Fibrinogen In Group Research Articles

γ/IgG ratio: role in distinguishing monoclonal spikes from fibrinogen

Serum protein electrophoresis (SPEP) is a standard screening method for detecting monoclonal gammopathies. Presence of fibrinogen, however, can mimic a true monoclonal spike and interfere with accurate monoclonal protein identification. We describe a novel approach for distinguishing fibrinogen spikes from true monoclonal spikes. We classified 600 individual patient samples into four groups: group 1, 58 samples with a fibrinogen spike; group 2, 127 samples with a spike due to a monoclonal gammopathy; group 3, 181 samples with previously established monoclonal gammopathies but resolved posttreatment; and group 4, 234 control samples without monoclonal gammopathies. The value of using a γ region fraction/IgG ratio in distinguishing fibrinogen from true monoclonal spikes was assessed. The γ/IgG ratio in the fibrinogen group is significantly (P<0.0001) higher than this ratio in the other three groups. A γ/IgG ratio cut-off value of 1.13 discriminates true monoclonal gammopathies from fibrinogen. Moreover, exclusion of elevated IgA or IgM cases improves the ratio's predictive power. The probability cut-off is 0.756, corresponding to a γ/IgG ratio of 1 (93% sensitivity, 91% specificity). Using the γ/IgG ratio improves the screening power of SPEP and offers a simple and reliable diagnostic tool for distinguishing fibrinogen spikes from true monoclonal spikes.

Recombinant factor VIIa reduces bleeding after blunt liver injury in coagulopathic, hypofibrinogenaemic pigs

BackgroundRecombinant factor VIIa (rFVIIa) has been successfully used in various clinical conditions to treat severe coagulopathy, but its efficacy may be affected by the underlying conditions. We therefore investigated the efficacy of rFVIIa treatment under conditions of hypofibrinogenaemia in a pig model of blunt liver injury. MethodsSevere haemodilution was instigated in four groups of seven anaesthetized pigs. Before inflicting liver injury, animals were assigned to receive either 70 mg kg−1 fibrinogen (fibrinogen group) or placebo (control group). Thirty seconds after injury, rFVIIa (180 µg kg−1) (rFVIIa and fibrinogen+rFVIIa groups) or vehicle (control and fibrinogen groups) was administered. Haemodynamic variables, coagulation parameters, and blood loss were monitored for 2 h. Histology was examined to evaluate the presence of thrombi and the consistency of liver injury. ResultsAt the end of the observation period, total blood loss [median (range)] decreased in all intervention groups [fibrinogen: 1275 (1221–1439) ml, P=0.036; rFVIIa: 966 (923–1136) ml, P=0.008; fibrinogen+rFVIIa: 678 (475–756) ml, P=0.008] when compared with control animals [blood loss: 1752 (1735–2221) ml]. The mortality rate in the control group was 100%, whereas only 42% of fibrinogen-substituted animals died (P=0.023). All animals treated with rFVIIa or fibrinogen+rFVIIa (P<0.001) survived and no signs of thromboembolism were observed. ConclusionsrFVIIa under conditions of hypofibrinogenaemia exhibited a positive impact on coagulation parameters and a reduction in blood loss. These effects were significantly improved after prior substitution with fibrinogen.

Use of inflammatory factors combined with multi-slice spiral computer tomography for preoperative staging and operative strategy in colon cancer

To determine the clinical value of C-reactive protein(CRP), fibrinogen (FIB), or serum amyloid A protein (SAA) combined with 64 multi-slice computed tomography (MSCT) for preoperative staging and operative strategy in colon cancer. Patients with colon cancer were prospectively enrolled at the West China Hospital of Sichuan University from November 2007 to July 2009,and were equally randomized into 3 groups undergoing different preoperative evaluation: MSCT combined with CRP(CRP group), MSCT combined with FIB (FIB group), and MSCT combined with SAA (SAA group). The agreement between preoperative staging and postoperative pathologic staging and that between expected surgical procedure and procedure adopted were compared. Baseline characteristics among three groups were similar(P>0.05). In CRP group, the accuracies of preoperative staging T, N, M and TNM were 65.7%, 72.4%, 100% and 66.7%, respectively. In FIB group, the accuracies of preoperative staging T, N, M and TNM were 71.4%, 74.3%, 99.0% and 65.7%, respectively. In SAA group, the accuracies of preoperative staging T, N, M and TNM were 60.0%, 55.2%, 96.2%and 51.4%, respectively. The accuracies of N and TNM staging in CRP group and FIB group were significantly higher than those in SAA group(P<0.05). However, there were no significant differences between FIB and CRP group(P>0.05). There were no significant differences in accuracy of predicting surgical procedures among three groups(93.3%, 92.3% and 87.6%, P>0.05). Combined assessment of MSCT and CRP or FIB may improve the accuracy of preoperative staging and procedure prediction, and is superior to MSCT combined with SAA.

Prophylactic Fibrinogen Infusion in Cardiac Surgery Patients: Effects on Biomarkers of Coagulation, Fibrinolysis, and Platelet Function

We have recently reported that prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass grafting (CABG) surgery. Because fibrinogen for the first time was administered to patients without hereditary fibrinogen deficiency or ongoing bleeding, a detailed analysis of the effects of fibrinogen concentrate on biomarkers of coagulation, fibrinolysis, and platelet function was performed. Twenty CABG patients with preoperative plasma fibrinogen levels <3.8 g/L were included in a prospective study. Patients were randomized to preoperative infusion of 2 g fibrinogen concentrate (fibrinogen group) or no infusion (control group). Activated partial thromboplastin time (aPTT), prothrombin time, activated clotting time, and plasma concentrations of fibrinogen, antithrombin, thrombin-antithrombin complex, prothrombin fragment 1.2, and D-dimer, thromboelastometry, platelet count, and platelet aggregometry were analyzed before and 15 minutes after infusion, and 2 and 24 hours after surgery. Fifteen minutes after infusion of fibrinogen concentrate, fibrinogen plasma levels increased by 0.6 ± 0.2 g/L (P < .001 between groups), and induced minimal changes in aPTT and plasma levels of antithrombin, while remaining variables remained unchanged. After surgery, fibrinogen levels no longer differed between groups. D-dimer was significantly higher after surgery in the fibrinogen group (P = .03), while none of the other markers were statistically different between groups. Infusion of 2 g fibrinogen to cardiac surgery patients, without hereditary or acquired fibrinogen deficiency or ongoing bleeding, results in no or minimal changes in biomarkers reflecting coagulation and platelet function. An increased release of fibrin degradation products was detected after surgery in fibrinogen-treated patients.

Effects of different fibrinogen concentrations on blood loss and coagulation parameters in a pig model of coagulopathy with blunt liver injury

IntroductionThe early application of fibrinogen could potentially reverse haemodilution-induced coagulopathy, although the impact of varying concentrations of fibrinogen to reverse dilutional coagulopathy has not been studied in vivo. We postulated that fibrinogen concentration is correlated with blood loss in a pig model of coagulopathy with blunt liver injury.MethodsCoagulopathy was induced in 18 anaesthetized pigs (32 ± 1.6 kg body weight) by replacing 80% of blood volume with hydroxyethylstarch 130/0.4 and Ringer's lactated solution, and re-transfusion of erythrocytes. Animals were randomly assigned to receive either 70 mg kg-1 (F-70) or 200 mg kg-1 (F-200) fibrinogen or placebo before inducing blunt liver injury using a force of 225 ± 26 Newton. Haemodynamics, coagulation parameters and blood loss were monitored for 2 hours. After death, histological examination of internal organs was performed to assess the presence of emboli and the equality of liver injury.ResultsPlasma dilution caused severe coagulopathy. Measured by thromboelastography fibrinogen restored coagulation dose-dependently. Total blood loss was significantly lower and survival better in both fibrinogen groups as compared to controls (P < 0.05). Between the F-70 (1317 ± 113 ml) and the F-200 group (1155 ± 232 ml) no significant difference in total blood loss could be observed, despite improved coagulation parameters in the F-200 group (P < 0.05). Microscopy revealed even injury pattern and no (micro) thrombi for either group.ConclusionsRestoring fibrinogen with 70 or 200 mg kg-1 after severe dilutional coagulopathy safely improved coagulation and attenuated blood loss after experimental blunt liver trauma. The higher dosage of fibrinogen was not associated with a further reduction in blood loss.

Erythrocyte aggregability and AB0 blood groups.

It is not established whether there is an association between erythrocyte aggregation and AB0 blood type, as glycophorins carry sialic acid which is responsible for the negative erythrocyte surface charge and the antigenicity for AB0 blood groups. We have determined erythrocyte aggregation by means of the Myrenne aggregometer in 114 healthy volunteers, along with plasma lipids, fibrinogen and AB0 blood groups. No differences in erythrocyte aggregation (EA0 and EA1) were observed when subjects with 0 (n = 45) and non-0 (n=69) blood group were compared (P = 0.624 and P = 0.838, respectively). Fibrinogen was statistically lower in 0 group compared with non-0 group (P = 0.012). Erythrocyte aggregation (EA0 and EA1) correlated significantly with both lipids and fibrinogen (P < 0.01). When erythrocyte aggregation was dichotomized as EA1 > or = 8, no association was found with 0 and non-0 blood groups (P > 0.05) but it was associated with high lipid levels: T-Chol > 220 mg/dl, TG > 175 mg/dl and high fibrinogen levels > 300 mg/dl (P = 0.035; P = 0.030; P = 0.010, respectively). Erythrocyte aggregation does not seem to be associated with blood groups, but rather with plasma lipids and fibrinogen.

Association of Interleukin-1 gene polymorphisms with central obesity and metabolic syndrome in a coronary heart disease population

The objective of this study was to determine whether single nucleotide polymorphisms (SNPs) in the Interleukin-1 (IL-1) gene family are associated with central obesity and metabolic syndrome in a coronary heart disease population. The IL-1 alpha C-889T (rs1800587) and IL-1 beta +3954 (rs1143634) SNPs were studied in a Western Australian coronary heart disease (CHD) population (N = 556). Subjects who were TT homozygous at either SNP had larger waist circumference (IL-1 alpha: 1.8 cm greater, P = 0.04; IL-1 beta: 4 cm greater, P = 0.0004) compared with major allele homozygotes. Individuals with two copies of the IL-1 alpha:IL-1 beta T:T haplotype had greater waist circumference (4.7 cm greater, P = 0.0001) compared to other haplotypes. There was a significant interaction between the IL-1 beta SNP and BMI level on waist circumference (P = 0.01). When the cohort was stratified by median BMI, TT carriers for IL-1 beta with above median BMI had greater waist circumference (6.1 cm greater, P = 0.007) compared to baseline carriers, whilst no significant association was seen in the below median group. Similarly, when the cohort was stratified by median fibrinogen level (IL-1 alpha interaction P = 0.01; IL-1 beta interaction P = 0.04), TT carriers for both SNPs in the above median fibrinogen group had greater waist circumference (IL-1 alpha 2.7 cm greater, P = 0.007; IL-1 beta 3.3 cm greater, P = 0.003) compared with major allele homozygotes. This association was not seen in the below median group. Also, we found a trend of increased metabolic syndrome for IL-1 beta TT homozygotes (P = 0.07). In conclusion, our findings suggest that in a CHD population IL-1 gene polymorphisms may be involved in increased central obesity, and the genetic influences are more evident among patients who have a higher level of obesity or inflammatory markers.

High Levels of Inflammatory Biomarkers Are Associated with Increased Allele-Specific Apolipoprotein(a) Levels in African-Americans

A role of inflammation for cardiovascular disease (CVD) is established. Lipoprotein(a) [Lp(a)] is an independent CVD risk factor where plasma levels are determined by the apolipoprotein(a) [apo(a)] gene, which contains inflammatory response elements. We investigated the effect of inflammation on allele-specific apo(a) levels in African-Americans and Caucasians. We determined Lp(a) levels, apo(a) sizes, allele-specific apo(a) levels, fibrinogen and C-reactive protein (CRP) levels in 167 African-Americans and 259 Caucasians. Lp(a) levels were increased among African-Americans with higher vs. lower levels of CRP [<3 vs. > or =3 mg/liter (143 vs. 108 nmol/liter), P = 0.009] or fibrinogen (<340 vs. > or =340 mg/liter, P = 0.002). We next analyzed allele-specific apo(a) levels for different apo(a) sizes. No differences in allele-specific apo(a) levels across CRP or fibrinogen groups were seen among African-Americans or Caucasians for small apo(a) sizes (<22 kringle 4 repeats). Allele-specific apo(a) levels for medium apo(a) sizes (22-30 kringle 4 repeats) were significantly higher among African-Americans, with high levels of CRP or fibrinogen compared with those with low levels (88 vs. 67 nmol/liter, P = 0.014, and 91 vs. 59 nmol/liter, P < 0.0001, respectively). No difference was found for Caucasians. Increased levels of CRP or fibrinogen are associated with higher allele-specific medium-sized apo(a) levels in African-Americans but not in Caucasians. These findings indicate that proinflammatory conditions result in a selective increase in medium-sized apo(a) levels in African-Americans and suggest that inflammation-associated events may contribute to the interethnic difference in Lp(a) levels between African-Americans and Caucasians.

Abstract 1094: Inflammation Results In Increased Allele-specific Apo(a) Levels In African Americans: Potential Explanation For Inter-ethnic Difference?

Background: The role of inflammation in the pathogenesis of cardiovascular disease (CVD) is well recognized. Lipoprotein(a), Lp(a), is an independent CVD risk factor where plasma levels are largely determined by apo(a) gene size. Allele-specific apo(a) levels are higher among African Americans (AA) compared to Caucasians (C), and the most pronounced inter-ethnic difference is seen for medium-sized apo(a) alleles. This difference remains unexplained. The apo(a) gene contains response elements for inflammatory factors. However, the effect of inflammation on Lp(a) level, particularly on allele-specific apo(a) levels is unknown. Objective: We investigated the effect of inflammation measured by two acute-phase reactants (CRP and fibrinogen) on allele-specific apo(a) levels in AA and C. Methods: We determined Lp(a) levels, apo(a) sizes, allele-specific apo(a) levels, fibrinogen and CRP levels in 167 AA and 259 C. Results: Lp(a) levels were increased among AA with higher vs. lower CRP (&gt;3 mg/dl) or fibrinogen (&gt;340 mg/dl) levels (143 vs. 108 nmol/l, P =0.009, and 146 vs. 105 nmol/l, P =0.002, respectively). We next analyzed allele-specific apo(a) levels for different apo(a) sizes. No differences in allele-specific apo(a) levels across CRP (&gt;3 vs. ≤3 mg/dl) or fibrinogen (&gt;340 vs. ≤340 mg/dl) groups were seen among AA or C for small apo(a) sizes (&lt;22 K4). Allele specific apo(a) levels for medium apo(a) sizes (23–30 K4) were significantly higher among AA with high levels of CRP or fibrinogen compared to those with low levels (88 vs. 67 nmol/l, P =0.014 and 91 vs. 59 nmol/l, P&lt; 0.0001, respectively). In contrast, there were no significant differences in allele-specific apo(a) levels across CRP or fibrinogen groups among C with medium sized apo(a) alleles. Conclusion: Increased levels of CRP or fibrinogen are associated with higher allele-specific medium-sized apo(a) levels in AA, but not in C. Our results implicate that a pro-inflammatory stimulus may result in a selective increase in Lp(a) levels among AA carrying medium-sized apo(a). These findings provide a potential explanation for differences in Lp(a) levels between African Americans and Caucasians and suggest that inflammation-associated events may contribute to this inter-ethnic difference.

The effect of fibrinogen concentrate on thrombocytopenia.

The hypothesis that the administration of fibrinogen concentrate enables restoration of impaired clot formation and increased bleeding in severe thrombocytopenia was tested. Thirty pigs were anesthetized, instrumented for blood sampling (routine coagulation tests, modified thrombelastography ROTEM, hemodynamic monitoring and platelet apheresis to a target below 30 x 10(9) L(-1) after splenectomy. Thereafter 10 each of the animals randomly received two apheresis platelet concentrates, 250 mg kg(-1) fibrinogen concentrate or normal saline solution. A standardized liver injury was subsequently inflicted to induce uncontrolled hemorrhage. Median (Q1, Q3) clot firmness increased significantly more in thrombocytopenic pigs after fibrinogen administration (42 mm (41, 43) to 60 mm (57, 63)) than following platelet transfusion (40 mm (37, 45) to 52 mm (48, 55), P = 0.0004) or placebo (45 mm (41, 48) to 45 mm (43, 46), P = 0.0002). Median blood loss velocity after liver injury was significantly less with fibrinogen (33 mL min(-1), P = 0.005) than with platelets (62 mL min(-1), P = 0.037) or saline (84 mL min(-1), P = 0.005), and median survival time after liver injury was 55 min in the fibrinogen, 26 min in the platelet (P = 0.035) and 19 min in the saline group (P = < 0.0001). These data show for the first time that impaired clot formation during thrombocytopenia improves with administration of fibrinogen concentrate, which results in a slowdown of blood loss and prolonged survival.

Efficacy of synthetic and biological bioadhesives in scleral tunnel phacoemulsification in eyes with high myopia

Purpose: To study the efficacy of a synthetic (cyanoacrylate) and a biological (fibrinogen) bioadhesive in sealing scleral tunnel incisions in cataract surgery.Setting: Private institution with academic orientation.Methods: This controlled clinical study comprised 126 eyes with high myopia (axial length >28.0 mm) divided into three groups based on method of incision closure: 10-0 nylon anchor suture; cyanoacrylate (Histoacryl®); fibrinogen (Tissucol®). Phacoemulsification was done through a double-valved scleral tunnel incision with an 8.0 mm arc. In all eyes, a hyperconcave, 7.0 mm optic, posterior chamber intraocular lens was implanted.Results: Mean induced astigmatism at 12 weeks was 0.18 diopter (D) in the suture group, 0.50 D in the cyanoacrylate group, and 0.43 D in the fibrinogen group. The difference between the bioadhesive groups and the suture group was not significant. A mild inflammatory reaction occurred in the cyanoacrylate group. In the fibrogen group, 3 eyes developed postoperative hypotony requiring reclosing of the incision with sutures and 5 eyes developed intraoperative hypotony requiring suture closure. These eyes were not included in the refractive analysis. These complications led to the suspension of the fibrinogen portion of the study after uneventful use of the bioadhesive in 26 eyes.Conclusion: The results of this study indicate that bioadhesives, especially synthetic ones such as cyanoacrylate, are an effective alternative to sutures in scleral tunnel cataract surgery. Future improvements in bioadhesives could extend their application to other ocular incision types.

Studies on the Functionality of Newly Synthesized Fibrinogen after Treatment of Acute Myocardial Infarction with Streptokinase, Increase in the Rate of Fibrinopeptide Release

In 15 patients with acute myocardial infarction who received 1,500,000 U of streptokinase, the gradual appearance of newly synthesized fibrinogen and the fibrinopeptide release during the first 35 h after SK treatment were evaluated. At 5 h the fibrinogen circulating in plasma was observed as the high molecular weight fraction (HMW-Fg). The concentration of HMW-Fg increased continuously, and at 20 h reached values higher than those obtained from normal plasma. HMW-Fg represented about 95% of the total fibrinogen during the first 35 h. The degree of phosphorylation of patient fibrinogen increased from 30% before treatment to 65% during the first 5 h, and then slowly declined to 50% at 35 h. The early rates of fibrinopeptide A (FPA) and phosphorylated fibrinopeptide A (FPAp) release are higher in patient fibrinogen than in isolated normal HMW-Fg and normal fibrinogen after thrombin addition. The early rate of fibrinopeptide B (FPB) release is the same for the three fibrinogen groups. However, the late rate of FPB release is higher in patient fibrinogen than in normal HMW-Fg and normal fibrinogen. Therefore, the newly synthesized fibrinogen clots faster than fibrinogen in the normal steady state. In two of the 15 patients who had occluded coronary arteries after SK treatment the HMW-Fg and FPAp levels increased as compared with the 13 patients who had patent coronary arteries. These results provide some support for the idea that an increased synthesis of fibrinogen in circulation may result in a procoagulant tendency. If this is so, the HMW-Fg and FPAp content may serve as a risk index for thrombosis.

Intraplatelet levels of VWF: AG and fibrinogen in myeloproliferative disorders

Several platelet function abnormalities have been described in the myeloproliferative syndromes. We have measured the intraplatelet vWF:Ag and fibrinogen (FI) in the platelet lysates by Laurell technique in 11 patients with polycythemia vera (PV),10 with essential thrombocythemia (ET), 14 with chronic myelocytic leukaemia (CML) and 3 with myelofibrosis (MF) and these results were correlated with platelet function abnormalities.Decreased intraplatelet levels of vWF:Ag and FI were found in all the patients with ET and MF,in 8 out of 11 PV and 3 out of 14 CML. A statistical significant correlation was observed between the intraplatelet levels of vWF:Ag and FI in the control group and in CML and PV, but no correlation was found in ET and MF. No correlation was observed between the plasmatic and the intraplatelet levels of vWF:Ag and FI in any group. Evidences of platelet activation (spontaneous platelet aggregation or circulating platelet aggregates) were observed in 40% of the cases with ET and PV, and all these cases had low intraplatelet levels of both antigens. None of the cases with HF had evidences of platelet activation and 2 out of 14 patients with CML had platelet activation. The deficiency of the dense bodies was less frequent than the depletion of the alpha granules (5 out of 11 PV, 4 out of 10 ET, 6 out of 14 CML and 2 out of 3 MF).The low intraplatelet contents of vWF:Ag and FI, more frequently observed in ET and PV, may be the result of platelet activation and in vivo release, but megakaryocyte dysfunction is more likely in myelofibrosis.

Fibrinogen-induced vitreous membranes.

Fibrinogen was injected in the vitreous cavity of 29 rabbits with follow-up for 75 days. Vitreous membrane formation was detected by indirect ophthalmoscopy and confirmed by histopathological study. Membrane formation was significantly more common in the fibrinogen group than in the control group. Fifteen days after injection, the membranes decreased in size and gave place to vitreous liquefaction in the majority of eyes in the fibrinogen group. Histochemical stains for fibrinogen were positive in half of the vitreous membranes. Fibrinogen is thought to be transformed into a long fibrin polymer forming a matrix for surrounding cells to proliferate in the vitreous. An effective fibrinolytic system in the vitreous explains the ultimate resolution of most of the fibrinogen-induced membranes. Simple fibrinogen injections do not provide a good model for long-term vitreous band formation, yet they add more evidence to the role of fibrin in the pathogenesis of vitreoproliferative diseases. The spontaneous resolution of some proliferative vitreoretinopathies parallels the reversibility of most of the fibrinogen-induced vitreous membranes.

The fundamental molecular event in muscular contraction.

ASTBURY1 2 suggested that the fundamental event in the contraction of muscle might involve a characteristic of the keratin–myosin–epidermin–fibrinogen group of fibrous proteins to which myosin belongs, namely, the folding or collapsing of polypeptide chains from the α-configuration into the supercontracted state. While it has been shown that isolated myosin and actomyosin supercontracts after reasonably mild chemical or physical treatment2,3, no X-ray evidence has been forthcoming so far to show that the shrinkage of actomyosin gels after treatment with adenosine triphosphate is accompanied by a corresponding configurational change4. Moreover, there is the difficulty of reconciling this approach with recent concepts of a two-phase actin–myosin system shortening by close-range5 or long-range6 interaction of filaments coiling or sliding over one another in a regular stepwise fashion.

Action of thrombin in the clotting of fibrinogen.

IN spite of much literature on the clotting of blood, the exact mechanism of the final event, the mode of transformation of soluble fibrinogen to insoluble fibrin by the action of thrombin, remains unknown. The concept of thrombin as a hydrolytic or proteolytic enzyme1,2 has fallen into disfavour3, and in recent years other plausible but unproved mechanisms have been proposed4–6. In a study7 of the proteins of the keratin–myosin–fibrinogen group by end-group assay with fluorodinitrobenzene8, only small amounts of terminal amino-groups could be detected in fibrinogen, although the amounts were not sufficiently small to conclude, as in the case of myosin and tropomyosin, that the molecule is constructed of cyclo-peptide units. The action of purified thrombin, however, results consistently in the appearance of amino-terminal residues of glycine, and whatever the ensuing mechanism, we believe that the fundamental enzymic step in the transformation of fibrinogen to fibrin is associated first with the appearance of these groups. This action of thrombin, which tentatively may be considered as a very specific proteolysis, was discovered independently in Cambridge and in Leeds, and for this reason the relevant observations are reported jointly.

Structures of α-Keratin and Synthetic Polypeptides

THE quest for the structure of the α-form of members of the keratin–myosin–epidermis–fibrinogen group of fibrous proteins has recently been encouraged by the discovery among X-ray photographs of synthetic polypeptides of a diffraction diagram that looks as if it might very well be of the α-type1–5. We have already given a preliminary discussion1 of this possibility, and it naturally continues to engage our close attention ; but we are not yet able to share the confidence of our fellow investigators2–5 either in the genuineness of the supposed α-diagram or in the correctness of the intramolecular fold put forward to explain it. Having worked, with my colleagues, so long on the problem of the keratin–myosin–epidermis–fibrinogen group, I may be allowed to recall some of our earlier results and conclusions which have still not lost their force and which simply cannot be overlooked if we are to come finally to the right answer.