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PubMed1980

Immunochemical quantitation of serum complement components in SFD and AFD infants.

Components of complement (protein concentrations of C1q, C3, C3-activator, C4, C5 and C9 and whole complement (hemolytic activity)) were measured in sera from full-term small-for-date (SFD) and appropriate-for-date (AFD) infants and their mothers. (1) Half the SFD infants showed lower C1q levels than the AFD infants. (2) SFD infants showed the same levels of C3 as AFD infants. (3) Although SFD infants showed slightly higher levels of C3-activator than AFD infants, there was no significant difference. (4) SFD infants and AFD infants showed the same level of C4. (5) With respect to C5, half the SFD infants showed lower levels than the AFD infants. (6) Levels of C9 in the SFD infants were essentially the same as those in the AFD infants. (7) The amount of protein in every complement component of an infant was smaller than that of the mother. In AFD infants, the infant-maternal ratios were 0.64 for C1q, 0.45 for C3, 0.29 for C3-activator, 0.43 for C4, 0.54 for C5 and 0.12 for C9. (8) The whole complement titers of umbilical cord sera from the AFD infants were approximately one half of those of the maternal sera. This is due to the smaller amount of complement protein itself in the infant sera. (9) The whole complement titers of umbilical cord serum agreeably correlate with gestational weeks and birth weight of the infants. (10) The whole complement titer in full-term SFD infants was lower than that in normal full-term AFD infants.

Complement C1↗
PubMed1997

Overexpression of Crry protects mesangial cells from complement-mediated injury.

Crry is a membrane-associated complement regulatory protein expressed on glomerular mesangial, endothelial, and epithelial cells, which reduces C3/C5 convertase activity. This study utilized an overexpression strategy to determine the functional significance of Crry in cultured rat mesangial cells. A Crry expression vector was constructed and was tagged with a c-myc epitope that allowed transfected Crry to be distinguished from the constitutively expressed protein. In stable clones, overexpressed Crry was clearly detected immunocytochemically both by anti-c-myc and anti-Crry antibody in a membrane localization. The overexpression of Crry was also confirmed by Western blotting and immunoprecipitation. To determine if overexpression of Crry by mesangial cells confers a protective effect from complement attack, complement-mediated cell lysis assays were performed. Crry-transfected mesangial cells demonstrated complete resistance to complement-mediated cell lysis, which was reversed by neutralization of Crry with both monoclonal antibody and F(ab')2 fragments of the antibody. This study also investigated the role of Crry in protecting cells from the effects of sublytic complement attack. Overexpressed Crry suppressed antibody/complement induced production of superoxide, one of the inflammatory mediators induced by sublytic complement attack. Immunocytochemical staining confirmed a reduction in C3 and C5b-9 deposition in Crry-transfected cells. These results demonstrate directly that transfected Crry functions as a potent protector of mesangial cells against complement-mediated injury. Crry may play an important role in modulating the glomerular response to immune injury in vivo.

Animals↗
PubMed2003

Prevention of cardiac cell injury during acute myocardial infarction: possible role for complement inhibition.

The purpose of this article is to describe mechanisms of cell death in patients with acute myocardial infarction, particularly the activation of the complement system. Various pro-inflammatory cytokines, released by the inflamed tissue, play a role in the activation of the complement system. Several complement inhibitors have been developed to reduce tissue damage following ischemia. According to animal studies the deleterious effects of activators of the complement system can be diminished by complement inhibition. Several clinical studies have been conducted for the potential treatment of cell injury during acute myocardial infarction. C1 inhibitor dose-dependently inhibited complement activation and appeared to reduce myocardial injury after reperfusion therapy in patients with acute myocardial infarction. C1 inhibitor dose-dependently reduced plasma levels of C4 activation fragments. In addition, cardiac enzymes (troponin T and creatine kinase-MB) returned to baseline levels more rapidly among patients treated with C1 inhibitor, compared with controls. Furthermore, preliminary results from a placebo-controlled trial indicate that treatment with intravenous pexelizumab (anti-C5 antibody) was well tolerated in a large number of patients undergoing coronary artery bypass graft surgery. Further, more randomized trials are necessary to clarify the clinical significance of this new and innovative treatment with complement inhibition.

Animals↗
PubMed2000

Generation of complement fragment C5a in milk is variable among cows.

The appearance of chemotactic fragments of complement at sites of infection is an important component of innate immunity. The contribution of C5a, the most biologically active complement fragment, to the recruitment of phagocytes in milk is not well defined, in particular the amount of C5a that is released in normal milk before inflammation. The generation of C5a in normal milk upon activation of complement by invading bacteria depends on the amount of available C5 and on the activity of the C3/C5-convertase of the alternative pathway. Concentrations of C5 were measured in one fore and one rear uninfected quarter of 19 Holstein cows. Values were consistent within cows, but widely dispersed among cows (0.19 to 1.94% blood concentration). C5 concentrations in milk were loosely related to concentrations in blood. By comparison, the range of milk concentrations of C3 (1.4 to 4.4%, mean 2.46 +/- 0.63% of blood concentration) was narrower. Two groups of six cows with high milk concentrations of C5 (cows H5: mean = 1.31%) and six cows with low milk concentrations of C5 (cow L5: mean = 0.21%) were constituted for further analysis of complement activation. There was a positive correlation between concentrations in milk of BSA and C5, but not between concentrations of BSA and C3. The activities of the C3- and C5-convertases were assessed through the deposition on complement-activating bacteria (Streptococcus agalactiae) of C3 and C5 fragments, respectively. The deposition of C3 was 1.7-fold higher, and the deposition of C5 was 2.75-fold higher in milk from H5 cows than in milk of L5 cows. Higher concentrations of C5 and better functioning of C5-convertase were mirrored by a much higher concentration of C5a in milk from H5 cows (12.30 ng/ml) than in milk of L5 cows (0.76 ng/ml) after activation of complement with zymosan. These results indicate that cows differed widely in their capacity to generate C5a in milk before inflammation, and that milk C5 concentrations were a primary limiting factor for C5a generation. Cows with the lowest milk concentrations of C5 are likely unable to use the complement system for the initial recruitment of leukocytes.

Animals↗
PubMed2000

Complement-dependent acute-phase expression of C-reactive protein and serum amyloid P-component.

The acute-phase response (APR) is regulated by TNF-alpha, IL-1beta, and IL-6 acting alone, in combination, or in concert with hormones. The anaphylotoxin C5a, generated during complement activation, induces in vitro the synthesis of these cytokines by leukocytes and of acute-phase proteins by HepG2 cells. However, there is no clear evidence for a role of C5a or any other complement activation product in regulation of the APR in vivo. In this study, using human C-reactive protein (CRP) transgenic mice deficient in C3 or C5, we investigated whether complement activation contributes to induction of the acute-phase proteins CRP and serum amyloid P-component (SAP). Absence of C3 or C5 resulted in decreased LPS-induced up-regulation of the CRP transgene and the mouse SAP gene. Also, LPS induced both the IL-1beta and IL-6 genes in normocomplementemic mice, but in complement-deficient mice it significantly induced only IL-6. Like LPS injection, activation of complement by cobra venom factor led to significant elevation of serum CRP and SAP in normocomplementemic mice but not in complement-deficient mice. Injection of recombinant human C5a into human CRP transgenic mice induced the IL-1beta gene and caused significant elevation of both serum CRP and SAP. However, in human CRP transgenic IL-6-deficient mice, recombinant human C5a did not induce the CRP nor the SAP gene. Based on these data, we conclude that during the APR, C5a generated as a consequence of complement activation acts in concert with IL-6 and/or IL-1beta to promote up-regulation of the CRP and SAP genes.

Acute-Phase Reaction↗
PubMed2002

Transgenic expression of a soluble complement inhibitor protects against renal disease and promotes survival in MRL/lpr mice.

To investigate the role of complement in lupus nephritis, we used MRL/lpr mice and a transgene overexpressing a soluble complement regulator, soluble CR1-related gene/protein y (sCrry), both systemically and in kidney. Production of sCrry in sera led to significant complement inhibition in Crry-transgenic mice relative to littermate transgene negative controls. This complement inhibition with sCrry conferred a survival advantage to MRL/lpr mice. In a total of 154 animals, 42.5% transgene-negative animals had impaired renal function (blood urea nitrogen > 50 mg/dl) compared with 16.4% mice with the sCrry-producing transgene (p < 0.001). In those animals that died spontaneously, MRL/lpr mice with the sCrry-producing transgene did not die of renal failure, while those without the transgene did (blood urea nitrogen values of 46.6 +/- 9 and 122 +/- 29 mg/dl in transgene-positive and transgene-negative animals, respectively; p < 0.001). Albuminuria was reduced in those transgenic animals in which sCrry expression was maximally stimulated (urinary albumin/creatinine = 12.4 +/- 4.3 and 36.9 +/- 7.7 in transgene-positive and transgene-negative animals, respectively; p < 0.001). As expected in the setting of chronic complement inhibition, there was less C3 deposition in glomeruli of sCrry-producing transgenic mice compared with transgene-negative animals. In contrast, there was no effect on glomerular IgG deposition, levels of anti-dsDNA Ab and rheumatoid factor, or spleen weights between the two groups. Thus, long-term complement inhibition reduces renal disease in MRL/lpr mice, which translates into improved survival. MRL/lpr mice in which complement is inhibited still have spontaneous mortality, yet this is not from renal disease.

Animals↗
PubMed1979

The septic burned patient: a model for studying the role of complement and immunoglobulins in opsonization of opportunist micro-organisms.

Studies were performed to determine the effects of septicemia on complement levels and activities and opsonic function in septic and nonseptic burned patients. None of the nonseptic burned patients had consumption of classical pathway activity during their clinical course. Patients who did not survive septicemia had consumption of all of the classical complement components (C1-C5) prior to and during their septic episodes. Patients who survived septicemia had multiple patterns of classical complement pathway consumption. In these patients, classical pathway activity was restored to normal following the last positive blood culture. Alternative complement pathway consumption was demonstrated in only one of the septic burned patients, as evidenced by decreased factor B and C3b INA levels and decreased C3 and C5 conversion in sera treated with 10 mM ethylene glycol tetraacetic acid and 10 mM MgCl(2) (MgEGTA) and in untreated sera. In all of the other septic patients and in the nonseptic patients, reduction in C3 and C5 conversion in MgEGTA sera and untreated sera was not associated with decrease in factor B or C3b INA. Reduction in complement levels and activities did not reduce the ability of the patients' sera to promote phagocytosis and intracellular killing of their infecting micro-organisms by normal human peripheral polymorphonuclear leukocytes. The results indicate that measurement of classical pathway activity in burned patients can be used as a diagnostic tool for predicting the severity of septic episodes and for monitoring recovery. In addition, the observation that complement consumption did not reduce the opsonic capacity of the patients' sera for their infecting micro-organisms suggests that current concepts regarding the role of immunoglobulins and complement in opsonization of opportunist micro-organisms require re-evaluation.

Adolescent↗
PubMedDate not supplied

Functions of human complement inhibitor C4b-binding protein in relation to its structure.

Considering the destructive potential of the complement cascade, it is no surprise that there are several complement inhibitors present in blood and expressed on virtually all cells of the body to protect self tissue. C4b-binding protein (C4BP) is a potent soluble inhibitor of the classical and lectin pathways of complement. This large (500 kDa) plasma glycoprotein consists of seven identical 75 kDa alpha-chains and a unique 40 kDa beta-chain that are held together by disulphide bridges. Both types of subunit are almost exclusively composed of complement control protein (CCP) domains. In recent years, detailed studies of structure-function relationships have yielded new understanding of the interactions between C4BP and the activated complement factors C4b and C3b, heparin, and vitamin K-dependent anticoagulant protein S. This review describes the localization of binding sites for a number of C4BP ligands in relation to well-established and novel functions of C4BP such as complement inhibition, protection of apoptotic cells from complement, CD40-dependent stimulation of B cells, and the contribution of a number of human pathogens to pathogenesis.

Apoptosis↗
PubMed1992

Complement receptors in atherosclerotic lesions.

Accumulation of cholesterol in the tunica intima of arteries is a feature of atherosclerotic development. Recently, the demonstration of oxidized LDL in atherosclerotic lesions considerably strengthened the possibility of its role in the atherogenesis in vivo. However, the mechanism of lipid accumulation in monocyte-derived macrophages has not yet been clarified. It has been reported that the complement system may be related to atherosclerosis. In this report, complement receptors in the atherosclerotic lesions obtained from autopsy sample were investigated. Initially C3b receptors were detected using sheep erythrocytes bearing human C3b (EAC1423b cells). EAC1423b cells adherent to only aortic sections showing intimal thickening, but not to intact artery. Second, immunostaining of consecutive aortic sections was performed. Apo B and C5b-9 complex were stained using the indirect immunoperoxidase method, and macrophage, C3b receptor (CR1) and C3bi receptor (CR3) were stained using monoclonal antibody in the alkaliphosphatase anti-alkaliphosphatase method. In the intact artery of 3 month old patient, antigen- specific staining were not observed. In intimal thickening and atheroma of older patients, consecutive sections suggested that complement receptor-expressing cells were macrophages. Staining for apo B antigen existed at extracellular site in the intima, and C5b-9 complex was observed in intima and partially in the media. The above data showed that macrophage complement receptors were expressed in the atherosclerotic lesions when the complement system was activated. We conclude that these data suggest that the complement system and complement receptors may be related to the uptake of LDL by macrophages.

Adolescent↗
PubMed1991

Complement activation in relation to development of preeclampsia.

Six hundred eighty-five primigravidas followed as a series had complement activation evaluated by the formation of anaphylatoxins (C3a and C5a) and terminal C5b-9 complement complexes in venous blood. Samples for complement determinations were obtained four times during pregnancy, in pregnancy weeks 12-16, 20-24, 28-32, and 34-36. Seven of the women developed preeclampsia and one of them the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome). Eleven others with uncomplicated pregnancies were selected as a control group. Plasma samples were taken from these 18 women at delivery and 1 and 7 days after delivery. At delivery, plasma C5a levels were significantly greater in the preeclamptics than in controls, and four of the seven preeclamptics had elevated plasma C3a values compared with controls. One week after delivery, these plasma anaphylatoxins had returned to normal. Elevations of the anaphylatoxins could not be detected before the women developed clinical signs of preeclampsia. No alterations in terminal C5b-9 complement complexes could be observed in the women with preeclampsia. However, the women who developed HELLP syndrome had elevated plasma concentrations of C3a, C5a, and terminal C5b-9 complement complex at delivery. These values returned to the normal range 1 week after delivery. We conclude that complement activation in the systemic circulation does not occur early in pregnancy and that plasma concentrations of C3a, C5a, or terminal C5b-9 complement complex cannot be used as predictors of preeclampsia.

Adult↗
PubMed1990

[Study of the complement system. General principles and perspectives].

Measurement of complement in clinical medicine is traditionally based on the determination of CH50 and immunochemical and/or functional measurement of complement proteins C1q, factor B, C3 and C4. The interpretation of these measurements, as far as complement activation is concerned, can however be difficult as these tests do not allow to discriminate between consumption due to activation, hereditary deficiency, increased rate of synthesis or even hyposynthesis. This explains why their use as markers of evolutivity in diseases where complement activation is occurring has given variable results. New tests for complement activation have been more recently introduced. These are mainly the measurements of the anaphytotoxins, the degradation products of C3 and the membrane attack complex. As these tests reflect more directly complement activation, they may be more reliable markers. The immunochemical and functional measurements of C1-inhibitor are of special interest as they are the tests which allow definitive diagnosis of the hereditary angio-oedema. General principles for the interpretation of the different tests used to evaluate the complement system are presented and discussed.

Anaphylatoxins↗
PubMed1979

In vitro fixation of guinea pig complement by renal biopsies.

The in vitro fixation of heterologous complement by cryostat sections of human renal biopsy material was studied to determine the mechanism of complement activation. Various types of guinea pig sera with different parts of the complement system inhibited were used, the fixation of complement being detected by direct immunofluorescence. Cases of idiopathic focal nephritis with mesangial IgA (mesangial IgA disease), Henoch-Schönlein purpura (HSP) and mesangio-capillary glomerulonephritis (MCGN) fixed complement by the alternative pathway alone and in systemic lupus erythematosus (SLE) both the classical and alternative pathways were involved. Only one of the seven cases of membranous glomerulonephritis fixed complement and this was by the classical pathway. After prior treatment with C3b inactivator, the in vitro complement fixation in mesangial IgA disease, HSP and MCGN was greatly reduced. In SLE it was slightly reduced and in membranous glomerulonephritis there was no change. This is a convenient method of studying the biological properties of complexes which is believed to reflect the in vivo behaviour of the tissue deposited complex.

Animals↗
PubMed1994

Defective regulation of complement by the sickle erythrocyte: evidence for a defect in control of membrane attack complex formation.

A prominent clinical manifestation of sickle cell disease (SCD) is hemolytic anemia. Although complement activation can lead to intravascular hemolysis, its role in the hemolysis of SCD is not known. Because normal red blood cells induced to vesiculate by treatment with calcium and ionophore become sensitive to damage by activated complement and because sickle cells release microvesicles as they circulate, we postulated that sickle cells might also be unusually sensitive to complement-dependent hemolysis. Complement activation is tightly regulated on the membrane of the normal erythrocyte; therefore, defective complement regulation by the sickle cell would be necessary for complement-dependent hemolysis to occur. These studies show a defect in the regulation of membrane attack complex (C5b-9) formation in sickle erythrocytes, particularly in the most dense cells. The defect is characterized by increased binding of C5b-7 and of C9 to denser sickle cells and results in increased susceptibility of sickle cells to C5b-9-mediated (reactive) lysis initiated by either C5b6 or activated cobra venom factor. Among the densest sickle cells, irreversibly sickled cells are especially sensitive to reactive lysis. The similarity of this defect to that previously described in a patient with paroxysmal nocturnal hemoglobinuria suggests that complement-mediated hemolysis could play a role in the anemia of SCD.

Adenosine Triphosphate↗
PubMed1995

Activation of the classical pathway of complement by tobacco glycoprotein (TGP).

Tobacco glycoprotein (TGP), a polyphenol-rich glycoprotein isolated from tobacco leaves, activates the classical complement pathway through a mechanism that appears to involve direct interaction with C1q. A binding site on C1q for TGP can be localized by competitive inhibition with DNA to a region located in the junction between the collagen-like and globular regions of the molecule. A protein with activity similar to TGP has also been isolated from cigarette smoke condensate (TGP-S); it shares a binding site on C1q with TGP and has similar functional activity, with the exception that complement activation does not proceed to formation of a C3 cleaving enzyme. The ability of TGP and TGP-S to activate complement can be partially duplicated using polyphenols associated with tobacco leaf and smoke, i.e., chlorogenic acid and rutin. These polyphenols also compete with TGP for a binding site on immobilized C1q, suggesting that the polyphenol portion of TGP is critical for activation of complement. These results provide an additional mechanism for complement activation by cigarette products that, in vivo, could result in a localized complement depletion, generation of biologically active complement cleavage products, and initiation of an inflammatory response.

Complement Activation↗
PubMed1999

Immunoglobulin M-enriched human intravenous immunoglobulin prevents complement activation in vitro and in vivo in a rat model of acute inflammation.

An important antiinflammatory mechanism of intravenous immunoglobulin preparations (IVIG) is their ability to block complement activation. The purpose of this study was to compare the complement-inhibitory activity of four IVIG preparations differing in isotype composition. The preparations were: (1) IVIgG (48 g/L IgG, 2 g/L IgA; Intraglobin F); (2) Pentaglobin (38 g/L IgG, 6 g/L IgM, 6 g/L IgA); (3) IVIgM (35 g/L IgM, 12 g/L IgA, 3 g/L IgG); and (4) IVIgA (41 g/L IgA, 9 g/L IgG), all from Biotest Pharma GmbH, Dreieich, Germany. Their complement inhibitory activity was assessed in vitro by measurement of the blocking of C1q-, C4-, and C3 deposition on solid-phase aggregated rabbit IgG by enzyme-linked immunosorbent assay (ELISA). Complement inhibition in this ELISA was best for IVIgM, followed by Pentaglobin and IVIgG; IVIgA did not exhibit an inhibitory effect. Control experiments with excess concentrations of C1q as well as with C1q-depleted serum showed that the inhibitory effects of IVIG were not caused by complement activation and thus, consumption, but that C4 and C3 were scavenged by IgM and to a lesser extent by IgG. These results were confirmed in vivo in the rat anti-Thy 1 nephritis model, in which a single dose of 500 mg/kg of IVIgM prevented C3-, C6-, and C5b-9 deposition in the rat glomeruli, whereas the effect of IVIgG was much less pronounced. Reduction of complement deposition was paralleled by a diminished albuminuria, which was completely absent in the IVIgM-treated rats. IVIgM and to a lesser extent IVIgG also prevented rat C3 deposition on cultured rat glomerular mesangial cells in vitro, but did not influence anti-Thy 1 binding. Neither IVIgM nor Pentaglobin nor IVIgG negatively affected in vitro phagocytosis of Escherichia coli (E coli) by human granulocytes. In conclusion, we have shown that IgM enrichment of IVIG preparations enhances their effect to prevent the inflammatory effects of complement activation.

Animals↗
PubMed1980

Hemolytic complement activity in normal human donor corneas.

Normal human donor corneas were minced into small fragments and eluted for 16 to 23 hours at 4 degrees C. The corneal eluates were then studied for hemolytic complement activity of C1, C4, C2, C3, C5, C6, and C7 with 50% hemolysis (CH50) of sensitized sheep RBCs. Sera from ten normal volunteers were also assayed for hemolytic complement activity in CH50 units per milliliter. For each complement component, the mean hemolytic activity in corneas was compared with the mean hemolytic activity in sera. These comparisons suggest that molecular weight may be a factor in determining the concentration of complement components in the cornea. The present study provides normal values of hemolytic complement activity for further studies of complement consumption in corneal diseases.

Adult↗
PubMed2003

Activation of the complement system by different autologous transfusion devices: an in vitro study.

BACKGROUND: The aim of the present investigation was to study whether autologous transfusion devices activate the complement system and whether complement-activated blood is more vulnerable to further activation during processing. STUDY DESIGN AND METHODS: Forty-eight blood units were randomized to be processed by one of three different salvage systems: Group 1 underwent whole blood filtration (hemofiltration) (n=16); Group 2 underwent continuous processing, saline washing, and centrifugation (CATS, Fresenius AG ) (n=16); and Group 3 underwent saline washing and centrifugation (Cell-Saver, Haemonetics Corp.) (n=16). Eight blood units for each system were activated with cobra venom factor (CVF) at a concentration of 0.2 U per mL whole blood before processing. C activation was studied by determinations of C4d, Bb, C3a, and SC5b-9. Samples were drawn from whole blood, processed blood, and the waste bags. RESULTS: The concentrations of Bb, C3a, and SC5b-9 in whole blood after activation with CVF were significantly elevated compared to blood that was not activated (p < 0.01). Processed blood from hemofiltration contained significantly higher levels of complement-split products than techniques that use washing and centrifugation. The concentrations of SC5b-9 in blood processed by hemofiltration were higher in the experiments with CVF activation (p < 0.05). CONCLUSION: The tested autologous transfusion systems did not themselves activate the complement system, and complement-activated blood was not more vulnerable to further activation during processing. A blood-salvaging technique that used washing and centrifugation reduced elevated concentrations of complement-split products, whereas hemofiltration did not.

Blood Transfusion, Autologous↗
PubMed1979

Complement activation in asymptomatic patients with sickle cell anaemia.

Previous reports have suggested that a defect in serum complement may contribute to the increased susceptibility to infection shown by patients with sickle cell anaemia (SCA). In order to define the nature of any complement abnormality in SCA, we investigated the complement system in eighty-seven patients during asymptomatic periods, and analysed factor B turnover in a small sample. In these patients geometric mean serum concentrations of functionally active factor B and factor D, and of C3 and C4 protein (expressed as a percentage of normal reference serum) wer lower than in controls (78% vs 107%, P less than 0.001, 86% vs 103%, P less than 0.001, 91% vs 100%, P less than 0.01, 89% vs 105%, P less than 0.05 respectively). The ratio of the serum concentration of functionally active factor B to factor B protein was lower in patients than in controls (means 75% s.d. 16% vs mean 93%, s.d. 22% P less than 0.001), indicating a functional deficiency of factor B protein. In addition, the fractional catabolic rate of radiolabelled factor B was markedly increased in four out of seven asymptomatic patients studied, and was inversely related to the functional factor B concentration in serum (r = -0.59, P less than 0.05); factor B synthesis was uniformly increased. Complement activation was not related to the presence of circulating C1q binding material. We conclude that complement activation, rather than defective synthesis as previously suggested, contributes to the abnormalities in complement componenet concentration and function in asymptomatic subjects with sickle cell anaemia.

Adolescent↗