, Juraj Payer2 and Manfred Herold3
(1)
National Institute for Rheumatic Diseases, Piestany, Slovakia
(2)
Fifth Department of Internal Medicine, Comenius University University Hospital, Bratislava, Slovakia
(3)
Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria
C1 A component of complement (C), consisting of three subunits, C1q, C1r and C1s. In the classical pathway of activating C, the subunit C1q binds to an immune complex containing an IgM or IgG antibody, which is a signal for the creation of the macromolecular complex C1q-C1r-C1s stabilised by Ca2+ ion and initiation of the whole complement cascade.
C1-inhibitor This is a regulatory glycoprotein of the complement system that binds to C1r and C1s, thereby blocking their activity (C1). What’s more, it facilitates the dissociation of the active C1 component complex and hampers further activation of complement. A hereditary angiooedema develops in the C1-inhibitor deficiency.
C2 A component of the complement system. It is split into C2a and C2b fragments by the C14b enzyme, which is formed after activation of C1 and C4 components. The C2b fragment is a serine protease which participates in further complement activation. The C4b2b complex is formed, which serves as C3-converting enzyme of the classical pathway.
C3 A component of the complement system that plays a central role in all pathways of complement activation. Two polypeptide chains form this glycoprotein. Its molecule has a unique thiolester bond whose hydrolysis is fundamental for the alternative pathway of complement activation. With the action of C3-converting enzymes, it is cleaved to C3a and C3b fragments. The C3a fragment belongs to anaphylatoxins, whilst the C3b fragment can become either a component of C5-converting enzymes or can acquire an opsonising function. The C3b fragment participates in immunoadherence reactions through its CR1 to CR4 receptors localised mainly on professional phagocytes and certain other cells.
C3a receptor A binding receptor for C3a fragment. It is localised on neutrophils (stimulating aggregation, the release of lysosomal content and the formation of reactive oxygen species), macrophages (activation, stimulation of IL-1 secretion) and mast cells (stimulating the release of anaphylaxis mediators).
C3-convertases Enzymes cleaving C3 into C3a and C3b fragments. There are two enzymes: C3-convertase of the classical pathway – C4b–C2a complex and C3-convertase of the alternative pathway – C3bBb complex.
C4 A component of the complement system cleaved by C1s of the activated C1 component into C4a and C4b fragments. The C4a fragment belongs to anaphylatoxins, whilst the C4b fragment is a component of a C3-converting enzyme of the classical pathway (C4b2b). C4 and C2 deficiency is often associated with systemic lupus erythematosus or glomerulonephritis.
C4BP A protein binding C4b fragment, regulatory molecule of the complement system. It regulates the activity of C4b fragment.
C5 A glycoprotein composed of two polypeptide chains. The C5-converting enzymes cleave it into C5a and C5b fragments. The C5a fragment has anaphylatoxic (anaphylatoxins) and chemotactic activities towards professional phagocytes. The C5b fragment couples with the C6 component, thereby creating a membrane-attacking complex (complement, MAC). A very rare C5 deficiency manifests in increased sensitivity to Neisseria-induced infections.
C5a receptor A receptor specifically binding the C5a fragment. It is localised on mast cells and basophils (anaphylaxis), professional phagocytes (chemotaxy, release of the content of granules, stimulation of reactive oxygen species production) and thrombocytes (stimulation of the aggregation and release of the content of granules).
C6 A component of the complement system that is a part of the membrane-attacking complex (complement, MAC).
C7 A component of the complement system that is a part of the membrane-attacking complex.
C8 A component of the complement system that is a part of the membrane-attacking complex.
C9 A component of the complement system that is a typical perforin. After binding to the C5b678 complex, it polymerises and so creates a definitive structure of membrane-attacking complex, which enables the formation of a number of holes in the cytoplasmic membrane of target cells and, consequently, its lysis.
Calcaneal spur A spur under the heel bone, which occurs particularly in older individuals and may cause pain during walking (plantar fasciitis). Treatment is based on the use of a special relieving insert.
Calcific tendinitis Deposition of calcium in tendons, often leading to inflammation. Symptoms include chronic and relapsing pain. Acute painful inflammation develops when the calcification infiltrates the subacromial bursa referred to as bursitis calcarea.
Calcifying tendinopathies, enthesopathies and periarthritis Calcific tendinitis, bursitis or enthesitis are characterised by the presence of hydroxyapatite microcrystals (calcium phosphate) at the point of the damaged tendon and its insertion, which may penetrate into the adjacent bursa in the form of crystals. In calcifying periarthritis, the crystals accumulate in the periarticular fibrous tissue.
Calcineurin A protein phosphatase specific for serine and threonine. It is an enzyme that eliminates the phosphate groups binding the above-mentioned amino acids from proteins. This dephosphorylation of the proteins has a significant regulatory effect on their biological activities. In T lymphocytes, calcineurin stimulates the transcription factor NF-AT, which activates the promotor region of the gene coding for IL-2. The immunosuppressive agents cyclosporin A and tacrolimus fuse in lymphocytes in the presence of immunophilins, and the resulting complex inhibits calcineurin. This leads to an IL-2 deficiency and blocks T-lymphocyte activity.
Calcitonin A polypeptide hormone eliminated by mammals through parafollicular cells of the thyroid gland and in more primitive animals through ultimobranchial bodies. It has hypocalcaemic effects and attenuates bone resorption. By acting on receptors located on osteoclasts, it reduces their activity and survival. It was one of the first antiresorptive preparations in the treatment of osteoporosis. Predominantly, the salmon calcitonin was used, which was replaced by recombinant human hormone in the form of a nasal spray. In 2012, due to higher incidence of malignant diseases in patients treated with calcitonin, the distribution of calcitonin in the form of a nasal spray was suspended, and its use in injection form was limited.
Calcitriol 1,25-dihydroxycholecalcipherol is active form of vitamin D in the body. Through its action on the intestine, kidneys and bone tissue, it increases calcium plasma concentration. In the treatment of osteoporosis, it is significant in patients with defect in vitamin D hydroxylation in liver (position 25) or kidneys (position 1), either as a result of some chronic disease of these organs, adverse effect of administered pharmaceuticals or decreased alpha-hydroxylase kidney activity in advanced age. Calcitriol deficiency leads to the development of hypocalcaemia with increased parathyroid hormone secretion.
Calcium oxalate calcification A calcification process caused by calcium oxalate microcrystals. It is a sign of hyperoxalemia occurring due to disturbance of the internal environment, especially in dialysis patients.
Calcium requirements in diet Amongst other things, sufficient intake of calcium from the diet is inevitable for reaching genetically predetermined peak bone mass in emerging adulthood. Calcium attenuates parathyroid hormone secretion and increases the level of endogenous calcitonin, which suppresses osteoresorption. Most calcium is found in milk and dairy products; in case their restricted intake is a must, it often has to be pharmacologically supplemented. In adults, a total calcium intake up to approximately 2000 mg daily may still be regarded as safe. Higher doses may lead to adverse effects (constipation, nephrolithiasis).
Optimal daily supply of calcium (mg)
Age | Dose in mg | |
|---|---|---|
Children | 0–6 months | 400 |
6–12 months | 600 | |
1–5 years | 800 | |
6–10 years | 800–1200 | |
Adolescents | 11–24 years | 1200–1500 |
Men | 25–65 years | 1000 |
Over 65 years | 1500 | |
Women | Since 25 years to menopause | 1000 |
Postmenopausal, using HRT | 1000 | |
Postmenopausal, without HRT | 1200–1500 | |
Older than 65 years, pregnant, breastfeeding | 1200–1500 |
A daily calcium intake of up to 2000–2500 mg is considered safe. It is hazardous only in patients with nephrolithiasis and increased absorption of calcium from the intestine. Higher doses are usually unnecessary and may have adverse effects (constipation, renal stones). If the patient does not ingest enough calcium in the diet (intolerance of milk products, high fat content in the ingested products, etc.), then there are a number of calcium preparations available.
Canakinumab Canakinumab (Ilaris®) is a selective, fully human, monoclonal antibody that inhibits IL-1 beta. Canakinumab is approved in more than 60 countries, including in the EU, USA, Switzerland and Japan for the treatment of cryopyrin-associated periodic syndromes (CAPS) in adults and children aged 2 years and older with a body weight of 7.5 kg or above. CAPS are a group of rare, lifelong, genetic, autoinflammatory diseases based on a defect in the gene that produces a protein called cryopyrin which leads to inflammation with symptoms such as fever, rash, joint pain and tiredness. Canakinumab is also approved in systemic juvenile idiopathic arthritis (SJIA) in patients aged 2 years and older who have active disease and have not responded adequately to NSAIDs and systemic corticosteroids. Canakinumab is used on its own or in combination with methotrexate. Children with a body weight of 7.5 kg or above are given 4 mg per kilogram body weight (up to a maximum dose of 300 mg) as subcutaneous injection every 4 weeks.
Canakinumab may be used for the treatment of patients with acute gouty arthritis who suffer frequent attacks and whose symptoms cannot be managed with current treatment options. The recommended dose is 150 mg given as a single injection under the skin as soon as possible after the start of an attack. For patients who require further doses, there should be an interval of at least 12 weeks between two applications.
CaSR – calcium-sensing receptor A membrane receptor monitoring extracellular concentration of calcium ions. When increased, it activates phospholipase C through G protein, which results in increase of intracellular calcium concentration and decrease of parathyroid hormone secretion. In a homozygote, its inactivating mutation leads to a serious, life-threatening hypercalcaemia; in a heterozygote, a so-called benign familial hypocalciuric hypercalcaemia (see term) is developed. Effects of the receptor may be influenced pharmacologically. Calcimimetics (e.g. cinacalcet) activate the receptor and subsequently attenuate parathyroid hormone secretion. They can be used in secondary hyperparathyroidism, for example, in renal failure. On the contrary, calcilytics attenuate the receptor, and their potential to be used in osteoporosis therapy is explored, as there is a possibility of slight and regulated stimulation of secretion of parathyroid hormone with anabolic effect on the bone tissue.
Caplan’s syndrome – see Rheumatoid pneumoconiosis (Caplan’s syndrome).
Capsular pattern With certain joints (shoulder, hip, etc.), in the course of a pathological process such as in osteoarthrosis, upon furrowing of the capsule movement limitation appears always in the specific predilection direction earlier than in other directions. Cyriax (Dr. James Cyriax, 1905–1985, Orthopaedic Surgeon in England) referred to this evolutional sequence of movement pattern typical for the given joint ‘capsular pattern’. In the shoulder joint, it begins with limitation of external rotation then abduction and ends with limitation of internal rotation. In the hip joint, it begins with internal rotation, followed by abduction, and ending with external rotation.
Carpal tunnel syndrome (CTS) This is the most frequently occurring peripheral nerve compression syndrome. It accounts for 20 % of all compression syndromes and is the cause of 50 % of all cases of brachialgia. It is twice as frequent in women than in men and usually occurs after the age of 50. The dominant hand is affected more frequently, and in the case of bilateral impairment, more serious lesions affect the dominant site.
► Clinical symptoms
The most frequent symptom of CTS is nocturnal paraesthetic brachialgia. Patients wake up in the night experiencing paraesthesiae and a subjective feeling of finger oedema; however, there are no objective signs of the oedema. The pain may radiate up to the elbow and shoulder. Massage, change of the position of upper limb or ‘shaking’ the hand may provide relief. The feeling of clumsy fingers and finger paraesthesiae gradually subsides in the morning.
Caspases Cysteine aspartate-specific proteases are enzymes cleaving the polypeptide chain between the aspartic acid and any other amino acid using a cysteine residue. They have a fundamental role at the start of cellular apoptosis, in inflammatory reactions (mainly in the nervous tissue) and in the proteolytic conversion of inactive cytokine precursors, such as pro-interleukin-1β, which is converted by caspase 1 (termed also ICE–IL-1β converting enzyme) to an active IL-1β. Currently, ten different caspases are known, termed caspase 1–10. Caspases 1, 4 and 5 participate mainly in inflammatory responses, whilst caspases 2, 3 and 10 play an exclusive role in initiating apoptosis.
‘Knock-out’ mice that lack the gene coding for caspase 1 are unable to produce IL-1, have significantly reduced levels of IFN-γ and are resistant to the endotoxin shock induced by lipopolysaccharide. Mice without the gene coding for caspase 3 lack the ability to eliminate neurons impaired by apoptosis, which leads to a number of abnormalities especially in the brain tissue. The caspases are synthesised in the form of enzymatically inactive precursor proteins. Their conversion to active forms is accomplished following contact of the Fas receptor with Fas ligand, TNF-α with its receptor, via activity of granzyme B (granzymes) and perforins released from cytotoxic T lymphocytes and NK-cells (which is the essence of their cytotoxic effect) or by autoproteolysis. The proteolytic reactions made by caspases result in interruption of the cell cycle, elimination of homeostatic and reparation mechanisms, initiation of the separation of individual cells from its surrounding tissue, disintegration of structural components of the cell and the labelling of dying cells for ingestion by macrophages. The activity of caspases is controlled by several natural or synthetic inhibitors.
CaSR (calcium-sensing receptor) modulators Newly developed preparations influencing CaSR are divided into calcimimetics and calcilytics. The calcimimetics activate CaSR thereby inhibiting the secretion of PTH. Currently, cinacalcet is the only available calcimimetic drug used mainly in the treatment of secondary hyperparathyroidism in patients with chronic renal disease. The calcilytics are CaSR antagonists inhibiting CaSR thereby stimulating the secretion of PTH. At present, NPS 2143 is the only representative of calcilytics. The calcilytics are regarded as a possible future alternative for the treatment of postmenopausal osteoporosis, because of a presumed osteoformation effect due to a regular, repeated and mild increase of PTH secretion. Ca SR modulators are regarded as prospective preparations for the treatment of disturbances of phosphate-calcium metabolism.
Cauda equina syndrome (CES) A potentially serious neurological disease causing saddle anaesthesia, bilateral weakness of the calf muscles, Achilles tendon areflexia, dysfunction of the ano-vesico-genital area with impairment of sphincters and impotence, as well as polyradicular pain of lumbar and sacral nerve roots. The syndrome is most frequently caused by herniation of an intervertebral disc into sacral roots of the spine, rarely by malignancies or by a late form of ankylosing spondylitis. Chronic compression of the cauda has an indistinct course, which can be manifested only by ano-vesicular sphincters impairment and radicular pain in the lower extremities. The diagnosis of CES in patients suffering from lumbar pain requires urgent surgical intervention.
Causalgia A burning pain sensation after a painful stimulus. It is elicited by damage to the sympathetic nervous system. The sensation is localised to the area of innervation of the injured nerve or its surrounding environment. It is linked to autonomic changes (trophic, vascular).
CD (cluster of differentiation) The CD system is a group of surface attributes (antigens) on cells according to which it is possible to establish the type, the differentiation and developmental stage of the cell or certain other characteristics
CD1 Glycoprotein molecules which are connecting with beta2-microglobulin into dimer similar to antigen HLA class I. They are far less polymorph than alpha-chains of antigen HLA class I.
CD2 (LFA-2) This transmembrane glycoprotein is localised especially on thymocytes and adult T lymphocytes. It is a receptor adsorbing sheep erythrocytes and so creates the basis for various rosette tests for determining T-cell counts. The adhesive molecule LFA-3 is a natural ligand for CD2.
CD3 This is a complex molecule composed of five polypeptide chains – members of the immunoglobulin superfamily – linked with antigen receptors of T-cells (TCR). It is a typical marker for all adult T lymphocytes. CD3 transmits the signal from TCR into the cell.
CD4 A glycoprotein belonging to the immunoglobulin superfamily is a typical surface marker for T-helper (TH) lymphocytes. In much lower counts, it also appears on the surface of macrophages, monocytes, dendritic cells, cells of Langerhans and several others. It participates in the presentation of exogenous antigens by antigen-presenting cells in the form of a complex with MHC class II of HLA antigens. It serves as a receptor for HIV infection, leading to AIDS.
CD5 A single-chain glycoprotein localised on B lymphocytes, as well as on T lymphocytes. B-cells can be divided into the two subsets CD5+ and CD5− depending on the presence or absence of CD5. The CD5+-cells produce natural antibodies, primarily of IgM isotype, enforcing the elimination of ill-conditioned or unnecessary inherent antigens and cell structures. An increased CD5+-cell count has been found in certain autoimmune disorders (juvenile diabetes mellitus, Hashimoto’s thyroiditis and systemic lupus erythematosus). The cause for the increased autoantibody formation can be due to the fact that CD5+-cells produce IL-10, which inhibits the activity of TH1-cells, shifting the TH1/TH2 balance towards increased activity of TH2-cells and thus increased autoantibody formation. The CD72 is the ligand for CD5.
CD8 A transmembrane glycoprotein which is a member of the immunoglobulin superfamily and a typical surface sign of cytotoxic (TC) T lymphocytes. They participate in recognising antigens on the surface of the target cells, where they are present in the form of a complex of immunogenic peptides with MHC class I of HLA antigens.
CD11 This is a family of three different glycoproteins forming α-chains (CD11a, CD11b and CD11c), which together with an identical β-chain (characterised by differentiation antigen CD18) create three heterodimeric molecules of leukoadhesive integrins: LFA-1 (CD11a/CD18), Mac-1 or CR3 (CD11b/CD18) and gp150,95 or CR4 (CD11c/CD18). They participate mainly in adhesive interactions between leucocytes and endothelial cells during initiation of inflammatory reactions. Their ligands (anti-receptors) on the endothelial cells are intercellular adhesive molecules ICAM-1 (CD54) and ICAM-2 (CD102).
CD15 An adhesive polysaccharide antigen referred to as Lewis’ antigen X. It is localised on the surface of neutrophils and other leucocytes. Via weak adhesive reactions with selectins E and P (selectins) on the surface of endothelial cells, it creates a background for the ‘rolling’ of leucocytes over the endothelium (in inflammation).
CD16 A differentiation antigen having the function of a low-affinity Fc receptor for IgG (FcγRIII). It is localised on the surface of neutrophils, macrophages, eosinophils and NK-cells. It facilitates the phagocytosis of particles opsonised by IgG antibodies and participates in ADCC (antibody-dependent cellular cytotoxicity) reactions. It is regarded a typical feature of NK-cells.
CD19 An antigen found on the surface of all B lymphocytes (characteristic feature of B-cells).
CD20 A non-glycosylated phosphoprotein expressed on the surface of all mature B-cells. Its function is unknown. It is a useful marker in B-cell lymphomas, hairy cell leukaemia and B-cell chronic lymphatic leukaemia. It is the target for the monoclonal antibody (rituximab) in the treatment of lymphoma, and B-cell-mediated diseases such as systemic lupus erythematosus and rheumatoid arthritis.
CD21 An antigen found on the surface of all B lymphocytes (characteristic feature of B-cells) and follicular dendritic cells. It functions as the receptor for the C3d fragment of the complement (CR2), as well as a receptor for the Epstein–Barr virus.
CD22 A typical surface antigen found on all B lymphocytes (characteristic feature of B-cells). It is lost during transformation of a B lymphocyte to a plasma cell (secreting antibodies).
CD25 A single-chain glycoprotein creating the α-chain of the receptor for interleukin-2 (IL-2R). It is localised on activated T and B lymphocytes and macrophages.
CD28 This glycoprotein homo-dimer can be found on T lymphocytes and serves as a co-stimulatory molecule whose ligand is the CD80 (B7) antigen on antigen-presenting cells and B lymphocytes. The CD28-CD80 interaction provides the lymphocytes with a second co-stimulatory signal that is fundamental for their activation.
CD31 This is an adhesive molecule referred to also as PECAM-1 (platelet/endothelial cell adhesion molecule). It is localised on the surface of the granulocytes, monocytes, macrophages, B lymphocytes, NK-cells and endothelial cells. It is of cardinal importance in transendothelial migration of leucocytes to the focus of inflammation.
CD35 An antigen representing CR1, the receptor for C3b and C4b fragments of complement. It can be found on a number of cells including neutrophils, eosinophils, monocytes, B-cells and erythrocytes. It plays an important role in eliminating circulating immune complexes.
CD40 A co-stimulatory molecule localised on the surface of B lymphocytes. The CD40L molecule, found on the surface of T-helper lymphocytes, is the ligand of CD40. The CD40–CD40L interaction provides the B-cell with a second signal necessary for its transformation to an antibody synthesising plasma cell.
CD44 A transmembrane molecule found on the surface of leucocytes, erythrocytes and thrombocytes. It functions as a receptor for hyaluronic acid. Through the CD44 molecule, the cell can bind to the intercellular substance and accomplish other adhesive reactions, especially those between leucocytes and endothelial cells, during initiation of the inflammatory reaction but also during nidation of cancer cells in the course of a metastatic process. In line with the above-mentioned, the increased expression of CD44 is found on metastasising cells or, for example, on epithelial cells in patients with bronchial asthma.
CD45 This membrane glycoprotein is found in a great number of copies on all haematopoietic cells except erythrocytes and thrombocytes. It exists in at least eight isoforms where the CD45RA molecule is typical for memory and activated T-cells. The individual isoforms differ in molecular weight, but they all possess a cytoplasmic component with protein tyrosine phosphatase activity. Through its effect, the tyrosine units of membrane glycoproteins can dephosphorylate and so modulate the transmission of activating signals into the cell.
CD46 Regulatory factor of the complement system MCP (membrane cofactor protein) found on the surface of haematopoietic and other cells. It regulates the activation of complement via cleavage of the C3b component thereby preventing the activation of other complement components in its proximity. Its presence on trophoblast cells contributes to mother’s tolerance to the foetus. This has been proven by clinical experience where women lacking the CD46 molecule on their trophoblast cells suffer miscarriages. Another regulatory factor of complement, DAF (CD55) acts in a similar way.
CD50 The intercellular adhesive molecule ICAM-3, which is a ligand for LFA-1 (CD11), belongs to the immunoglobulin superfamily and is found mainly on differentiated leucocytes.
CD54 The intercellular adhesive molecule ICAM-1, whose ligand is LFA-1 (CD11), is localised mainly on endothelial cells and follicular dendritic cells. It is also a receptor for rhinovirus.
CD55 A single-chain glycoprotein bound to phosphatidylinositol and found on the surface of haematopoietic and other cells, where it functions as a regulator of the complement system (DAF, CD46).
CD56 This adhesive molecule is the basic differentiation antigen of NK-cells. It can be found also on neurons (N-CAM).
CD58 A single-chain adhesive glycoprotein mainly found on haematopoietic and other cells. It is also referred to as LFA-3 (leucocyte function antigen 3) and is a ligand for the CD2 antigen.
CD62 A family of adhesive molecules (selectins) that includes three members: CD62E, E-selectin (found especially on endothelial cells); CD62L, L-selectin (found on the surface of granulocytes and lymphocytes); and CD62P, P-selectin (found on endothelial cells and thrombocytes).
CD64 A single-chain glycoprotein with a function for the high-affinity Fc receptor for IgG (FcγRI). It is localised on macrophages and monocytes.
CD66 A family of at least five antigens that are found on neutrophils (CD66a), eventually on all granulocytes (CD66b) and on certain cancer cells. For instance, CD66c is a typical antigen of neutrophils and colorectal carcinoma cells and CD66e which is also referred to as a carcinoembryonic antigen (CEA).
CD72 A heterodimeric glycoprotein, which is a typical feature of B lymphocytes and is a ligand for CD5.
CD79 A group of two transmembrane glycoproteins that are components of the antigen receptor of B lymphocytes (antigen receptors). The CD79a represents an Igα chain (having been referred to as MB1), whilst the CD79b represents Igβ chain (B29). They are localised on the surface of all adult B lymphocytes.
CD80 A co-stimulatory molecule found on the surface of antigen-presenting cells, including B lymphocytes. Its ligand is CD28.
CD88 An antigen on granulocytes, mast cells, macrophages and smooth muscle cells. It is a receptor for anaphylatoxin C5a.
CD102 An adhesive molecule belonging to the immunoglobulin superfamily and is found on the endothelial cells, lymphocytes and monocytes. It is also referred to as ICAM-2. Its anti-receptor on the leucocytes is the integrin LFA-1 (CD11).
CD106 A vascular cell adhesive molecule (VCAM-1) that is found on the cells of vascular endothelium, and during the transendothelial migration of leucocytes, it reacts with VLA-4 (CD49d/CD29) molecules on their surface (inflammation).
CD115 An antigen present on monocytes, on macrophages and on the placenta. It acts as the receptor for macrophage colony-stimulating factor (M-CSFR).
CD116 An antigen present on monocytes, macrophages, neutrophils, eosinophils, fibroblasts and endothelial cells. It acts as a receptor for granulocyte and macrophage colony-stimulating factor (GM-CSFR).
CD117 An antigen present on the progenitor cells of bone marrow. It acts as the receptor for stem cell growth factor (SCFR), also referred to as c-kit.
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