Frequency of thrombophilia determinant factors in patients with livedoid vasculopathy and treatment with anticoagulant drugs - a prospective study

Background Livedoid vasculopathy (LV) is a chronic idiopathic disease characterized by painful purpuric macules on lower extremities. Its exact aetiology remains uncertain, but thrombotic and microcirculatory phenomena have been implicated as possible pathogenic factors. Objectives To assess prospectively the frequency of thrombophilia and to verify the effectiveness of anticoagulant therapy among LV patients. Methods Thirty-four LV patients were tested for prothrombin time, activated partial thromboplastin time, antithrombin activity, protein C and S activity, anticardiolipin antibodies, lupus anticoagulant, prothrombin gene mutation, factor V Leiden mutation, methylenetetrahydrofolate reductase mutation, plasma homocysteine and fibrinogen. Thirteen of these patients were treated with anticoagulant drugs (either warfarin or heparin). Results Of 34 patients, 18 (52%) presented laboratory abnormalities of procoagulant conditions. Positive treatment response to anticoagulant therapy was observed in 11 patients. Improvement of pain was obtained in 1-3 weeks, an average of 1.8 week. Complete healing of the lesions was observed in about 2.3 months. Remission was sustained even after treatment interruption and lasted an average 7.8 months. No severe adverse effects were noticed. Conclusion The authors suggest all patients with diagnosis of LV to be investigated for thrombophilic status. Anticoagulant drugs were well tolerated and seemed to be effective in treating not only LV symptoms but also its ulcerations.

Involvement of circulating platelets on the hyperalgesic response evoked by carrageenan and Bothrops jararaca snake venom

Background: The role of platelets in hemostasis is well known, but few papers have reported their role in pain and edema induced by inflammatory agents. Objective: To evaluate the role of circulating platelets in the local injury induced by two diverse inflammatory agents, Bothrops jararaca venom (Bjv) and carrageenan. Methods: Rats were (i) rendered thrombocytopenic by administration of polyclonal anti-rat platelet IgG (ARPI) or busulfan, or (ii) treated with platelet inhibitors (aspirin or clopidogrel). Edema formation, local hemorrhage and the pain threshold were assessed after intraplantar injection of Bjv or carrageenan in rat hind paws. Additionally, whole platelets or platelet releasate were tested whether they directly induced hyperalgesia. Results: Platelet counts were markedly diminished in rats administered with either ARPI (+/- 88%) or busulfan (+/- 96%). Previous treatment with ARPI or busulfan slightly reduced edema induced by Bjv or carrageenan. Injection of Bjv, but not of carrageenan, induced a statistically significance increase in hemorrhage in the hind paws of thrombocytopenic rats. Remarkably, hyperalgesia evoked by Bjv or carrageenan was completely blocked in animals treated with ARPI or busulfan, or pre-treated with aspirin or clopidogrel. On the other hand, intraplantar administration of whole platelets or platelet releasate evoked hyperalgesia, which was inhibited by pre-incubation with alkaline phosphatase. Conclusions: Thrombocytopenia or inhibition of platelet function drastically reduced hyperalgesia induced by injection of carrageenan or Bjv; moreover, platelets per se secrete phosphorylated compounds involved in pain mediation. Thus, blood platelets are crucial cells involved in the pain genesis, and their role therein has been underestimated.

Traditional risk factors for cardiovascular disease in primary antiphospholipid syndrome (APS) when compared with secondary APS: a study with 96 patients

Objective: To evaluate the prevalence of traditional risk factors in patients with primary antiphospholipid syndrome (APS) in comparison to those with systemic lupus erythematosus-secondary APS. Methods: Transversal study of 96 APS patients (Sapporo`s criteria). Demographic and clinical data, cardiovascular risk factors and drug use were investigated. Results: Thirty-nine Primary APS and 57 secondary APS were included. The groups did not differ regarding age (38.5 +/- 9.9 vs. 39.4 +/- 10.5 years, p=0.84) and female gender (84.6 vs. 96.5%, p=0.06), respectively. Arterial events were more observed in primary than secondary APS (59 vs. 36.8%, p=0.04) patients. No difference was seen concerning venous and obstetric events. In regard to traditional risk factors for cardiovascular disease, both groups were comparable related to current or previous smoking, sedentarism, family history for coronary disease, systemic hypertension, diabetes mellitus, overweight and obesity. The frequencies of altered lipid profiles were alike in the two groups, except for a higher prevalence of low HDL-c levels in primary APS group (84.6 vs. 45.5%, p=0.0001). Concerning drug use, no significant differences were observed related to chloroquine and statin use, however the secondary APS patients had a higher rate of prednisone use (10.2 vs. 57.9%, p<0.001) as well as mean dose of corticosteroid (1.5 +/- 5.7 vs. 9.2 +/- 12.5mg/ /day, p=0.0001). Conclusion: Traditional risk factors for cardiovascular disease are present and comparable between patients with primary and secondary APS, except for a high frequency of low HDL-c in primary APS patients.

Induction and maintenance of in vivo ventricular fibrillation in rabbits

Aim: To provide new sustainable in vivo models of ventricular fibrillation in rabbits. Methods: New Zealand rabbits were submitted to anaesthesia and mechanical ventilation. after which ventricular fibrillation was induced through electrical stimulation (for 2 min at 100 Hz, with 2-ms pulses, 10 mA. and 10V) directly to the heart. To that end, the animals were divided into two groups: right ventricle (n = 11) and left ventricle (n = 11). In group right ventricle, the thoracic cavity was exposed, and a catheter was introduced into the right ventricle via the right jugular vein. in group left ventricle, the thorax remained closed, and the catheter was introduced into the left ventricle via the left common carotid artery (cervical access). Results: Sustained ventricular fibrillation was achieved in 100% of group right ventricle rabbits (n = 11 and in 82% of group left ventricle rabbits (n = 9). Conclusion: Both models proved appropriate for achieving sustained ventricular fibrillation. However, in view of the invasiveness of the procedure adopted in group right ventricle, the experimental conditions used in group left ventricle seemed more physiological and more effective in inducing sustained ventricular fibrillation. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Adipose tissue mesenchymal stem cell expansion in animal serum-free medium supplemented with autologous human platelet lysate

BACKGROUND: Mesenchymal stem cells (MSCs) have been considered for human regenerative therapy applications, and safe culture and expansion protocols are needed especially in the context of interspecies contamination. Human platelet lysate (PL) has been proposed as animal serum substitute during in vitro MSC expansion. In this work, a simplified and efficient method to obtain autologous PL to replace animal serum in cell culture applications is described. STUDY DESIGN AND METHODS: PL obtained by freezing and centrifugation procedures was tested as medium supplement for human adipose mesenchymal stem cell (hASC) culture. Differential proliferation, immunophenotypic changes, and differentiation under PL or fetal bovine serum (FBS) were assessed. RESULTS: In contrast to 10% FBS supplementation, cell population doubling time was significantly lower when hASCs were cultured with the same concentration of PL ( PL 22.9 +/- 1.5 hr vs. FBS 106.7 +/- 6.5 hr, t test, p < 0.05). Furthermore, hASCs maintained with 2.5% PL supplementation also showed satisfactory results. Immunophenotypic analysis revealed no differences between hASCs cultivated with PL or FBS supplementation and both cultures retained the potential to differentiate into adipose cells. These results demonstrate that autologous PL obtained from the same donor can be used as animal serum substitute in hASC culture. CONCLUSIONS: Taken together, evidence is provided that platelets provided by a single donor are sufficient to obtain PL for hASC propagation for clinical-scale applications mitigating the potential untoward side effects associated with the use of animal-derived reagents.

Which is the best technique for hepatic venous reconstruction in pediatric living-donor liver transplantation? Experience from a single center

Background/purpose: The introduction of the piggyback technique for reconstruction of the liver outflow in reduced-size liver transplants for pediatric patients has increased the incidence of hepatic venous outflow block (HVOB). Here, we proposed a new technique for hepatic venous reconstruction in pediatric living-donor liver transplantation. Methods: Three techniques were used: direct anastomosis of the orifice of the donor hepatic veins and the orifice of the recipient hepatic veins (group 1); triangular anastomosis after creating a wide triangular orifice in the recipient inferior vena cava at the confluence of all the hepatic veins (group 2); and a new technique, which is a wide longitudinal anastomosis performed at the anterior wall of the inferior vena cava (group 3). Results: In groups 1 and 2, the incidences of HVOB were 27.7% and 5.7%, respectively. In group 3, no patient presented HVOB (P = .001). No difference was noted between groups 2 and 3. Conclusions: Hepatic venous reconstruction in pediatric living-donor liver transplantation must be preferentially performed by using a wide longitudinal incision at the anterior wall of the recipient inferior vena cava. As an alternative technique, triangulation of the recipient inferior vena cava, including the orifices of the 3 hepatic veins, may be used. Published by Elsevier Inc.

Ranolazine Exerts Potent Effects on Atrial Electrical Properties and Abbreviates Atrial Fibrillation Duration in the Intact Porcine Heart

Introduction: In vitro studies and ambulatory ECG recordings from the MERLIN TIMI-36 clinical trial suggest that the novel antianginal agent ranolazine may have the potential to suppress atrial arrhythmias. However, there are no reports of effects of ranolazine on atrial electrophysiologic properties in large intact animals. Methods and Results: In 12 closed-chest anesthetized pigs, effects of intravenous ranolazine (similar to 9 mu M plasma concentration) on multisite atrial effective refractory period (ERP), conduction time (CT), and duration and inducibility of atrial fibrillation (AF) initiated by intrapericardial acetylcholine were investigated. Ranolazine increased ERP by a median of 45 ms (interquartile range 29-50 ms; P < 0.05, n = 6) in right and left atria compared to control at pacing cycle length (PCL) of 400 ms. However, ERP increased by only 28 (24-34) ms in right ventricle (P < 0.01, n = 6). Ranolazine increased atrial CT from 89 (71-109) ms to 98 (86-121) ms (P = 0.04, n = 6) at PCL of 400 ms. Ranolazine decreased AF duration from 894 (811-1220) seconds to 621 (549-761) seconds (P = 0.03, n = 6). AF was reinducible in 1 of 6 animals after termination with ranolazine compared with all 6 animals during control period (P = 0.07). Dominant frequency (DF) of AF was reduced by ranolazine in left atrium from 11.7 (10.7-20.5) Hz to 7.6 (2.9-8.8) Hz (P = 0.02, n = 6). Conclusions: Ranolazine, at therapeutic doses, increased atrial ERP to greater extent than ventricular ERP and prolonged atrial CT in a frequency-dependent manner in the porcine heart. AF duration and DF were also reduced by ranolazine. Potential role of ranolazine in AF management merits further investigation. (J Cardiovasc Electrophysiol, Vol. 20, pp. 796-802, July 2009).

Laparoscopic resection of uncinate process of the pancreas

Solid pseudopapillary neoplasm of the pancreas is an uncommon but distinctive pancreatic neoplasm with low metastatic potential [1]. Therefore, whenever feasible, an organ-preserving operation should be performed. As previously reported, women with solid pseudopapillary neoplasm of the pancreas may be best treated by more conservative procedures [2]. Recently, laparoscopic pancreatic resections became more common and are being performed in highly specialized centers. There are only six cases of laparoscopic resection for solid pseudopapillary neoplasm of pancreas published in the English literature and, to our knowledge, laparoscopic resection of uncinate process of the pancreas has never been reported [3-6]. This video demonstrates the technical aspects of a totally laparoscopic resection of the uncinate process of the pancreas in a patient with solid pseudopapillary neoplasm. A 26-year-old woman with a 4-cm solid pseudopapillary pancreatic neoplasm was referred for surgical treatment. According to preoperative echoendoscopy, there was a safe margin between neoplasm and main pancreatic duct. The patient was placed in supine position with the surgeon standing between her legs. Four trocars, one 10-mm and three 5-mm, were used. At inspection, the inferior vena cava, transverse colon, duodenum, and pancreas are clearly identified. A Kocher maneuver was performed with complete exposure of pancreatic head and uncinate process. The uncinate process was dissected from the superior mesenteric vein and venous branches were divided between metallic clips or by use of laparoscopic coagulation shears (LCS; Ethicon Endo Surgery Industries, Cincinnati, OH, USA). Blood supply of the duodenum was preserved by ligature of small pancreatic branches from inferior pancreatoduodenal artery. Transection of pancreatic parenchyma was performed using laparoscopic coagulation shears, which is an effective tool for cutting the pancreas [7, 8]. Surgical specimen was removed through a suprapubic incision inside a retrieval bag. A hemostatic absorbable tissue (Surgicel; Ethicon Inc., Cincinnati, OH) was placed in the cutting pancreatic surface, and one round 19F Blake abdominal drain (Ethicon) was left in place. Operative time was 180 minutes and blood loss estimated in 40 ml with no blood transfusion. Hospital stay was 4 days. The patient did not have postoperative pancreatitis or pancreatic leakage, and the abdominal drain was removed on the tenth postoperative day. Final pathology confirmed the diagnosis of solid pseudopapillary neoplasm of pancreas with free surgical margins. The patient was well and asymptomatic 2 months after the procedure. Laparoscopic resection of uncinate process of the pancreas is safe and feasible and should be considered for patients suffering from pancreatic neoplasms.

The frequency of anti-beta(2)-glycoprotein I antibodies is low and these antibodies are associated with pulmonary hypertension in mixed connective tissue disease

The objective of this study is to evaluate the prevalence of antiphospholipid antibodies, mainly anti-beta(2)-glycoprotein I (anti-beta(2)-GPI), and their possible clinical and laboratory relevance in mixed connective tissue disease (MCTD). This study included 39 consecutive patients with MCTD (Kasukawa`s criteria) from January, 2005, to March, 2007, and compared them with 21 age- and sex-matched healthy controls. IgG and IgM anticardiolipin (aCL) and anti-beta(2)-GPI were measured by ELISA. Lupus anticoagulant (LA) was detected by functional coagulation tests. Medium to high titres of aCL and anti-beta(2)-GPI antibodies were found in sera from four (10.2%) MCTD patients. One of these patients was found to be positive for IgM aCL, IgM anti-beta(2)-GPI and LA antibodies simultaneously. Additionally, this patient had a previous history of foetal loss in the second trimester and new-onset pulmonary arterial hypertension (PAH). The other three patients had none of the manifestations of antiphospholipid syndrome (APS) or PAH. The mean value of IgG anti-beta(2)-GPI was higher among those MCTD patients with PAH than in the group without PAH (34.2 +/- 46.8 vs 12.3 +/- 9.1, P = 0.018). None of the controls were positive for antiphospholipid antibodies. High to moderate titres of anti-beta(2)-GPI as well as APS were rare in MCTD, and these antibodies may be correlated with the development of PAH in these patients. Lupus (2009) 18, 618-621.

Hemostatic changes and clinical sequelae after on-pump compared with off-pump coronary artery bypass surgery: a prospective randomized study

Objective To delineate the effects of extracorporeal bypass on biomarkers of hemostasis, fibrinolysis, and inflammation and clinical sequelae. Methods Patients were assigned prospectively and randomly to either on-pump (n=41) or off-pump (n=51) coronary bypass surgery. The concentrations of C-reactive protein, fibrinogen, D-dimer, and plasminogen activator inhibitor type-1 in blood were quantified before and after (1 and 24 h) surgery. Similar surgical and anesthetic procedures were used for both groups. Clinical events were assessed during initial hospitalization and at the end of I year. Results The concentrations of plasminogen activator inhibitor type-1 and D-dimer were greater compared with preoperative values 1 and 24 h after surgery in both groups, but their concentrations increased to a greater extent 24 h after surgery in the on-pump group (P<0.01). The concentration of C-reactive protein did not change appreciably immediately after surgery in either group but increased in a parallel manner 24 h after either on-pump or off-pump surgery (P<0.01). Bypass surgery in the on-pump group was associated with greater blood loss during surgery and more bleeding after surgery (P <= 0.01). The incidence of all other complications was similar in the two groups. Conclusion On-pump surgery was associated with biochemical evidence of a prothrombotic state early after surgery but no greater incidence of thrombotic events was observed. The prothrombotic state might be a consequence of extracorporeal bypass, compensation in response to more bleeding, or both in patients undergoing on-pump surgery. Coron Artery Dis 20:100-105 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Initial hepatosplanchnic blood flow distribution and oxygen metabolism in experimental model of hypotensive brain death

Background: Organs from the so-called marginal donors have been used with a significant higher risk of primary non function than organs retrieved from the optimal donors. We investigated the early metabolic changes and blood flow redistribution in splanchnic territory in an experimental model that mimics marginal brain-dead (BD) donor. Material/Methods: Ten dogs (21.3 +/- 0.9 kg), were subjected to a brain death protocol induced by subdural balloon inflation and observed for 30 min thereafter without ally additional interventions. Mean arterial and intracranial pressures, heart rate, cardiac output (CO), portal vein and hepatic artery blood flows (PVBF and HABF, ultrasonic flowprobe), and O(2)-derived variables were evaluated. Results: An increase in arterial pressure, CO, PVBF and HABF was observed after BD induction. At the end, an intense hypotension with normalization in CO (3.0 +/- 0.2 VS. 2.8 +/- 2.8 L/min) and PVBF (687 +/- 114 vs. 623 +/- 130 ml/min) was observed, whereas HABF (277 33 vs. 134 28 ml/min, p<0.005) remained lower than baseline values. Conclusions: Despite severe hypotension induced by sudden increase of intracranial pressure, the systemic and splanchnic blood flows were partially preserved without signs of severe hypoperfusion (i.e. hyperlactatemia). Additionally, the HABF was mostly negatively affected in this model of marginal BD donor. Our data suggest that not only the cardiac output, but the intrinsic hepatic microcirculatory mechanism plays a role in the hepatic blood flow control after BD.

Pediatric Antiphospholipid Syndrome: Clinical and Immunologic Features of 121 Patients in an International Registry

OBJECTIVES. The purpose of this study was to obtain data on the association of antiphospholipid antibodies with clinical manifestations in childhood and to enable future studies to determine the impact of treatment and long-term outcome of pediatric antiphospholipid syndrome. PATIENTS AND METHODS. A European registry extended internationally of pediatric patients with antiphospholipid syndrome was established as a collaborative project of the European Antiphospholipid Antibodies Forum and Lupus Working Group of the Pediatric Rheumatology European Society. To be eligible for enrollment the patient must meet the preliminary criteria for the classification of pediatric antiphospholipid syndrome and the onset of antiphospholipid syndrome must have occurred before the patient`s 18th birthday. RESULTS. As of December 1, 2007, there were 121 confirmed antiphospholipid syndrome cases registered from 14 countries. Fifty-six patients were male, and 65 were female, with a mean age at the onset of antiphospholipid syndrome of 10.7 years. Sixty (49.5%) patients had underlying autoimmune disease. Venous thrombosis occurred in 72 (60%), arterial thrombosis in 39 (32%), small-vessel thrombosis in 7 (6%), and mixed arterial and venous thrombosis in 3 (2%). Associated nonthrombotic clinical manifestations included hematologic manifestations (38%), skin disorders (18%), and nonthrombotic neurologic manifestations (16%). Laboratory investigations revealed positive anticardiolipin antibodies in 81% of the patients, anti-beta(2)-glycoprotein I antibodies in 67%, and lupus anticoagulant in 72%. Comparisons between different subgroups revealed that patients with primary antiphospholipid syndrome were younger and had a higher frequency of arterial thrombotic events, whereas patients with antiphospholipid syndrome associated with underlying autoimmune disease were older and had a higher frequency of venous thrombotic events associated with hematologic and skin manifestations. CONCLUSIONS. Clinical and laboratory characterization of patients with pediatric antiphospholipid syndrome implies some important differences between antiphospholipid syndrome in pediatric and adult populations. Comparisons between children with primary antiphospholipid syndrome and antiphospholipid syndrome associated with autoimmune disease have revealed certain differences that suggest 2 distinct subgroups. Pediatrics 2008; 122: e1100-e1107

Conus perimedullary arteriovenous fistula in a child: unusual angio-architectural features and pathophysiology

Introduction The perimedullary arteriovenous fistulas are located on the pial surface and are usually supplied by spinal medullary arteries, that is, either by the anterior or posterior spinal arteries, with no intervening nidus between the feeder arteries and the venous drainage. The clinical findings are, more commonly, caused by progressive radiculomedullary ischemic processes secondary to steal vascular mechanism. As the vascular supply to the spinal cord and to the arteriovenous fistulas (AVF) is not shared with one another, the vascular steal phenomenon cannot be implicated in this case`s physiopathology. Most probably, the mass effect caused by the giant venous dilatation was the pathophysiological mechanism involved in this lesion Case report The authors describe the case of a 6-year-old girl with an intradural ventral arteriovenous fistula, with a giant venous dilatation, fed directly by L2 and L3 radiculomedullary arteries at the conus medullaris. There was no arterial supply to the fistula from the anterior or posterior spinal arteries. Selective spinal angiography showed an arteriovenous fistula supplied directly by two radiculomedullary arteries, with a large draining vein caudally. Interposing the arterial and venous vessels was a giant venous aneurysmal dilatation located ventral to the conus medullaris and extending from L3 to T6. The patient was successfully treated by a surgical approach through a laminotomy from L3 to T11. Conclusion The type IV-C spinal arteriovenous malformations or perimedullary AVFs are rare lesions predominately described at the conus medullaris with various types of angio-architecture and controversial treatment.

One-stage laparoscopic bisegmentectomy 7-8 and bisegmentectomy 2-3 for bilateral colorectal liver metastases

Bisegmentectomy 7-8 is feasible even in the absence of a large inferior right hepatic vein. To our knowledge, this operation has never been performed by laparoscopy. This study was designed to present video of pure laparoscopic bisegmentectomy 7-8 and bisegmentectomy 2-3 in one-stage operation for bilateral liver metastasis. A 67-year-old man with metachronous bilobar colorectal liver metastasis was referred for surgical treatment after neoadjuvant chemotherapy. CT scan disclosed two liver metastases: one located between segments 7 and 8 and another one in segment 2. At liver examination, another metastasis was found on segment 3. We decided to perform a bisegmentectomy 7-8 along with bisegmentectomy 2-3 in a single procedure. The operation began with mobilization of the right liver with complete dissection of retrohepatic vena cava. Inferior right hepatic vein was absent. Right hepatic vein was dissected and encircled. Upper part of right liver, containing segment 7 and 8, was marked with cautery. Selective hemi-Pringle maneuver was performed and right hepatic vein was divided with stapler. At this point, liver rotation to the left allowed direct view and access to the superior aspect of the right liver. Liver transection was accomplished with harmonic scalpel and endoscopic stapling device. Bisegmentectomy 2-3 was performed using the intrahepatic Glissonian approach. The specimens were extracted through a suprapubic incision. Liver raw surfaces were reviewed for bleeding and bile leaks. Operative time was 240 minutes with no need for transfusion. Recovery was uneventful. Patient was discharged on the fifth postoperative day. Patient is well with no evidence of disease 14 months after liver resection. Tumor markers are within normal range. Bisegmentectomy 7-8 may increase resectability rate in patients with bilateral lesions. This operation can be performed safely by laparoscopy. Preservation of segments 5 and 6 permitted simultaneous resection of segments 2 and 3 with adequate liver remnant.

Oxidant generation predominates around calcifying foci and enhances progression of aortic valve calcification

Objective - We hypothesized that reactive oxygen species ( ROS) contribute to progression of aortic valve ( AV) calcification/ stenosis. Methods and Results - We investigated ROS production and effects of antioxidants tempol and lipoic acid ( LA) in calcification progression in rabbits given 0.5% cholesterol diet +10(4) IU/d Vit.D-2 for 12 weeks. Superoxide and H2O2 microfluorotopography and 3-nitrotyrosine immunoreactivity showed increased signals not only in macrophages but preferentially around calcifying foci, in cells expressing osteoblast/ osteoclast, but not macrophage markers. Such cells also showed increased expression of NAD(P) H oxidase subunits Nox2, p22phox, and protein disulfide isomerase. Nox4, but not Nox1 mRNA, was increased. Tempol augmented whereas LA decreased H2O2 signals. Importantly, AV calcification, assessed by echocardiography and histomorphometry, decreased 43% to 70% with LA, but increased with tempol (P <= 0.05). Tempol further enhanced apoptosis and Nox4 expression. In human sclerotic or stenotic AV, we found analogous increases in ROS production and NAD(P) H oxidase expression around calcifying foci. An in vitro vascular smooth muscle cell (VSMC) calcification model also exhibited increased, catalase-inhibitable, calcium deposit with tempol, but not with LA. Conclusions - Our data provide evidence that ROS, particularly hydrogen peroxide, potentiate AV calcification progression. However, tempol exhibited a paradoxical effect, exacerbating AV/vascular calcification, likely because of its induced increase in peroxide generation.