[Clinical research at the European LeukemiaNet].
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Acute Disease↗
Biomedical subjects
G Finazzi
Publications and source records attributed to G Finazzi.
A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS).
BACKGROUND: The optimal intensity of oral anticoagulation for the prevention of recurrent thrombosis in patients with antiphospholipid antibody syndrome is uncertain. Retrospective studies show that only high-intensity oral anticoagulation [target international normalized ratio (INR) >3.0] is effective but a recent randomized clinical trial comparing high (INR range 3.0-4.0) vs. moderate (INR 2.0-3.0) intensities of anticoagulation failed to confirm this assumption. METHODS: We conducted a randomized trial in which 109 patients with antiphospholipid syndrome (APS) and previous thrombosis were given either high-intensity warfarin (INR range 3.0-4.5, 54 patients) or standard antithrombotic therapy (warfarin, INR range 2.0-3.0 in 52 patients or aspirin alone, 100 mg day(-1) in three patients) to determine whether intensive anticoagulation is superior to standard treatment in preventing symptomatic thromboembolism without increasing the bleeding risk. RESULTS: The 109 patients enrolled in the trial were followed up for a median time of 3.6 years. Mean INR during follow-up was 3.2 (SD 0.6) in the high-intensity warfarin group and 2.5 (SD 0.3) (P < 0.0001) in the conventional treatment patients given warfarin. Recurrent thrombosis was observed in six of 54 patients (11.1%) assigned to receive high-intensity warfarin and in three of 55 patients (5.5%) assigned to receive conventional treatment [hazard ratio for the high intensity group, 1.97; 95% confidence interval (CI) 0.49-7.89]. Major and minor bleeding occurred in 15 patients (two major) (27.8%) assigned to receive high-intensity warfarin and eight (three major) (14.6%) assigned to receive conventional treatment (hazard ratio 2.18; 95% CI 0.92-5.15). CONCLUSIONS: High-intensity warfarin was not superior to standard treatment in preventing recurrent thrombosis in patients with APS and was associated with an increased rate of minor hemorrhagic complications.
Administration, Oral↗
Diagnosis of Mycobacterium bovis infection in calves sensitized by mycobacteria of the avium/intracellulare group.
Because of the frequent exposure of cattle to mycobacteria of the avium/intracellulare group, an investigation was carried out into the possible repercussions thereof on the diagnosis of bovine tuberculosis. Three calves from a bovine tuberculosis-free herd, scored avian reactors in the gamma-interferon assay for bovine tuberculosis, were sedated and inoculated endotracheally with a virulent Mycobacterium bovis strain. Then, three other avian reactors were housed with the above donor calves. Mycobacterium bovis was isolated from the nasal swabs of the three endotracheally infected, donor calves. On these samples, TB complex-specific polymerase chain reaction (PCR) tests for IS6110 were also positive, albeit with a different time kinetics. The three contact-infected calves showed clear immunological signs of infection; however, their nasal swabs were always PCR-negative and only Mycobacterium avium was isolated. In the endotracheally infected donor calves there was a rise of the gamma-interferon responses to avian and bovine purified protein derivative (PPD) tuberculins, which reached the same stable plateau levels over the whole experiment. The above effect was also observed in the contact-infected calves, even though the response to avian PPD tuberculin always remained at a higher level. By using conventional bovine and avian PPD tuberculins, the comparative intradermal test was generally positive in endotracheally infected, as opposed to contact-infected calves; a positive intradermal test for M. bovis was obtained in two contact-infected calves by different bovine PPD tuberculins based on M. bovis bacillus Calmette-Guerin (BCG) secreted or somatic antigens. It was concluded that M. bovis infection may be concealed for some time in cattle sensitized by mycobacteria of the avium/intracellulare group and that different diagnostic procedures should be adopted for such animals.
Animals↗
Photoinhibition of Chlamydomonas reinhardtii in State 1 and State 2: damages to the photosynthetic apparatus under linear and cyclic electron flow.
The relationship between state transitions and photoinhibition has been studied in Chlamydomonas reinhardtii cells. In State 2, photosystem II activity was more inhibited by light than in State 1. In State 2, however, the D1 subunit was not degraded, whereas a substantial degradation was observed in State 1. These results suggest that photoinhibition occurs via the generation of an intermediate state in which photosystem II is inactive but the D1 protein is still intact. The accumulation of this state is enhanced in State 2, because in this State only cyclic photosynthetic electron transport is active, whereas there is no electron flow between photosystem II and the cytochrome b(6)f complex (Finazzi, G., Furia, A., Barbagallo, R. P., and Forti, G. (1999) Biochim. Biophys. Acta 1413, 117-129). The activity of photosystem I and of cytochrome b(6)f as well as the coupling of thylakoid membranes was not affected by illumination under the same conditions. This allows repairing the damages to photosystem II thanks to cell capacity to maintain a high rate of ATP synthesis (via photosystem I-driven cyclic electron flow). This capacity might represent an important physiological tool in protecting the photosynthetic apparatus from excess of light as well as from other a-biotic stress conditions.
Adenosine Triphosphate↗
The epidemiology of the antiphospholipid syndrome: who is at risk?
Arterial and venous thrombosis are the most common and clinically relevant events of the so-called antiphospholipid syndrome; they are reported in approximately one third of patients with the antiphospholipid (aPL) antibodies. APL antibodies are part of a wide family of immunoglobulins directed against proteins complexed with negatively charged phospholipids. They include lupus anticoagulants (LA), anticardiolipin (aCL) antibodies, and the most recently recognized anti-beta-2-glycoprotein I (beta 2-GPI) and antiprothrombin (aPT) antibodies. Previous thrombotic events and the presence of LA, particularly if identified by the dilute Russell viper venom test, appear to be the strongest risk factors for vascular complications. High-titer aCL antibodies have been reported to be associated with an increased thrombotic tendency, but this was not confirmed in all studies. The data only partially support the concept that anti-beta 2-GPI and aPT antibodies may be considered as independent risk factors for thrombosis. Further prospective studies are required.
Adolescent↗
Efficacy and safety of hydroxyurea in patients with essential thrombocythemia.
Hydroxy-urea has emerged as the treatment of choice in patients with essential thrombocythemia and an high risk of thrombosis because of its efficacy and only rare acute toxicity. However, there is some concern regarding the potential role of this drug in enhancing the risk of leukemic transformation. This risk suggests not to use hydroxyurea in young patients at low-risk for thrombosis. In these cases, major or fatal vascular occlusive complications are rare, and no data are available on the effectiveness of HU in reducing this rate. Sequential multiple chemotherapy, such busulphan followed by HU, should be avoided in any case because of the high risk of secondary leukemias.
Adult↗
Contrasted effects of inhibitors of cytochrome b6f complex on state transitions in Chlamydomonas reinhardtii: the role of Qo site occupancy in LHCII kinase activation.
We have investigated the relationship between the occupancy of the Q(o) site in the cytochrome b(6)f complex and the activation of the LHCII protein kinase that controls state transitions. To this aim, fluorescence emission and LHCII phosphorylation patterns were studied in whole cells of Chlamydomonas reinhardtii treated with different plastoquinone analogues. The analysis of fluorescence induction at room temperature indicates that stigmatellin consistently prevented transition to State 2, whereas 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone behaved as an inhibitor of state transitions only after the cells were preilluminated. The same effects were observed on the phosphorylation patterns of the LHCII proteins, while subunit V of the cytochrome b(6)f complex showed a different behavior. These findings are discussed on the basis of a dynamic structural model of cytochrome b(6)f that relates the activation of the LHCII kinase to the occupancy of the Q(o) site and the movement of the Rieske protein.
Animals↗
Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera.
Thrombohemorrhagic complications are a major cause of morbidity and mortality in patients with essential thrombocythemia (ET) and polycythemia vera (PV). The pathogenesis of these complications is not completely clarified. Several studies have described abnormalities of red blood cells and platelets in these patients. However, no studies are available on changes in the polymorphonuclear leukocytes (PMNs), which can play an important role in the activation of the hemostatic system. In patients with ET (n = 37) and PV (n = 34), a series of PMN activation parameters (PMN membrane CD11b and leukocyte alkaline phosphatase [LAP] antigen expression, cellular elastase content, plasma elastase, and myeloperoxidase levels) was evaluated simultaneously with the levels of plasma markers of endothelial damage (thrombomodulin and von Willebrand factor antigen) and hypercoagulation (thrombin-antithrombin complex, prothrombin fragment 1 + 2, and D-dimer). The results show the occurrence of PMN activation in both groups of patients compared with a control group of healthy subjects. An increase in CD11b and LAP expression by PMN membrane was observed, together with a significant increase in cellular elastase content, plasma elastase, and myeloperoxidase levels. In addition, patients had high plasma levels of endothelial and hypercoagulation markers compared with controls. For the first time, these data show that in ET and PV, 2 hematologic conditions that place patients at increased risk for thrombosis, an in vivo leukocyte activation occurs and is associated with laboratory signs of endothelium and coagulation system activation. (Blood. 2000;96:4261-4266)
Adult↗
Kinetic effects of the electrochemical proton gradient on plastoquinone reduction at the Qi site of the cytochrome b6f complex.
We have investigated the effects of the light-induced thylakoid transmembrane potential on the turnover of the b(6)f complex in cells of the unicellular green alga Chlamydomonas reinhardtii. The reduction of the potential by either decreasing the light intensity or by adding increasing concentrations of the ionophore carbonylcyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) revealed a marked inhibition of the cytochrome b(6) oxidation rate (10-fold) without substantial modifications of cytochrome f oxidation kinetics. Partial recovery of this inhibition could be obtained in the presence of ionophores provided that the membrane potential was re-established by illumination with a train of actinic flashes fired at a frequency higher than its decay. Measurements of isotopic effects on the kinetics of cytochrome b(6) oxidation revealed a synergy between the effects of ionophores and the H(2)O-D(2)O exchange. We propose therefore, that protonation events influence the kinetics of cytochrome b(6) oxidation at the Qi site and that these reactions are strongly influenced by the light-dependent generation of a transmembrane potential.
Animals↗
Recurrence after first cerebral infarction in young adults.
OBJECTIVE: We have investigated recurrence of stroke in a consecutive series of young adults, aged 16 to 45 years, after a first cerebral infarction. METHODS: From January 1, 1988 to December 31, 1996 we submitted those patients to a diagnostic protocol including angiographic, cardiological, and haematological investigations. The patients were followed at 6 month intervals up to December 31, 1998. RESULTS: We have evaluated and followed-up 135 patients, 71 men and 64 women, who were 3.99% of all the admitted stroke patients. At 12 months after stroke, 83 patients had returned to work, 40 patients were mildly to moderately handicapped, 4 were using a wheel-chair, and 8 had died. Follow-up was 26 to 123 months (mean 68.8). Recurrence of stroke, always of ischaemic nature, was seen in 15 patients (11.1%), 3 to 76 months after the first stroke (mean 27.4), for an annual incidence of 2.26%. Recurrence was significantly associated with Partial Anterior Circulation Syndrome and Haematological subtype of first stroke (respectively, P = 0.0209 and P = 0.0135, chi2 test), but not with age (< or = or > 35 years) or risk factors. Repetition of stroke was never fatal, but it caused heavy disability in 13 patients, 8 of whom had completely or nearly completely recovered after the first event. CONCLUSIONS: Our data suggest that recurrence of stroke is a major clinical problem also for the patients aged less than 45 years and that it might be more frequent with specific clinical syndromes and etiologic subtypes of first stroke.
Adolescent↗
The G1691 --> A mutation of factor V, but not the G20210 --> A mutation of factor II or the C677 --> T mutation of methylenetetrahydrofolate reductase genes, is associated with venous thrombosis in patients with lupus anticoagulants.
Arterial and venous thrombosis are the most common manifestations of antiphospholipid syndrome. To investigate whether genetic determinants contribute to their thrombotic risk, we studied the prevalence of the G1691 --> A mutation in the gene coding for factor V, the G20210 --> A mutation in the prothrombin gene and the C677 --> T mutation in the methylenetetrahydrofolate reductase gene in 152 patients with lupus anticoagulants. One hundred and twenty-eight cases (84%) also had increased titres of anticardiolipin antibodies. History of thrombosis was present in 96 patients (63%); 67 suffered from venous thrombosis only, 23 cases had arterial thrombosis only, six patients had both venous and arterial thrombosis. Five patients were heterozygous for the G1691 --> A mutation in the factor V gene (3%). All of them (100%) suffered from venous thrombosis compared with 68 out of the 147 cases without the mutation (46%) (P = 0.0474). The prevalence of the G20210 --> A mutation in the prothrombin gene was evaluated in 145 patients; eight of these patients were heterozygous (5%). Four of these patients (50%) experienced venous thrombosis compared with 65 out of the 137 patients without the mutation (47%) (P = ns). Neither mutation was associated with arterial thrombotic events. No patient carried both mutations. The C677 --> T mutation in the methylenetetrahydrofolate reductase gene was assessed in 83 patients; 15 of them (18%) were homozygous and 37 (44%) were heterozygous. There was no significant association between the status of the mutation and history of venous and arterial thrombosis. No significant correlation was found among the three groups. In conclusion, only the G1691 --> A mutation in the factor V gene was associated with the thrombotic risk of patients with lupus anticoagulants.
Antibodies, Anticardiolipin↗
Second malignancies in patients with essential thrombocythaemia treated with busulphan and hydroxyurea: long-term follow-up of a randomized clinical trial.
We have previously demonstrated that hydroxyurea (HU) reduces the rate of vascular complications in patients with essential thrombocythaemia (ET) at high risk of thrombosis. However, the relatively short follow-up (median 27 months) did not enable the evaluation of the risk of developing secondary malignancies. In this study, we report the long-term outcome of the 114 patients included in the trial: 56 patients randomized to receive HU and 58 patients to receive no cytoreductive therapy. Before randomization, 15 patients had been treated with busulphan. During the observation period, 29 patients (50%) shifted from the control to the HU group mainly because of thrombosis. Median follow-up was 73 months (range 3-94). Analysis was by intention to treat and, when indicated, by treatment. When analysed by intention to treat, 46 out of 54 patients (85%) originally randomized in the HU group are alive, compared with 49 of 58 patients (84%) in the control group [not significant (n.s.)]. Five patients (9%) in the HU group and 26 patients (45%) in the control group had thrombosis (P < 0.0001). Seven patients (13%) in the HU group developed secondary acute leukaemia, myelodysplastic syndromes or solid tumours, compared with only one of the control group patients (1.7%) (P = 0.032). The occurrence of secondary malignancies was also analysed by treatment: none of the 20 patients who had never been treated with chemotherapy developed neoplasia vs. three of the 77 patients given HU only (3.9% n.s.) and five of the 15 patients given busulphan plus HU (33% P < 0. 0001). This study showed that: (a) HU reduced the risk of thrombosis in ET patients; (b) the sequential use of busulphan and HU significantly increased the risk of second malignancies; and (c) overall survival was not affected by HU therapy.
Acute Disease↗
Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study.
Severe hepatic veno-occlusive disease (VOD) is a recognized complication of autologous and allogeneic stem cell transplantation (SCT) that is often fatal. Defibrotide (DF) is a polydeoxyribonucleotide that has been found to have anti-thrombotic, anti-ischaemic and thrombolytic properties without causing significant anticoagulation. Preliminary studies have demonstrated activity for DF in the treatment of VOD, with minimal associated toxicity. In the present study, 40 patients who fulfilled established criteria for VOD were treated with DF on compassionate grounds in 19 European centres; 28 patients met risk criteria predicting progression of VOD and fatality or had evidence of multiorgan failure (MOF), and were defined as 'poor-risk'. DF was commenced intravenously at a median of 14 d (range, -2 d to 53 d) post SCT at doses ranging from 10 to 40 mg/kg. The median duration of therapy was 18 d (range, 2--71 d). Twenty-two patients showed a complete response (CR) (bilirubin < 34.2 micromol/l and resolution of signs/symptoms of VOD and end-organ dysfunction) [CR = 55%, confidence interval (CI) 40--70%] and 17 patients (43%) are alive beyond d +100. Ten poor-risk patients showed a complete response (CR = 36%, CI 21--51%). These results demonstrate that DF is an active treatment for VOD following SCT and a randomized trial is now underway in order to further evaluate its role.
Acute Disease↗
Diagnosis and treatment of polycythemia vera and possible future study designs of the PVSG.
The present study describes clinicopathological criteria to distinguish the 5 sequential stages proposed by Wasserman et al in the natural history of newly diagnosed PV patients. The European Working Group on MPD (EWG.MPD) extended and modified the PVSG diagnostic criteria of PV by including bone marrow histopathology. From the results of prospective randomized studies in PV it became evident that new clinical trials in previously untreated PV patients should focus on comparing interferon-alpha, a non-leukemogenic approach, versus a potential leukemogenic myelosuppressive treatment modality. Hydroxyurea appears to be the least leukemogenic myelosuppressive agent in long-term prospective clinical PV-studies extending observation periods of more than 10 years. The rational for using IFN-alpha as a first-line treatment option in newly diagnosed PV-patient include its effectiveness to abate constitutional symptoms and to induce a complete remission thereby avoiding phlebotomy, iron deficiency, and macrocytosis associated with hydroxyurea. Moreover IFN-alpha may prevent or delay the development of postpolycythemic myelofibrosis if used early in the course of the disease. Clinicians will be reluctant to postpone the use of hydroxyurea in early stage PV as long as a conservative approach using phlebotomy aiming at a hematocrit below 0.45, plus low-dose aspirin for the control platelet function or anagrelide for the control platelet number is used to keep the patient healthy. Low-dose aspirin will prevent the microvascular thrombotic complications of thrombocythemia associated with PV in remission after phlebotomy, but lacks myelosuppressive activity. Control of megakaryocyte maturation and reduction of platelet production to normal (<400 x 10(9)/l) by relatively low doses of anagrelide will predict a significant reduction of vascular complications in the early stages of PV, may prevent progression to myelofibrosis during follow-up of PV and very probable will postpone the use of hydroxyurea treatment for controlling the platelet count in PV. Large scale randomized clinical trials in PV are proposed, which should aim not only for clinical and hematological response, safety, efficacy, but should also assess toxicity, the need for phlebotomy and whether the development of progressive disease such as splenomegaly, pruritus, myelofibrotic myeloid metaplasia, spent phase, myelodysplasia and acute leukemia can be delayed or prevented by IFN-alpha as compared to a conservative approach of phlebotomy plus low-dose aspirin or anagrelide followed by hydroxyurea when signs of myeloproliferative activity became evident.
Blood Platelets↗
Diagnosis of essential thrombocythemia at platelet counts between 400 and 600x10(9)/L. Gruppo Italiano Malattie Mieloproliferative Croniche(GIMMC).
BACKGROUND AND OBJECTIVE: Diagnostic criteria for essential thrombocythemia (ET) remain essentially negative, that is, exclusion of other myeloproliferative diseases and causes of reactive thrombocytosis. A platelet count above 600x10(9)/L is still generally considered an absolute diagnostic criterion although new protocols for positive diagnostic criteria have recently been proposed, reducing the stringency of a definite platelet limit. This study demonstrates that a platelet count 600x10(9)/L is not a reliable diagnostic criterion for ET, especially in the early stages. DESIGN AND METHODS: An ongoing retrospective study by the GIMMC analyzed 2,316 ET patients diagnosed between 1986 and 1995. Of these 2,316 patients, diagnosed according to the PVSG criteria, 68 had a platelet count 600x10(9)/L and were analyzed separately; 37 out of 68 were excluded from this analysis because of a follow-up shorter than 2 years and/or because of treatment with myelosuppressive agents. The remaining 31 patients were the subjects of our study. RESULTS: After a median follow-up of 4.56 years (range 2-9.6 years) none of the 31 patients had a spontaneous decrease of platelets to the normal range. Transformation to a different chronic myeloproliferative disorders was never observed and no patient developed a condition known to produce reactive thrombocytosis. During follow-up, 23 patients (74%) were treated with anti-aggregating drugs, mainly aspirin. The disease did not evolve into acute leukemia in any patient, 1 had a thrombotic event and none presented hemorrhagic episodes. Median platelet count during follow-up was 534x10(9)/L (range 398-997x10(9)/L). INTERPRETATION AND CONCLUSIONS: Long term follow-up has documented that our 31 patients were correctly diagnosed as having ET, although platelet count was 600x10(9)/L. Our patients were probably in a early phase of their disease and following updated PVSG criteria would have been misdiagnosed leading to incomplete recognition of the natural history of the disease. Further, because an early diagnosis could also have a clinical relevance, our results outline the need for new criteria for the diagnosis of ET. The exclusion of patients with a platelet count between 400 and 600x10(9)/L may prevent patients, nevertheless at risk of vascular complications, from being treated.
Adolescent↗
State transitions, cyclic and linear electron transport and photophosphorylation in Chlamydomonas reinhardtii.
The relationship between state transitions and the kinetic properties of the electron transfer chain has been studied in Chlamydomonas reinhardtii. The same turnover rate of cytochrome f was found in state 1 and 2. However, while DBMIB was inhibitory in both states, DCMU was effective only in state 1. These observations suggest that linear electron transport was active only in state 1, while a cyclic pathway around photosystem (PS) I operated in state 2. The reversible shift from linear to cyclic electron transport was modulated by changes of PSII antenna size, which inactivated the linear pathway, and by oxygen, which inhibited the cyclic one. Attainment of state 2, under anaerobiosis in the dark, was associated with the decline of the ATP/ADP ratio in the cells and the dark reduction of the intersystem carriers. Upon illumination of the cells, the ATP/ADP ratio increased in a few seconds to the aerobic level. Then, several minutes later, the F(m) returned to the state 1 level, and O(2) evolution was reactivated. This suggests that ATP, though required for photosynthesis, is not the rate-limiting factor in the reactivation of photosynthetic O(2) evolution, which is rather controlled by the redox state of the electron carriers.
Adenosine Diphosphate↗
Coinheritance of the HR2 haplotype in the factor V gene confers an increased risk of venous thromboembolism to carriers of factor V R506Q (factor V Leiden).
With the aim of establishing whether the HR2 haplotype in factor V affects the risk of venous thromboembolism, a retrospective multicenter cohort study was performed in 810 family members identified through 174 probands who suffered from at least 1 episode of deep vein thrombosis and/or pulmonary embolism and had an inherited defect associated with thrombophilia (antithrombin, protein C, or protein S deficiency; factor V R506Q or prothrombin G20210A). Fifty-eight percent (468/810) of the family members had an inherited defect and 10% (47/468) were symptomatic. The HR2 haplotype was found in association with factor V R506Q more frequently in family members with venous thromboembolism (18%) than in those without (8%). Double heterozygosity for factor V R506Q and HR2 conferred a 3- to 4-fold increase in the relative risk of venous thromboembolism compared with factor V R506Q alone. The median age at first event was lower when the 2 defects were associated (46 v 52 years). No increase in risk of venous thromboembolism could be demonstrated when the HR2 haplotype was associated with inherited thrombophilic defects other than factor V R506Q. Because both factor V R506Q and the HR2 haplotype are very frequent, the effect of their coinheritance on the risk of venous thromboembolism might represent a clinically relevant issue, and screening for HR2 in carriers of factor V R506Q should be considered.
Adolescent↗
Effects of inhibitors on the activity of the cytochrome b(6)f complex: evidence for the existence of two binding pockets in the lumenal site.
The effects of two inhibitors of electron transfer in the cytochrome b(6)f complex have been studied in whole cells of Chlamydomonas reinhardtii. DNP-INT affected equally the two steps of the concerted oxidation of plastoquinol at the Q(o) site; it decreased the rates of both cytochrome f reduction and cytochrome b(6) turnover, without affecting the amplitude of their redox signals. On the contrary, DBMIB inhibited only the rate of cytochrome f reduction while reducing, at the same time, the amplitude of cytochrome b(6) signals. The accessibility of DNP-INT to the Q(o) site was unaffected by preillumination, while that of DBMIB was greatly enhanced, even after a single turnover of the cytochrome b(6)f complex. Similar results were obtained with a mutant strain (FUD2) where the Q(o) site has an affinity for plastoquinol that is diminished by a factor of approximately 50 [Finazzi, G., et al. (1997) Biochemistry 36, 2867-2874]. However, the binding of the two inhibitors was differentially influenced by the mutation: a factor of approximately 250 was calculated for DNP-INT and a factor of only approximately 5 for DBMIB. This suggests that they bind within the Q(o) site in two distinct pockets, which are differentially involved in the process of quinol oxidation, in agreement with a recent model where two distinct positions for the reduced and semireduced quinones are considered [Crofts, A. R., and Berry, E. A. (1998) Curr. Opin. Struct. Biol. 8, 501-509].
Animals↗