. Sante´-Lhoutellier, N. Sellier, E. Baeza, N. Jehl, Y. Jego, C. Beaumont, and E. LeBihan-Duval. 2005. Behavioral and physiological responses of three chicken breeds to pre-slaughter shackling and acute heat stress. Br Poult. Sci. 46:527-535.
DeLuca, H. F. 2004. Overview of general physiologic features and functions of vitamin D. Am. J. Clin. Nutr. 80:1689-1696.
DeVon, H. A., M. R. Piano, A. G. Rosenfeld, and D. A. Hoppensteadt. 2014. The association of pain with protein inflammatory biomarkers: A review of the literature. Nurs. Res. 63:51-62.
Dozier, W. A., J. P. Thaxton, S. L. Branton, G. W. Morgan, D. M. Miles, W. B. Roush, B. D. Lott, and Y. Vizzier-Thaxton. 2005. Stocking density effects on growth performance and processing yields of heavy broilers. Poult. Sci. 84:1332-1338.
Dozier, W. A., J. P. Thaxton, J. L. Purswell, H. A. Olanrewaju, S. L. Branton, and W. B. Roush. 2006. Stocking density effects on male broilers grown to 1.8 kilograms of body weight. Poult. Sci. 85:344-351.
Dubin, A. E., and A. Patapoutian. 2010. Nociceptors: the sensors of the pain pathway. J. Clin. Invest. 120:3760-3772.
Duncan, I. J. H., and D. Fraser. 1997. Understanding animal welfare. In Animal welfare (M. C. Appleby and B. O. Hughes, eds). CAB International, Wallingford, England, pp. 19-31.
Dybdahl, B., A. Wahba, E. Lien, T. H. Flo, A. Waage, N. Qureshi, O. F. Sellevold, T. Espevik, and A. Sundan. 2002. Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation 105:685-690.
Dziarski, R. 1994. Cell-bound albumin is the 70-kDa peptidoglycan-, lipopolysaccharide-, and lipoteichoic acid-binding protein on lymphocytes and macrophages. J. Biol. Chem. 269:20431-20436.
Eaton, J. W., P. Brandt, J. R. Mahoney, and J. J. Lee. 1982. Haptoglobin: a natural bacteriostat. Science 215:691-693.
ElGhmati, S. M., E. M. VanHoeyveld, J. A. G. VanStrijp, J. L. Ceuppens, and E. A. M. Stevens. 1996. Identification of haptoglobin as an alternative ligand for CD11b/CD18. J. Immunol. 156:2542-2552.
El-Wahab, A. A., D. Radko, and J. Kamphues. 2013. High dietary levels of biotin and zinc to improve health of foot pads in broilers exposed experimentally to litter with critical moisture content. Poult. Sci. 92:1774-1782.
Ekstrand, C., B. Algers, and J. Svedberg. 1997. Rearing conditions and foot-pad dermatitis in Swedish broiler chickens. Prev. Vet. Med. 31:167-174.
Ekstrand, C., T. E. Carpenter, I. Andersson, and B. Algers. 1998. Prevalence and control of foot-pad dermatitis in broilers in Sweden. Br. Poult. Sci. 39:318-324.
Escobar, G. A., R. C. McIntyre, E. E. Moore, F. Gamboni-Robertson, and A. Banerjee. 2006. Clathrin heavy chain is required for TNF-induced inflammatory signaling. Surgery, 140: 268-272.
Esparza, G. A., A. Teghanemt, D hang, T. L. Gioannini, and J. P. Weiss. 2012. Endotoxin albumin complexes transfer endotoxin monomers to MD-2 resulting in activation of TLR4. Innate Immunity 18:478-491.
Estevez, I., R. C. Newberry, and L. A. Reyna. 1997. Broiler chickens: A tolerant social system? Etologia 5:19-29.
Estevez, I. 2007. Density allowances for broilers: Where to set the limits? Poult. Sci. 86:1265-1272.
Everse, J., and N. Hsia. 1997. The toxicities of native and modified hemoglobins. Free Radic. Biol. Med. 22:1075-1099.
Farquharson, C., C. C. Whitehead, J. S. Rennie, and N. Loveridge. 1993. In vivo effect of 1,25-dihydroxycholecalciferol on the proliferation and differentiation of avian chondrocytes. J. Bone Miner. Res. 8:1081-1088.
Fagoonee, S., J. Gburek, E. Hirsch, S. Marro, S. K. Moestrup, J. M. Laurberg, E. I. Christensen, L. Silengo, F. Altruda, and E. Tolosano. 2005. Plasma protein haptoglobin modulates renal iron loading. Am. J. Pathol. 166:973-983.
FAWC. 2010. Annual Review 2009-2010. Farm Animal Welfare Council. London, UK.
Feddes, J. J., E. J. Emmanuel, and M. J. Zuidhoft. 2002. Broiler performance, body weight variance, feed and water intake, and carcass quality at different stocking densities. Poult. Sci. 81:774-779.
Ferrante, V., S. Lolli, S. Marelli, G. Vezzoli, F. Sırrı, and L. G. Cavalchini. 2006. Effect of light programmes, bird densities and litter types on broilers welfare. XII European Poultry Conference, Verone, Italy. 10-14 September.
Flower, D. R., A. C. T. North, and C. E. Sansom. 2000. The lipocalin protein family: structural and sequence overview. Biochim. Biophys. Acta Protein Struct. Mol. Enzymol. 1482:9-24.
FMI-NCCR. 2003. Animal welfare program, June 2003 Report. Washington, DC.
Fournier, T., N. Medjoubi-N, and D. Porquet, D. 2000. Alpha-1-acid glycoprotein. Biochim. Biophys. Acta. 1482:157-171.
Fukui, H. 2005. Relation of endotoxin, endotoxin binding proteins and macrophages to severe alcoholic liver injury and multiple organ failure. Alcohol. Clin. Exp. Res. 29:172S-179S.
Gaardbo Thomsen, M., 1992. Influence of increasing stocking rates on performance and carcass quality of broilers. Page 285-287 in Proc 4th Eur. Symp. on poultry welfare. C. J. Savory and B. O. Hughes, ed. UFAW, Edinburgh, UK.
Galley, H. F. 2010. Bench-to-bedside review: targeting antioxidants to mitochondria in sepsis. Crit. Care 14:230. DOI: 10.1186/cc9098
Galley, H. F. 2011. Oxidative stress and mitochondrial dysfunction in sepsis. Br. J. Anaesth. 107:57-64.
Gebhardt, K., H. Brenner, T. Stürmer, E. Raum, W. Richter, M. Schiltenwolf, and M. Buchner. 2006. The course of high-sensitive C-reactive protein in correlation with pain and clinical function in patients with acute lumbosciatic pain and chronic low back pain - a 6 months prospective longitudinal study. Eur. J. Pain 10:711-719.
Georgieva1, T. M., V. N. Koinarski, V. S. Urumova, P. D. Marutsov, T. T. Christov, J. Nikolov, T. Chaprazov, K. Walshe, R. S. Karov, I. P. Georgiev, and Z. V. Koinarski. 2010. Effects of Escherichia coli infection and Eimeria tenella invasion on blood concentrations of some positive acute phase proteins (haptoglobin (PIT 54), fibrinogen and ceruloplasmin) in chickens. Rev. Med. Vet. 161:84-89.
Gilar, M., A. Belenky, and B. H. Wang. 2001. High-throughput biopolymer desalting by solid-phase extraction prior to mass spectrometric analysis. J. Chromatogr. A 921:3-13.
Gilbertson-White, S., B. E. Aouizerat, and C. Miaskowski. 2010. Methodologic issues in the measurement of cytokines to elucidate the biological basis for cancer symptoms. Biol. Res. Nurs. 13:15-24.
Gill, C. 1997. Organic trace metal assays. Feed Int. 18:18-22.
Gioannini, T. L., D. Zhang, A. Teghanemt, and J. P. Weiss. 2002. An essential role for albumin in the interaction of endotoxin with lipopolysaccharide-binding protein and sCD14 and resultant cell activation. J. Biol. Chem. 277:47818-47825.
Gitlin, D., and A. Pericelli. 1970. Synthesis of serum albumin, prealbumin, alpha-fetoprotein, alpha-1-antitrypsin and transferrin by the human yolk sac. Nature 228:995-997.
Goetzl, E. J., M. Banda, and D. Leppert. 1996. Matrix metalloproteinases in immunity. J. Immunol. 156:1-4.
Goodman, D. S., T. Peters, J. Robbins, and G. Schwick. 1981. Prealbumin becomes transthyretin. J. Biol. Chem. 256:12-14.
Graversen, J. H., M. Madsen, and S. K. Moestrup. 2002. CD163: A signal receptor scavenging haptoglobin-hemoglobin complexes from plasma. Int. J. Biochem. Cell Biol. 34:309-314.
Greene, J. A., R. M. Mccracken, and R. T. Evans. 1985. A contact dermatitis of broilers—Clinical and pathological findings. Avian Pathol. 14:23-38.
Grimes, J. L., J. Smith, and C. M. Williams. 2002. Some alternative litter materials used for growing broilers and turkeys. World’s Poult. Sci. J. 58:515-526.
Guatteo, R, O. Levionnois, D. Fournier, D. Gue´mene´, K. Latouche, C. Leterrier, P. Morme`de, A. Prunier, J. Servie` re, C. Terlouw, and P. Le Neindre. 2012. Minimising pain in farm animals: the 3S approach – ‘suppress, substitute, soothe’. Animal 6:1261-1274.
Gygi, S. P., and R. Aebersold. 2000. Mass spectrometry and proteomics. Curr. Opin. Chem. Boil. 4:489-494.
Hallquist, N. A., and K. C. Klasing. 1994. Serotransferrin, ovotransferrin and metallothionein levels during an immune response in chickens. Comp. Biochem. Physiol. B. Comp. Biochem. 108:375-384.
Harms, R. H., and C. F. Simpson. 1975. Biotin deficiency as a possible cause of swelling and ulceration of foot pads. Poult. Sci. 54:1711-1713.
Harms, R. H., and C. F. Simpson. 1977. Influence of wet litter and supplemental biotin on foot pad dermatitis in turkey poults. Poult. Sci. 56:2009-2012.
Haslam, S. M. 2003. The development of a unitary index for the assessment of welfare in meat chickens. PhD thesis, University of Bristol. Bristol, UK.
Haslam, S. M., T. G. Knowles, S. N. Brown, L. J. Wilkins, S. C. Kestin, P. D. Warriss, and C. J. Nicol. 2007. Factors affecting the prevalence of foot pad dermatitis, hock burn and breast burn in broiler chicken. Br. Poult. Sci. 48:264-275.
Havlis, J., H. Thomas, M. Sebela, and A. Shevchenko. 2003. Fast-response proteomics by accelerated in-gel digestion of proteins. Anal. Chem. 75:1300-1306.
Havukainen, H., D. Münch, A. Baumann, S. Zhong, Ø. Halskau, M. Krogsgaard, G. V. Amdam. 2013. Vitellogenin recognizes cell damage through membrane binding and shields living cells from reactive oxygen species. J. Biol. Chem. 288:28369-28381.
Heckert, R. A., I. Estevez, E. Russek-Cohen, and R. Pettit-Riley. 2002. Effects of density and perch availability on the immune status of broilers. Poult. Sci. 81:451-457.
Heinrich, P. C., J. V. Castell, and T. Andus. 1990. Interleukin-6 and the acute phase response. Biochem. J. 265:621-636
Herr, K., K. Bjoro, and S. Decker. 2006. Tools for assessment of pain in nonverbal older adults with dementia: a state-of-the-science review. J. Pain Symptom Manage. 31:170-192.
Hester, P. Y. 1994. The role of environment and management on leg abnormalities in meat-type fowl. Poult. Sci. 73:904-915.
Hocking, P. M., and K. Wu. 2013. Traditional and commercial turkeys show similar susceptibility to foot pad dermatitis and behavioural evidence of pain. Br. Poult. Sci. 54:281-288.
Holtet, T. L., K. L. Nielsen, M. Etzerodt, S. K. Moestrup, J. Gliemann, L. Sottrup-Jensen, and H. C. Thu`gersen. 1994. Recombinant a2M receptor binding domain binds to the a2M receptor with high affinity. Ann. NY. Acad. Sci. 737:480-482.
Huang, F., A. Khvorova, W. Marshall, and A. Sorkin. 2004. Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference. J. Biol. Chem. 279:16657-16661.
Huang, S. Y., J. H. Lin, Y. H. Chen, C. K. Chuang, E. C. Lin, M. C. Huang, H. F. S. Sun, and W. C. Lee. 2005. A reference map and identification of porcine testis proteins using 2-DE and MS. Proteomics 5:4205-4212.
Hvidberg, V., M. B. Maniecki, C. Jacobsen, P. H?jrup, H. J. M?ller, and S. K. Moestrup. 2005. Identification of the receptor scavenging hemopexin-heme complexes. Blood 106:2572-2579.
Iwasaki, K., M. Morimatsu, O. Inanami, E. Uchida, B. Syuto, M. Kuwabara, and M. Niiyama. 2001. Isolation, characterization, and cDNA cloning of chicken turpentine-induced protein, a new member of the scavenger receptor cysteine-rich (SRCR) family of proteins. J. Biol. Chem. 276:9400-9405.
Immenschuh, S., and G. Ramadori. 2000. Gene regulation of heme oxygenase-1 as a therapeutic target. Biochem. Pharmacol. 60:1121-1128.
Jacobs, J. M., J. N. Adkins, W. J. Qian, T. Liu, Y. Shen, D. G. Camp, and R. D. Smith. 2005. Utilizing human blood plasma for proteomic biomarker discovery. J. Proteome Res. 4:1073-1085.
Jayalakshmi, T., R. Kumararaj, T. Sivakumar, T. Vanan, and D. Thiagarajan. 2009. Influence of stocking densities on litter moisture, microbial load, air ammonia concentration and broiler performance. J. Vet. Anim. Sci. 5:80-86.
Jones, T. A., C. A. Donnelly, and M. S. Dawkins. 2005. Environmental and management factors affecting the welfare of chickens on commercial farms in the United Kingdom and Denmark stocked at five densities. Poult. Sci. 84:1155-1165.
Jonge, J., H. C. M. Trijp. 2013. The impact of broiler production system practices on consumer perceptions of animal welfare. Poult Sci. 92:3080-3095.
Jurgens, G., M. Muller, P. Garidel, M. H. Koch, H. Nakakubo, A. Blume, and K. Brandenburg. 2002. Investigation into the interaction of recombinant human serum albumin with Re-lipopolysaccharide and lipid A. J. Endotoxin Res. 8:115-126.
Kaneko, J. J. 1997. Serum proteins and the dysproteinemias, p117-138. In: Kaneko JJ, Harvey JW, Bruss ML, editors. Clinical biochemistry of domestic animals. San Diego (CA): Academic Press.
Khan, S. A., and F. H. Khan. 2004. Oxidized caprine alpha-2-macroglobulin: Damaged but not completely dysfunctional. Biochim. Biophys. Acta. 1674:139-148.
Kim, W. K., S. A. Bloomfield, and S. C. Ricke. 2011. Effects of age, vitamin D3, and fructooligosaccharides on bone growth and skeletal integrity of broiler chicks. Poult. Sci. 90:2425-2432.
Kol, A., A. H. Lichtman, R. W. Finberg, P. Libby, and E. A. Kurt-Jones. 2000. Cutting edge: heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells. J. Immunol. 164:13-17.
Kono, H., and K. L. Rock. 2008. How dying cells alert the immune system to danger. Nat. Rev. Immunol. 8:279-289.
Krane, S. M. 1994. Clinical importance of metalloproteinases and their inhibitors. Ann. NY. Acad. Sci 732:1-10.
Kristiansen, M., J. H. Graversen, C. Jacobsen, O. Sonne, H. J. Hoffman, S. K. Law, and S. K. Moestrup. 2001. Identification of the haemoglobin scavenger receptor. Nature 409:198-201.
Krysko, D. V., P. Agostinis, O. Krysko, A. D. Garg, C. Bachert, B. N. Lambrecht, and P. Vandenabeele. 2011. Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol. 32:157-164.
Lee, M. S., and Y. J. Kim. 2007. Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu. Rev. Biochem. 76: 447-480.
Leeson, S., and J. D. Summers. 2001. Scott’s Nutrition of the Chicken. Publ. Univ. Books, Guelph, Ontario Canada.
Levy, A. P., R. Asleh, S. Blum, N. S. Levy, R. Miller-Lotan, S. Kalet-Litman, Y. Anbinder, O. Lache, F. M. Nakhoul, R. Asaf, D. Farbstein, M. Pollak, Y. Z. Soloveichik, M. Strauss, J. Alshiek, A. Livshits, A. Schwartz, H. Awad, K. Jad, and H. Goldenstein. 2010. Haptoglobin: basic and clinical aspects. Antioxid. Redox Signal. 12:293-304.
Lim, W., W. Jeong, J. H. Kim, J. Y. Lee, J. Kim, F. W. Bazer, J. Y. Han, and G. Song. 2011. Differential expression of alpha 2 macroglobulin in response to diethylstilbestrol and in ovarian carcinomas in chickens. Reprod. Biol. Endocrinol. 9:137-146.
Lin, S., H. Yokoyama, V. E. Rac, and S. C. Brooks. 2012. Novel biomarkers in diagnosing cardiac ischemia in the emergency department: a systematic review. Resuscitation 83:684-691.
Lin, Z., A. Lo, D. M. Simeone, M. T. Ruffin, and D. M. Lubman. 2012. AnN-glycosylation analysis of human alpha-2-macroglobulin using an integrated approach. J. Proteomics Bioinform. 5:127-134.
Lindquist, S., and E. A. Craig. 1988. The heat-shock proteins. Annu. Rev. Genet. 22:631-677.
Liu, Y. C., M. R. Lee, C. J. Chen, Y. C. Lin, and H. C. Ho. 2015. Purification of Cu/Zn superoxide dismutase from Piper betle leaf and its characterization in the oral cavity. J. Agric. Food Chem. 63:2225-2232.
Loegering, D. J., and R. L. Michelle. 2011. Protein Kinase C and Toll-Like Receptor Signaling. Enzyme Res. 2011:537821. doi: 10.4061/2011/537821.
Logdberg, L., and L. Wester. 2000. Immunocalins: a lipocalin subfamily that modulates immune and inflammatory responses. Biochim. Biophys. Acta Protein Struct. Mol. Enzymol. 1482:284-297.
Lynn, N., and A. Elson. 1990. Which drinkers reduce possible downgrades. World Poultry 1:11-12.
Lynn, N. J., and H. H. Spechter. 1987. The effect of drinker design on broiler performance, water usage, litter moisture and atmospheric ammonia. FAC report No. 488, Gleadthorpe EHF, MedenVale, Mansfield, Notts, UK.
Ma, H., B. Wang, J. Zhang, F. Li, and J. Xiang. 2010. Multiple forms of alpha-2 macroglobulin in shrimp Fenneropenaeus chinesis and their transcriptional response to WSSV or Vibrio pathogen infection. Dev. Comp. Immunol. 34:677-684.
Mackie, E. J., W. Halfter, and D. Liverani. 1988. Induction of tenascin in healing wounds. J. Cell Biol. 107: 2757-2767.
Manley, P. N., J. B. Ancsin, and R. Kisilevsky. 2006. Rapid recycling of cholesterol: The joint biologic role of C-reactive protein and serum amyloid A. Med. Hypotheses 66:784-792.
Marco-Ramell, A., and A. Bassols. 2010. Enrichment of lowabundance proteins from bovine and porcine serum samples for proteomic studies. Res. Vet. Sci. 89:340-343.
Marco-Ramell, A., R. Pato, R. Peña, Y. Saco, X. Manteca, J. L. Ruiz de la Torre, and A. Bassols. 2011. Identification of serum stress biomarkers in pigs housed at different stocking densities. Br. Vet. J. 190:e66-e71.
Marouga, R., S. David, and E. Hawkins. 2005. The development of the DIGE system: 2D fluorescence difference gel analysis technology. Anal. Bioanal. Chem. 382:669-678.
Martland, M. F. 1984. Wet litter as a cause of plantar pododermatitis, leading to foot ulceration and lameness in fattening turkeys. Avian Pathol. 13:241-252.
Martland, M. F. 1985. Ulcerative dermatitis in broiler chickens: The effects of wet litter. Avian Pathol. 14:353-364.
Martrenchar, A., E. Boilletot, D. Huonnic, and F. Pol. 2002. Risk factors for foot-pad dermatitis in chicken and turkey broilers in France. Prev. Vet. Med. 52:213-226.
Mayne, R. K. 2005. A review of the aetiology and possible causative factors of foot pad dermatitis in growing turkeys and broilers. World’s Poult. Sci. J. 61:256-267.
Mayne, R. K., P. M. Hocking, and R. W. Else. 2006. Foot pad dermatitis develops at an early age in commercial turkeys. Br. Poult. Sci. 47:36-42.
Mayne, R. K., R. W. Else, and P. M. Hocking. 2007a. High litter moisture alone is sufficient to cause footpad dermatitis in growing turkeys. Br. Poult. Sci. 48:538-545.
Mayne, R. K., R. W. Else, and P. M. Hocking. 2007b. High dietary concentrations of biotin did not prevent foot pad dermatitis in growing turkeys and external scores were poor indicators of histopathological lesions. Br. Poult. Sci. 48:291-298.
Mayne, R. K., F. Powell, R. W. Else, P. Kaiser, and P. M. Hocking. 2007c. Foot pad dermatitis in growing turkeys is associated with cytokine and cellular changes indicative of an inflammatory immune response. Avian Pathol. 36:453-459.
McLean, J. A., C. J. Savory, and N. H. C. Sparks. 2002. Welfare of male and female broiler chickens in relation to stocking density as indicated by performance health and behaviour. Anim. Welfare 11:55-73.
McIlroy, S. G., E. A. Goodall, and C. H. McMurray. 1987. A contact dermatitis of broilers—Epidemiological findings. Avian Pathol. 16:93-105.
Mcnamara, P. J., K. R. Brouwer, and M. N. Gillespie. 1986. Autocoid binding to serum-proteins —interaction of platelet-activating-factor (PAF) with human-serum alpha-1-acid glycoprotein (Aag). Biochem. Pharmacol. 35:621-624.
Medzhitov, R., and C. Janeway. 2000. The Toll receptor family and microbial recognition. Trends Microbiol. 8:452-456.
Meluzzi, A., F. Sirri, C. Bianchi, C. Mazzini, and N. Brina. 2003. Benessere nell’allevamento del pollo da carne. Rivista di Avicoltura 72:29-32.
Meluzzi, A., F. Sirri, M. Betti, C. Bianchi, and A. Franchini. 2004. Effect of stocking density, litter depth and light regimen on foot-pad disorders of broiler chickens. In Proceedings 22nd World’s Poultry Congress, İstanbul, turkey.
Meluzzi, A., C. Fabbri, E. Folegatti, and F. Sirri. 2008. Survey of chicken rearing conditions in Italy: Effects of litter quality and stocking density on productivity, foot dermatitis and carcase injuries. Br. Poult. Sci. 49:257-264.
Meluzzi, A., F. Sirri, E. Folegatti, and C. Fabbri. 2008. Effect of less intensive rearing conditions on litter characteristics, growth performance, carcase injuries and meat quality of broilers. Br. Poult. Sci. 49:509-515.
Meuwis, M. A., M. Fillet, P. Geurts, D. de Seny, L. Lutteri, J. P. Chapelle, V. Bours, L. Wehenkel, J. Belaiche, M. Malaise, E. Louis, and M. P. Merville. 2007. Biomarker discovery for inflammatory bowel disease, using proteomic serum profiling. Biochem. Pharmacol. 73:1422-1433.
Michel, V., E. Prampart, L. Mirabito, V. Allain, C. Arnould, D. Huonnic, S. Le Bouquin, and O. Albaric. 2012. Histologically-validated footpad dermatitis scoring system for use in chicken processing plants. Br. Poult. Sci. 53:275-281.
Midwood, K., S. Sacre, A. M. Piccinini, J. Inglis, A. Trebaul, E. Chan, S. Drexler, N. Sofat, M. Kashiwagi, G. Orend, F. Brennan, and B. Foxwell. 2009. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat. Med. 15:774-780.
Mills, K. H. 2011. TLR-dependent T cell activation in autoimmunity. Nat. Rev. Immunol. 11:807-822.
Miranda-Ribera, A., C. Lecchi, V. Bronzo, L. Scaccabarozzi, P. Sartorelli, F. Franciosi, and F. Ceciliani. 2010. Down-regulatory effect of alpha1-acid glycoprotein on bovine neutrophil degranulation. Comp. Immunol. Microbiol. Infect. Dis. 33:291-306.
Moestrup, S. K., and H. J. Moller. 2004. CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann. Med. 36:347-354.
Molony, V., and J. E. Kent. 1997. Assessment of acute pain in farm animals using behavioral and physiological measurements. J. Anim. Sci. 75:266-272.
Monaco, H. L. 2000. The transthyretin-retinol-binding protein complex. Biochim. Biophys. Acta. 1482:65-72.
Montes‐Sandoval, L. 1999. An analysis of the concept of pain. J. Adv. Nurs. 29:935-941.
Moshage, H. 1997. Cytokines and the hepatic acute phase response. J. Pathol. 181:257-266.
Muller-Eberhard, U. 1988. Hemopexin. Methods Enzymol. 163:536-565.
Murata, H., N. Shimada, and M. Yoshioka. 2004. Current research on acute phase proteins in veterinary diagnosis: an overview. Br. Vet. J. 168:28-40.
Myron Johnson, A., G. Merlini., J. Sheldon, and K. Ichihara. 2007. Clinical indications for plasma protein assays: transthyretin (prealbumin) in inflammation and malnutrition. Clin. Chem. Lab. Med. 45:419-426.
Nagaraj, M., C. A. P. Wilson, B. Saenmahayak, J. B. Hess, and S. F. Bilgili. 2007. Efficacy of a litter amendment to reduce pododermatitis in broiler chickens. J. Appl. Poult. Res. 16:255-261.
Nairn, M. E., and A. R. A. Watson. 1972. Leg weakness of poultry—a clinical and pathological characterisation. Austral. Vet. J. 48:645-656.
Nakamura, A., K. Yasuda, H. Adachi, Y. Sakurai, N. Ishii, and S. Goto. 1999. Vitellogenin-6 is a major carbonylated protein in aged nematode, Caenorhabditis elegans. Biochem. Biophys. Res. Commun. 264:580-583.
Nancey, S., N. Hamzaoui, D. Moussata, I. Graber, J. Bienvenu, and B. Flourie. 2008. Serum interleukin-6, soluble interleukin-6 receptor and Crohn’s disease activity. Dig. Dis. Sci. 53:242-247.
NCC. 2005. Animal welfare guidelines and audit checklist. Washington, DC, USA.
Neves, D., L. F. Estrozi, V. Job, F. Gabel, G. Schoehn, and A. Dessen. 2012. Conformational states of a bacterial a2-Macroglobulin resemble those of human complement C3. PLoS ONE 7:e35384. doi:10.1371/journal.pone.0035384
Newton, A. C. 2003. Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem. J. 370:361-371.
NRC. 1994. Nutrient Requirements of Poultry. 9th rev. ed. Natl. Acad. Press, Washington, DC, USA.
Ogawa, K., M. Ito, K. Takeuchi, A. Nakada, M. Heishi, H. Sutol, K. Mitsuishi, Y. Sugitaa, H. Ogawa, and C. Ra. 2005. Tenascin-C is upregulated in the skin lesions of patients with atopic dermatitis. J. Dermatol. Sci. 40:35-41.
Oh, S. K., N. Pavlotsky, and A. I. Tauber. 1990. Specific binding of haptoglobin to human neutrophils and its functional consequences. J. Leukoc. Biol. 47:142-148.
O’Reilly, E. L., R. J. Burchmore, V. Sandilands, N. H. Sparks, C. Walls, and P. D. Eckersall. 2012. The plasma proteome and acute phase proteins of broiler chickens with gait abnormalities. In Editor? Farm animal proteomics pp. 177-180. Wageningen Academic Publishers. Netherlands
O''Reilly, E. L., and P. D. Eckersall. 2014. Acute phase proteins: a review of their function, behaviour and measurement in chickens. World''s Poult. Sci. J. 70:27-44.
Otterbein, L. E., M. P. Soares, K. Yamashita, and F. H. Bach. 2003. Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol. 24:449-455.
Ovelgönne, J. H., W. J. Landman, E. Gruys, A. L. Gielkens, and B. P. Peeters. 2001. Identical amyloid precursor proteins in two breeds of chickens which differ in susceptibility to develop amyloid arthropathy. Amyloid 8:41-51.
Paltrinieri, S. 2008. The feline acute phase reaction. Vet. J. 177:26-35.
Parkitny, L., J. H. McAuley, F. Di Pietro, T. R. Stanton, N. E. O’Connell, J. Marinus, J. V. Jacobus and G. L. Moseley. 2013. Inflammation in complex regional pain syndrome: a systematic review and meta-analysis. Neurology 80:106-117.
Perkins, D. N., D. J. Pappin, D. M. Creasy, and J. S. Cottrell. 1999. Probability-based protein identification by searching sequence database using mass spectrometry data. Electrophoresis 20:3551-3567.
Petek, M., R. Cibik, H. Yildiz, F. A. Sonat, S. S. Gezen, A. Orman, and C. Aydin. 2010. The influence of different lighting programs, stocking densities and litter amounts on the welfare and productivity traits of a commercial broiler line. Vet. Zootec. 51:36-43.
Petek, M., H. Üstüner, and D. Yeşilbağ. 2014. Effects of stocking density and litter type on litter quality and growth performance of broiler chicken. Kafkas Univ. Vet. Fak. Derg. 20:743-748.
Peterson, G. L. 1983. Determination of total protein. Methods Enzymol. 91:95-119.
Petersen, S. V., I. B. Thogersen, Z. Valnickova, M. S. Nielsen, J. S. Petersen, E. T. Poulsen, C. Jacobsen, T. D. Oury, S. K. Moestrup, J. D. Crapo, N. C. Nielsen, T. Kristensen, and J. J. Enghild. 2010. The concentration of extracellular superoxide dismutase in plasma is maintained by LRPmediated endocytosis. J. Free Radic. Biol. Med. 49:894-899.
Pettit-Riley, R., and I. Estevez. 2001. Effects of density on perching behavior of broiler chickens. Appl. Anim. Behav. Sci. 71:127-140.
Philippidis, P., J. C. Mason, B. J. Evans, I. Nadra, K. M. Taylor, D. O. Haskard, and R. C. Landis. 2004. Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery. Circulation research 94:119-126.
Piccinini, A. M., and K. S. Midwood. 2010. DAMPening inflammation by modulating TLR signalling. Mediators Inflamm. doi: 10.1155/2010/672395.
Platt, S., S. Buda, and K. D. Budras. 2001. The influence of biotin on foot pad lesions in turkey poults. pp. 143-148 in Proceedings of the 8th Symposium: Vitamine und Zusatzstoffe in der Ernahrung von Mensch und Tier, Germany. Micro Nutrients, Jena/Thuringia, Germany.
Proudfoot, F. G., H. W. Hulan, and D. R. Ramey. 1979. Effect of 4 stocking densities on broiler carcass grade, the incidence of breast blisters, and other performance traits. Poult. Sci. 58:791-793.
Puron, D., R. Santamaria, J. C. Segura, and J. L. Alamilla. 1995. Broiler performance at different stocking densites. J. Appl. Poult. Res. 4:55-60.
Qiu, F. M., J. K. Yu, Y. D. Chen, Q. F. Jin, M. H. Sui, and J. Huang. 2009. Mining novel biomarkers for prognosis of gastric cancer with serum proteomics. J. Exp. Clin. Cancer Res. 28:126-132.
Rath, N. C., N. B. Anthony, L. Kannan, W. E. Huff, G. R. Huff, H. D. Chapman, G. F. Erf, and P. Wakenell. 2009. Serum ovotransferrin as a biomarker of inflammatory diseases in chickens. Poult. Sci. 88:2069-2074.
Raymond, W. W., S. Su, A. Makarova, T. M. Wilson, M. C. Carter, D. D. Metcalfe, and G. H. Caughey. 2009. A2-Macroglobulin capture allows detection of mast cell chymase in serum and creates a reservoir of angiotensin II-generating activity. J. Immunol. 1:5770-5777.
Rehman, A. A., H. Ahsan, and F. H. Khan. 2013. α-2-Macroglobulin: A physiological guardian. J. Cell Physiol. 228:1665-1675.
Rinaldi, M., F. Ceciliani, C. Lecchi, P. Moroni, and D. D. Bannerman. 2008. Differential effects of a1-acid glycoprotein on bovine neutrophil respiratory burst activity and IL-8 production. Vet. Immunol. Immunopathol. 126:199-210.
Rittner, H. L., H. Machelska, and C. Stein. 2005. Leukocytes in the regulation of pain and analgesia. J. Leukoc. Biol. 78:1215-1222.
Roche, M., P. Rondeau, N. R. Singh, E. Tarnus, and E. Bourdon. 2008. The antioxidant properties of serum albumin. FEBS lett. 582:1783-1787.
Ross, P. L., Y. N. Huang, J. N. Marchese, B. Williamson, K. Parker, S. Hattan, N. Khainovski, S. Pillai, S. Dey, S. Daniels, S. Purkayastha, P. Juhasz, S. Martin, M. Bartlet-Jones, F. He, A. Jacobson, and D. J. Pappin. 2004. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol. Cell. Proteomics 3:1154-1169.
RSPCA. 2002. Welfare standards for chickens. West Sussex, UK.
Rutherford, K. M. D. 2002. Assessing pain in animals. Anim. Welfare 11:31-53.
Salter, D. M. 1993. Tenascin is increased in cartilage and synovium from arthritic knees. Br. J. Rheumatol. 32:780-786.
Sanotra, G. S., L. G. Lawson, and K. S. Vestergaard. 2001. Influence of stocking density on tonic immobility, lameness, and tibial dyschondroplasia in broilers. J. Appl. Anim. Welf. Sci. 4:71-87.
Sanotra, G. S., J. D. Lund, and K. S. Vestergaard. 2002. Influence of light-dark schedules and stocking density on behaviour, risk of leg problems and occurrence of chronic fear in broilers. Br. Poult. Sci. 43:344-354.
Sattar Khan, M. A., S. Nakamura, M. Ogawa, E. Akita, H. Azakami, and A. Kato. 2000. Bactericidal action of egg yolk phosvitin against Escherichia coliunder thermal stress. J. Agric. Food Chem. 48:1503-1506.
SCAHAW, 2000. The welfare of chickens kept for meat production (broilers). Scientific Committee in Animal Health and Animal Welfare. European Commission, Health and Consumer Protection Directorate General, Brussels, Belgium.
Schaible, U. E., and S. H. Kaufmann. 2004. Iron and microbial infection. Nat. Rev. Microbiol. 2:946-953.
Schmid, K., H. Kaufmann, S. Isemura, F. Bauer, J. Emura, T. Motoyama, M. Ishiguro, and S. Nanno. 1973. Structure of alpha1-acid glycoprotein — Complete amino-acid sequence, multiple amino-acid substitutions, and homology with immunoglobulins. Biochemistry 12:2711-2724.
Schneider-Brachert, W., V. Tchikov, J. Neumeyer, M. Jakob, S. Winoto-Morbach, J. Held-Feindt, M. Heinrich, O. Merkel, M. Ehrenschwender, D. Adam, R. Mentlein, D. Kabelitz, and S. Schütze. 2004. Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles. Immunity 21:415-428.
Scott, E. M., A. M. Nolan, and J. L. Fitzpatrick. 2001. Conceptual and methodological issues related to welfare assessment: a framework for measurement. Acta Agri. Scand. Section A-Anim. Sci. 51:5-10.
Seehuus, S. C., K. Norberg, U. Gimsa, T. Krekling, and G. V. Amdam. 2006. Reproductive protein protects functionally sterile honey bee workers from oxidative stress. Proc. Natl. Acad. Sci. U. S. A. 103:962-967.
Shanawany, M. M. 1988. Broiler performance under high stocking densities. Br. Poult. Sci. 29:43-52.
Shao, D., J. He, J. Lu, Q. Wang, L. Chang, S. R. Shi, and T. H. Bing. 2015. Effects of sawdust thickness on the growth performance, environmental condition, and welfare quality of yellow broilers. Poult. Sci. 94:1-6.
Shepherd, E. M., and B. D. Fairchild. 2010. Footpad dermatitis in poultry. Poult. Sci. 89:2043-2051.
Shivakumar, M. C., J. Mulla, B. Pugashetti, and S. Nidagundi. 2004. Performance of broilers reared on different floor space. Indian J. Poult. Sci. 39:72-74.
Singer, M. 2014. The role of mitochondrial dysfunction in sepsis-induced multiorgan failure. Virulence 5:66-72.
Skomorucha, I., R. Muchacka, E. Sosnówka-Czajka, and E. Herbut. 2009. Response of broiler chickens from three genetic groups to different stocking densities. Ann. Anim. Sci. 9:175-184.
Smith, A, and W. T. Morgan. 1978. Transport of heme by hemopexin to liver—evidence for receptor-mediated uptake. Biochem. Biophys. Res. Comm. 84:151-157.
Smith, A., and W. T. Morgan. 1985. Hemopexin-mediated heme transport to the liver—evidence for a heme-binding protein in liver plasma-membranes. J. Biol. Chem. 260:8325-8329.
S?rensen, P., G. Su, and S. C. Kestin. 2000. Effects of age and stocking density on leg weakness in broiler chickens. Poult. Sci. 79:864-870.
Srikanth Babu, B. M., B. Pulla Reddy, V. H. S. Priya, A. Munshi, H. Surekha Rani, G. Suman Latha, V. Dayasagar Rao, and A. Jyothy. 2012. Cytokine gene polymorphisms in the susceptibility to acute coronary syndrome. Genet. Test. Mol. Biomarkers 16:359-365.
Stürmer, T., E. Raum, M. Buchner, K. Gebhardt, M. Schiltenwolf, W. Richter, and H. Brenner. 2005. Pain and high sensitivity C reactive protein in patients with chronic low back pain and acute sciatic pain. Ann. Rheum. Dis. 64:921-925.
Su, G., P. S?rensen, and S. C. Kestin. 2000. A note on the effects of perches and litter substrate on leg weakness in broiler chickens. Poult. Sci. 79:1259-1263.
Su, S. J., and T. M. Yeh. 1996. Effects of alpha 1-acid glycoprotein on tissue factor expression and tumor necrosis factor secretion in human monocytes. Immunopharmacology 34:139-145.
Sun, Z. W., L. Yan, J. P. Zhao, H. Lin, and Y. M. Guo. 2013. Increasing dietary vitamin D3 improves the walking ability and welfare status of broiler chickens reared at high stocking densities. Poult. Sci. 92:3071-3079.
Taira, K., T. Nagai, O. B. I. Takeshi, and K. Takase. 2014. Effect of litter moisture on the development of footpad dermatitis in broiler chickens. J. Vet. Med. Sci. 76:583-586.
Taketani, S., H. Kohno, Y. Naitoh, and R. Tokunaga. 1987. Isolation of the hemopexin receptor from human placenta. J. Biol. Chem. 262:8668-8671.
Tanaka, T., M. Narazaki, and T. Kishimoto. 2014. IL-6 in inflammation, immunity, and disease. Cold Spring Harbor perspect. Biol. 6:a016295.
Tang, D., R. Kang, C. B. Coyne, H. J. Zeh1, and M. T. Lotze. 2012. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol. Rev. 249:158-175.
Taverna, M., A. L. Marie, J. P. Mira, and B. Guidet. 2013. Specific antioxidant properties of human serum albumin. Anaesth. Intensive Care. 3:4.
Theilgaard-Mönch, K., L. C. Jacobsen, M. J. Nielsen, T. Rasmussen, L. Udby, M. Gharib, P. D. Arkwright, A. F. Gombart, J. Calafat, S. K. Moestrup, B. T. Porse, and N. Borregaard. 2006. Haptoglobin is synthesized during granulocyte differentiation, stored in specific granules, and released by neutrophils in response to activation. Blood 108:353-361.
Thomas, D. G., V. Ravindran, D. V. Thomas, B. J. Camden, Y. H. Cottam, P. C. Morel, and C. J. Cook. 2004. Influence of stocking density on the performance, carcass characteristics and selected welfare indicators of of broiler chicken. Vet. J. 52:76-81.
Tolosano, E., and F. Altruda. 2002. Hemopexin: Structure, function, and regulation. DNA Cell Biol. 21:297-306.
Tolosano, E., S. Fagoonee, N. Morello, F. Vinchi, and V. Fiorito. 2010. Heme scavenging and the other facets of hemopexin. Antioxid. Redox Signal. 12:305-320.
Tomhave, A. E., and K. C. Seeger. 1945. Floor space requirements of broilers. Delaware Agric. Exp. Sta. Bull. 255.
Tonack, S., M. Aspinall-O''Dea, R. E. Jenkins, V. Elliot, S. Murray, C. S. Lane, N. R. Kitteringham, J. P. Neoptolemos, and E. Costello. 2009. A technically detailed and pragmatic protocol for quantitative serum proteomics using iTRAQ. J. Proteomics 73:352-356.
Travis, J., and G. S. Salvesen. 1983. Human plasma proteinase inhibitors. Annu. Rev. Biochem. 5:655-709.
Tsai, T. H., E. Song , R. Zhu, C. Di Poto, M. Wang, Y. Luo, R. S. Varghese, M. G. Tadesse, D. H. Ziada, C. S. Desai, K. Shetty, Y. Mechref, and H. W. Ressom. 2015. LC-MS/MS-based serum proteomics for identification of candidate biomarkers for hepatocellular carcinoma. Proteomics 15:2369-2381.
Tseng, D. Y., Y. N. Chen, G. H. Kou, C. F. Lo and C. M. Kuo. 2001. Hepatopancreas is the extraovarian site of vitellogenin synthesis in black tiger shrimp, Penaeus monodon. Comp. Biochem. Physiol., Part A Mol. Integr. Physiol. 129:909-917.
Tucker, S. A., and A. W. Walker. 1999. Hock burn in broilers. Pages 33-50 in Recent Developments in Poultry Nutrition 2. J. Wiseman and P. C. Garnsworthy (Eds.) Nottingham University Press, Thrumpton, UK.
Tufail, M., and M. Takeda. 2008. Molecular characteristics of insect vitellogenins. J. Insect. Physiol. 54:1447-1458.
Turk, R., C. Piras, M. Kovačić, M. Samardžija, H. Ahmed, M. De Canio, A. Urbani, Z. F. Meštrić, A. Soggiu, L. Bonizzi, and P. Roncada. 2012. Proteomics of inflammatory and oxidative stress response in cows with subclinical and clinical mastitis. J. Proteomics 75:4412-4428.
Uhlar, C. M., and A. S. Whitehead. 1999. Serum amyloid A, the major vertebrate acute-phase reactant. Eur. J. Biochem. 265:501-523.
Underwood, E. J., and N. F. Suttle. 1999. The Mineral Nutrition of Livestock. 3rd ed. CABI Publishing, New York, NY, USA.
US Poultry and Egg Export Council. 2009. US chicken feet kicked out of China. http://www.thepoultrysite.com/poultrynews/18142/us-chicken-feet-kicked-out-of-china Accessed July 18. 2016.
Uzum, M. H., and H. D. Oral Toplu. 2013. Effects of stocking density and feed restriction on performance, carcass, meat quality characteristics and some stress parameters in broilers under heat stress. Revue. Med. Vet. 164:546-554.
Vabulas, R. M., P. Ahmad-Nejad, S. Ghose, C. J. Kirschning, R. D. Issels, and H. Wagner. 2002. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J. Biol. Chem. 277:15107-15112.
Van Leuven, F. 1984. Human a2 macroglobulin. Mol. Cell Biochem. 58:121-128.
Wall, P. D. 1992. Defining pain in animals. In: Short, C.E., VanPoznak, A. (Eds.), Animal Pain. Churchill Livingstone, New York, pp. 63-79.
Wang, G., C. Ekstrand, and J. Svedberg. 1998. Wet litter and perches as risk factors for the development of foot pad dermatitis in floor-housed hens. Br. Poult. Sci. 39:191-197.
Watkins, L. R., S. F. Maier, and L. E. Goehler. 1995. Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states. Pain 63:289-302.
Webb, C. M., G. Zaman, J. R. Mosley, R. P. Tucker, L. E. Lanyon, and E. J. Mackie. 1997. Expression of tenascin-C in bones responding to mechanical load. J. Bone Miner. Res. 12: 52-58.
Welfare Quality®. 2009. Welfare Quality® assessment protocol for poultry (broiler, laying hen). Welfare Quality® Consortium, Lelystad, Netherlands.
Whitehead, C. C. 1990. Pages 6-58 in Biotin in Animal Nutrition. Animal Nutrition and Health, Vitamins and Fine Chemicals Division, Roche, Basel, Switzerland.
Wicher, K. B., and E. Fries. 2006. Haptoglobin, a hemoglobin-binding plasma protein, is present in bony fish and mammals but not in frog and chicken. Proc. Natl. Acad. Sci. U. S. A. 103:4168-4173.
Wicher, K. B. and E. Fries. 2010. Evolutionary aspects of hemoglobin scavengers. Antioxid. Redox Signal. 12:249-259.
Wu, K., and P. M. Hocking. 2011. Turkeys are equally susceptible to foot pad dermatitis from 1 to 10 weeks of age and foot pad scores were minimized when litter moisture was less than 30%. Poult. Sci. 90:1170-1178.
Wu, W. W., G. Wang, S. J. Baek, and R. F. Shen. 2006. Comparative study of three proteomic quantitative methods, DIGE, cICAT, and iTRAQ, using 2D gel-or LC-MALDI TOF/TOF. J. Proteome Res. 5:651-658.
Xie, H., G. R. Huff, W. E. Huff, J. M. Balog, and N. C. Rath. 2002a. Effects of ovotransferrin on chicken macrophages and heterophil-granulocytes. Dev. Comp. Immunol. 26:805-815.
Xie, H., G. R. Huff, W. E. Huff, J. M. Balog, P. Holt, and N. C. Rath. 2002b. Identification of ovotransferrin as an acute phase protein in chickens. Poult. Sci. 81:112-120.
Yerbury, J. J., M. S. Rybchyn, S. B. Easterbrook-Smith, C. Henriques, and M. R. Wilson. 2005. The acute phase protein haptoglobin is a mammalian extracellular chaperone with an action similar to clusterin. Biochemistry 44:10914-10925.
Youssef, I. M., A. Beineke, K. Rohn, and J. Kamphues. 2010. Effects of litter quality (moisture, ammonia, uric acid) on development and severity of foot pad dermatitis in growing turkeys. Avian Dis. 55:51-58.
Youssef, I. M. I., A. Beineke, K. Rohn, and J. Kamphues. 2012. Influences of increased levels of biotin, zinc or mannan‐oligosaccharides in the diet on foot pad dermatitis in growing turkeys housed on dry and wet litter. J. Anim. Physiol. Anim. Nutri. 96:747-761.
Zhang, S. C., Y. N. Sun, Q. X. Pang, and X. D. Shi. 2005. Hemagglutinating and antibacterial activities of vitellogenin. Fish Shellfish Immunol. 19:93-95.
Zhang, S., S. Wang, H. Li, and L. Li. 2011. Vitellogenin, a multivalent sensor and an antimicrobial effector. Int. J. Biochem. 43: 303-305.
Zimmermann, M. 1986. Behavioural investigations of pain in animals. In: Duncan, I. J. H., Molony, V. (Eds.), Assessing Pain in Farm Animals. Commission of the European Communities, Luxembourg, pp. 30-35.