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Biomedical subjects

C Jacobs

Publications and source records attributed to C Jacobs.

At least 37 records · Page 2Linked to original sources

[Severe contracture of the proximal interphalangeal joint in Dupuytren's disease: does capsuloligamentous release improve outcome?].

Purpose. Evaluation of effectiveness of capsuloligamentous release in severe PIP joint contractures in Dupuytren's disease. Method. Prospective study to compare the clinical outcome of eleven patients with severe contracture of the PIP joint due to Dupuytren's disease, in whom an additional capsulotomy was performed to reduce a residual flexion contracture of the PIP joint of 20 degree and more after release and excision of all diseased fascia, with the outcome of 32 patients with severe contracture of the PIP joint due to Dupuytren's disease, in whom the PIP joint contracture could be reduced by fasciectomy alone. Preoperatively all patients had a severe flexion contracture (60 degrees or greater) of one PIP joint. All patients underwent standardized operative treatment and postoperative extension splinting program for six months. Follow-up examinations included assessment of active range of motion at two, four, ten, 16 and 24 weeks after surgery. Results. In the noncapsulotomy group, preoperative contracture averaged 70.6 degrees and intraoperative residual contracture averaged 2 degrees. In the capsulotomy group, preoperative contracture averaged 78.6 degrees. Intraoperative residual contracture averaged 61.8 degrees before and 2 degrees after capsulotomy. At the final follow-up examination, PIP joint flexion contracture averaged 15 degrees in the noncapsulotomy group compared to 16 degrees in the capsulotomy group. Conclusion. Residual flexion contracture of a PIP joint after release and excision of all diseased fascia in Dupuytren's disease can be reduced by capsuloligamentous release. The data of this study showed no significant differences in the outcome at the final follow-up examination between patients with and without capsulotomy. Therefore, we recommend capsulotomy as treatment of residual flexion contracture of the PIP joint in Dupuytren's disease.

Adult↗

[Preoperative Intermittent Pneumatic Soft-Tissue Distraction in Patients with severe Dupuytren's Contracture].

PURPOSE: Evaluation of the outcome of preoperative intermittent pneumatic soft tissue distraction (IPD) in patients with severe contractures in Dupuytren's disease with special regards on recurrent deformities. METHOD: In a prospective study, nine patients with Dupuytren's contracture grade III and IV according to the classification of Tubiana were treated with a preoperative intermittent soft-tissue distraction using a pneumatic extension device followed by a standardized operative correction and follow-up program. Sixteen fingers were involved: grade I and II four fingers, grade III and IV twelve fingers. Nine fingers - grade III and IV seven fingers - in six patients had a recurrent deformity. RESULTS: The preoperative reduction of contracture simplifies the surgical treatment. Preoperatively using the IPD, the flexion contracture was reduced between 5 and 60 degrees. With an average of 29 (10 to 60) degrees, the improvement was greater in fingers with severe contracture (grade III and IV according to Tubiana) than in fingers with a minor contracture averaging 10 (5 to 25) degrees. In fingers with recurrent deformity, the reduction of the flexion contracture averaged 27 (5 to 60) degrees. There were no complications leading to break off of the distraction. CONCLUSION: The intermittent pneumatic distraction is a good alternative to the method introduced by Messina for preoperative soft-tissue distraction in patients with severe Dupuytren's contracture.

Aged↗

Childhood adversity, parental vulnerability and disorder: examining inter-generational transmission of risk.

BACKGROUND: An investigation of intergenerational factors associated with psychiatric disorder in late adolescence/early adulthood was undertaken to differentiate influences from maternal disorder, maternal poor psychosocial functioning and poor parenting, on offspring. METHOD: The sample comprised an intensively studied series of 276 mother-offspring pairs in a relatively deprived inner-city London area with high rates of lone parenthood and socio-economic disadvantage. The paired sample was collected over two time periods: first a consecutively screened series of mothers and offspring in 1985-90 (n = 172 pairs) and second a 'vulnerable' series of mothers and offspring in 1995-99 (n = 104 pairs). The vulnerable mothers were selected for poor interpersonal functioning and/or low self-esteem and the consecutive series were used for comparison. Rates of childhood adversity and disorder in the offspring were examined in the two groups. Maternal characteristics including psychosocial vulnerability and depression were then examined in relation to risk transmission. RESULTS: Offspring of vulnerable mothers had a fourfold higher rate of yearly disorder than those in the comparison series (43% vs. 11%, p < .001). They were twice as likely as those in the comparison series to have experienced childhood adversity comprising either severe neglect, physical or sexual abuse before age 17. Physical abuse, in particular, perpetrated either by mother or father/surrogate father was significantly raised in the vulnerable group. Analysis of the combined series showed that maternal vulnerability and neglect/abuse of offspring provided the best model for offspring disorder. Maternal history of depression had no direct effect on offspring disorder; its effects were entirely mediated by offspring neglect/abuse. Maternal childhood adversity also had no direct effect. CONCLUSIONS: Results are discussed in relation to psychosocial models of risk transmission for disorder. Maternal poor psychosocial functioning needs to be identified as a factor requiring intervention in order to stem escalation of risk across generations.

Adolescent↗

[Treatment of anemia in dialysis patients in France (1998-1999) (Study by ESAM-France)].

This paper reports the results observed in 3934 French patients who have been included in the prospective ESAM study (European Survey on anemia management) conducted between september 1998 and march 1999 in 14 european countries. This survey aimed at investigating the profile of the anemia and its treatment with recombinant erythropoietin (EPO) in patients treated with maintenance hemodialysis (90.5%) or peritoneal dialysis (9.5%) in 205 french centers prior to the release of the European Guidelines for treatment of renal anemia (EBPG). Only 7.9% of the HD patients and 24.7% of those treated with PD received EPO prior to start of dialysis therapy. At inception of the study (during which all patients received EPO, (before, at time of, or after start dialysis) only 40.2% of patients had an Hb concentration equal to or higher than 11 g/dl (median 10.6 g/dl). At the end of the six month's study this percentage had risen only by 3.6% (43.6%, median Hb 10.8 g/dl). The prescription and monitoring of the effects of iron salts supplementation appeared frequently unsatisfactory and account for a large part for these somewhat disappointing results. No statistically significant adverse effect nor influence on the short time mortality rate attributable to the administration of EPO is evidenced for this population of patients in this study.

Anemia↗

Supplementation with vitamin C and N-acetyl-cysteine increases oxidative stress in humans after an acute muscle injury induced by eccentric exercise.

There has been no investigation to determine if the widely used over-the-counter, water-soluble antioxidants vitamin C and N-acetyl-cysteine (NAC) could act as pro-oxidants in humans during inflammatory conditions. We induced an acute-phase inflammatory response by an eccentric arm muscle injury. The inflammation was characterized by edema, swelling, pain, and increases in plasma inflammatory indicators, myeloperoxidase and interleukin-6. Immediately following the injury, subjects consumed a placebo or vitamin C (12.5 mg/kg body weight) and NAC (10 mg/kg body weight) for 7 d. The resulting muscle injury caused increased levels of serum bleomycin-detectable iron and the amount of iron was higher in the vitamin C and NAC group. The concentrations of lactate dehydrogenase (LDH), creatine kinase (CK), and myoglobin were significantly elevated 2, 3, and 4 d postinjury and returned to baseline levels by day 7. In addition, LDH and CK activities were elevated to a greater extent in the vitamin C and NAC group. Levels of markers for oxidative stress (lipid hydroperoxides and 8-iso prostaglandin F2alpha; 8-Iso-PGF2alpha) and antioxidant enzyme activities were also elevated post-injury. The subjects receiving vitamin C and NAC had higher levels of lipid hydroperoxides and 8-Iso-PGF2alpha 2 d after the exercise. This acute human inflammatory model strongly suggests that vitamin C and NAC supplementation immediately post-injury, transiently increases tissue damage and oxidative stress.

Acetylcysteine↗

Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma: results of a multicenter randomized controlled trial.

PURPOSE: Although high-dose chemotherapy supported by autologous peripheral-blood progenitor-cell (PBPC) transplantation improves response rates and survival for patients with multiple myeloma, all patients eventually develop progressive disease after transplantation. It has been hypothesized that depletion of malignant plasma cells from autografts may improve outcome by reducing infused cells contributing to relapse. PATIENTS AND METHODS: A randomized phase III study using the CEPRATE SC System (Cellpro, Bothell, WA) to enrich CD34(+) autograft cells and passively purge malignant plasma cells was completed in 190 myeloma patients randomized to receive an autograft of CD34-selected or unselected PBPCs. RESULTS: After CD34 selection, tumor burden was reduced by 1.6 to 6.0 logs (median, 3.1), with 54% of CD34-enriched products having no detectable tumor. Median time to count recovery, number of transfusions, transplantation-related mortality, and days in hospital were equivalent between the two transplantation arms. With a median follow-up of 37 months, 33 patients (36%) in the selected and 34 patients (35%) in the unselected arm had died (P =.784). Median overall survival in the selected arm was reached at 50 months and is not reached at this time in the unselected arm (P =.78). Median disease-free survival was 100 versus 104 weeks (P =.82), with 67% of patients in the selected arm and 66% of patients in the unselected arm relapsing. CONCLUSION: This phase III trial demonstrates that although CD34 selection significantly reduces myeloma cell contamination in PBPC collections, no improvement in disease-free or overall survival was achieved.

Adult↗

Nanosuspensions as particulate drug formulations in therapy. Rationale for development and what we can expect for the future.

An increasing number of newly developed drugs are poorly soluble; in many cases drugs are poorly soluble in both aqueous and organic media excluding the traditional approaches of overcoming such solubility factors and resulting in bioavailability problems. An alternative and promising approach is the production of drug nanoparticles (i.e. nanosuspensions) to overcome these problems. The major advantages of this technology are its general applicability to most drugs and its simplicity. In this article, the production of nanoparticles on a laboratory scale is presented, special features such as increased saturation solubility and dissolution velocity are discussed, and special applications are highlighted, for example, mucoadhesive nanosuspensions for oral delivery and surface-modified drug nanoparticles for site-specific delivery to the brain. The possibilities of large scale production -- the prerequisite for the introduction of a delivery system to the market -- are also discussed.

Administration, Oral↗

Dynamic localization of a cytoplasmic signal transduction response regulator controls morphogenesis during the Caulobacter cell cycle.

We present evidence that a bacterial signal transduction cascade that couples morphogenesis with cell cycle progression is regulated by dynamic localization of its components. Previous studies have implicated two histidine kinases, DivJ and PleC, and the response regulator, DivK, in the regulation of morphogenesis in the dimorphic bacterium Caulobacter crescentus. Here, we show that the cytoplasmic response regulator, DivK, exhibits a dynamic, cyclical localization that culminates in asymmetric distribution of DivK within the two cell types that are characteristic of the Caulobacter cell cycle; DivK is dispersed throughout the cytoplasm of the progeny swarmer cell and is localized to the pole of the stalked cell. The membrane-bound DivJ and PleC histidine kinases, which are asymmetrically localized at the opposite poles of the predivisional cell, control the temporal and spatial localization of DivK. DivJ mediates DivK targeting to the poles whereas PleC controls its release from one of the poles at times and places that are consistent with the activities and location of DivJ and PleC in the late predivisional cell. Thus, dynamic changes in subcellular location of multiple components of a signal transduction cascade may constitute a novel mode of prokaryotic regulation to generate and maintain cellular asymmetry.

Bacterial Proteins↗

Production and characterisation of mucoadhesive nanosuspensions for the formulation of bupravaquone.

Bupravaquone is a new naphthoquinone antibiotic against Cryptosporidium parvum and other parasites. It has attracted interest for the treatment of C. parvum infections, because of the lack of a drug in the treatment of mostly AIDS patients. The bioavailability of bupravaquone is limited when given orally. To overcome the problem of the high elimination rate caused by diarrhoea, typical for C. parvum infections, bupravaquone was formulated as a mucoadhesive nanosuspension, i.e. combining the properties of mucoadhesive drug delivery systems, in this case hydro gels, with nanosuspensions. In this study different polymers/hydro gels were employed to create a prolonged retention time for the drug in the infected gastrointestinal tract (GIT). The second step to improve the bioavailability of bupravaquone was the formulation as nanosuspension. Therefore various concentrations of bupravaquone with different surfactants were tested. The production of these nanosuspensions was carried out by high pressure homogenisation. In addition to the classical stepwise production, about a new one step production method is described.

Animals↗

Primary cutaneous follicle center cell lymphomas and large B cell lymphomas of the leg descend from germinal center cells. A single cell polymerase chain reaction analysis.

Primary cutaneous B cell lymphomas are defined as non-Hodgkin lymphomas that occur in the skin without extracutaneous involvement for 6 mo after diagnosis. They are characterized by a less aggressive course and better prognosis than their nodal counterparts. According to the European Organization for Research and Treatment of Cancer classification, the major subentities of primary cutaneous B cell lymphoma are follicle center cell lymphomas, immunocytomas, and large B cell lymphomas of the leg, which differ considerably regarding their clinical behavior, the former two being indolent, the latter being of intermediate malignancy. In this study, we applied a single cell polymerase chain reaction approach to analyze immunoglobulin V(H)/V(L) genes in 532 individual B lymphocytes from histologic sections of four follicle center cell lymphomas localized on the head and trunk, and four large B cell lymphomas on the leg. We found: (i) in six of eight patients a clonal heavy chain, and in seven of eight patients a clonal light chain rearrangement, all being potentially productive; (ii) no bias in VH gene usage, in four of seven light chain rearrangements the V kappa germline gene IGVK3-20*1 was used; (iii) no biallelic rearrangements; (iv) all V(H)/V(L) genes are extensively mutated (mutation rate 5.4-16.3%); (v) intraclonal diversity in six of eight cases (three of each group); and (vi) low replacement vs silent mutation ratios in framework regions indicating preservation of antigen-receptor structure, as in normal B cells selected for antibody expression. Our data indicate a germinal center cell origin of primary cutaneous follicle center cell lymphomas and large B cell lymphomas independent of those belonging to one of these subentities.

Aged↗

The monitoring of heparin administration by screening tests in experimental dogs.

The objective of this study was to investigate the relationship between different screening tests of haemostasis and amidolytic plasma activities of unfractionated (standard) heparin in dogs. Different doses of intravenous (i.v.) [25, 50 or 100 IU Kg(-1)bodyweight (BW)] and subcutaneous (s.c.) heparin (250, 500 and 750 IU kg(-1)) were given to groups each of five clinically healthy adult beagles. Measurements of heparin activity with a factor Xa-dependent chromogenic substrate, activated partial thromboplastin time (APTT) (two different reagents), thrombin time (TT, two different thrombin activities in the reagent: 3 and 6 IU ml(-1)) and the reaction time of the resonance thrombogram (RTG -r) with two different measuring devices were performed at different times. The relationship between ratio values (actual/baseline values) of the coagulation tests and heparin activity was analysed based on regression analysis and correlation coefficient. The greatest alterations were seen for the TT([3 IU ml(-1)])and the RTG -r which were near or exceeded the upper limit of measuring range, if 25 IU kg(-1)BW heparin were given i.v. at heparin plasma levels of 0.54 +/- 0.13 IU ml(-1). These results show, that only APTT and TT measured with high thrombin activity assay appear suitable for guiding high dose heparin therapy in dogs. Averaged alterations of APTT ratio in canine plasma were less than those observed in people for similar plasma heparin levels, indicating that the guideline extrapolated from people for monitoring high dose heparin therapy using APTT may not be valid for use in dogs. After coagulation times had been converted into ratio values, based on regression analysis and Wilcoxon's test, differences of heparin sensitivity were found not only for TT measured with different thrombin activities but also for different APTT reagents (P < 0.001). The correlation between amidylotic antifactor Xa activity and ratio of coagulation times was only moderate and found to be lower for RTG -r (instrument 1: r(s)= 0.711; instrument 2: r(s)= 0.573) than for the other coagulation tests (r(s)= 0.822 to r(s)= 0.890). This indicates a considerable variability of the ratio values of the screening tests at defined heparin plasma activities. These results show, that blood coagulation tests in general are little or unsuitable for heparin antifactor-Xa activity control.

Animals↗

Erythropoietin enhances recovery after cisplatin-induced acute renal failure in the rat.

BACKGROUND: Erythropoietin (Epo) is a growth factor whose synthesis mainly takes place in the kidney. Epo has been shown to support the growth not only of erythroid progenitor cells but also of certain other cell types. We attempted to establish whether Epo enhances the recovery from acute renal failure induced by cisplatin. METHODS: Sprague-Dawley rats were randomized into three groups. In the cisplatin group, animals received one intraperitoneal injection of cisplatin (6 mg/kg) and a daily injection of placebo for 9 days. In the cisplatin+Epo group, animals received intrapertoneal cisplatin and a daily injection of Epo (100 IU/kg) for 9 days. In the control group, animals received both placebo preparations alone. Para-aminohippuric acid and inulin clearances were determined after 4 and 9 days to evaluate renal blood flow and glomerular filtration rate. In addition, light microscopy and immunohistochemistry examinations were performed, and in situ proliferating cell nuclear antigen (PCNA) staining was done to estimate the degree of renal tubular cell regenerative activity. The potential role of epithelial growth factor (EGF) was evaluated by semi-quantitative assessment of EGF immunostaining. RESULTS: Renal blood flow and glomerular filtration rate decreased significantly in cisplatin and cisplatin+Epo groups versus control group at day 4. However, at day 9, they both were significantly greater in cisplatin+Epo-treated animals than in rats that had received cisplatin alone. Tubular cell regeneration was significantly enhanced at day 4 in cisplatin+Epo group, compared with cisplatin and control groups respectively. EGF immunostaining was not significantly different between the three groups. CONCLUSION: Epo significantly enhanced the rate of recovery from acute renal failure induced by cisplatin. PCNA staining indicated that Epo might act directly via stimulation of tubular cell regeneration.

Acute Kidney Injury↗

Influence of metacarpophalangeal joint position on basal joint-loading in the thumb.

BACKGROUND: Conventional wisdom holds that hyperextension of the metacarpophalangeal joint of the thumb is secondary to degenerative subluxation of the trapeziometacarpal joint as occurs in osteoarthritis. We propose that a hypermobile metacarpophalangeal joint may have a causative role in the development of primary osteoarthritis at the base of the thumb by concentrating forces on the palmar aspect of the trapeziometacarpal joint. METHODS: Twenty fresh-frozen cadaveric forearm specimens were obtained post mortem from donors with no history of connective-tissue disease. Each specimen was categorized by its passive range of metacarpophalangeal joint motion. Testing was conducted with Fuji ultra-low-pressure-sensitive film while the hand was in the lateral-pinch mode with the metacarpophalangeal joint in each of the following positions: unrestrained, pinned in neutral, pinned in 30 degrees of flexion, and pinned in maximal hyperextension. Quantitative analysis of the trapezial contact surface at each of the metacarpophalangeal joint positions was performed, and the center of pressure was determined. Each specimen was then classified according to the extent of arthritic disease (nonarthritic, moderately arthritic, or affected by end-stage arthritis). RESULTS: In specimens affected by end-stage osteoarthritis, the center of pressure on the trapeziometacarpal joint moved dorsally by 56.8% of the length of the trapezial surface with metacarpophalangeal joint flexions of 30 degrees (p < 0.01), whereas the corresponding values were 28.2% and 40.9% in the hyperextended and neutral metacarpophalangeal joint positions, respectively. In specimens with moderate osteoarthritis, 30 degrees of metacarpophalangeal joint flexion also produced the most dorsal trapeziometacarpal center of pressure (44.8%); however, this center of pressure was not significantly different from the centers of pressure at the other metacarpophalangeal joint positions. In nonarthritic specimens, the center of pressure was again significantly more dorsal with metacarpophalangeal joint flexion of 30 degrees than it was at the other positions (p < 0.01). CONCLUSION: Metacarpophalangeal joint flexion effectively unloaded the most palmar surfaces of the trapeziometacarpal joint regardless of the presence or severity of arthritic disease in this joint.

Aged↗

Amidolytic heparin activity and values for several hemostatic variables after repeated subcutaneous administration of high doses of a low molecular weight heparin in healthy dogs.

OBJECTIVE: To determine effects of SC administration of repeated doses of a low molecular weight heparin (LMWH) in dogs. ANIMALS: 5 healthy dogs. PROCEDURE: Each dog received 6 injections (each injection, 150 U of anti-factor-Xa [anti-FXal/kg of body weight, SC) at 8-hour intervals. Blood samples were collected before and 2 hours after the first, second, third, and sixth injections to measure heparin activity, thrombin time, activated partial thromboplastin time (APTT), antithrombin activity, Hct, and platelet count. RESULTS: Heparin activity varied between 0.36+/-0.10 and 0.77+/-0.08 U of anti-FXa/ml (before and 2 hours after the third injection) and between 0.46+/-0.11 and 0.82+/-0.15 U of anti-FXa/ml (before and 2 hours after the sixth injection). Thrombin time and APTT were influenced only slightly. Platelet count, Hct, and antithrombin activity started to decrease significantly 2 hours after the second LMWH injection. Because of the increased consumption of antithrombin, antithrombin activity continuously decreased from 102.1+/-6.3% before the study to 91.0+/-3.0% at the end of the study. CONCLUSIONS AND CLINICAL RELEVANCE: Heparin plasma activity was only slightly higher than that recommended for LMWH treatment of humans, and none of the dogs had signs of increased bleeding. Thus, administration of heparin in accordance with this dosing regimen can be recommended for use in clinical studies. The screening tests investigated were not suitable for use in monitoring LMWH treatment of dogs. Assays that use chromogenic substrates are necessary to reliably monitor LMWH plasma concentrations in dogs.

Animals↗

Fc gamma R expression on macrophages is related to severity and chronicity of synovial inflammation and cartilage destruction during experimental immune-complex-mediated arthritis (ICA).

STATEMENT OF FINDINGS: We investigated the role of Fc gamma receptors (Fc gamma Rs) on synovial macrophages in immune-complex-mediated arthritis (ICA). ICA elicited in knee joints of C57BL/6 mice caused a short-lasting, florid inflammation and reversible loss of proteoglycans (PGs), moderate chondrocyte death, and minor erosion of the cartilage. In contrast, when ICA was induced in knee joints of Fc receptor (FcR) gamma-chain(-/-) C57BL/6 mice, which lack functional Fc gamma RI and RIII, inflammation and cartilage destruction were prevented. When ICA was elicited in DBA/1 mice, a very severe, chronic inflammation was observed, and significantly more chondrocyte death and cartilage erosion than in arthritic C57BL/6 mice. The synovial lining and peritoneal macrophages of naïve DBA/1 mice expressed a significantly higher level of Fc gamma Rs than was seen in C57BL/6 mice. Moreover, elevated and prolonged expression of IL-1 was found after stimulation of these cells with immune complexes. Zymosan or streptococcal cell walls caused comparable inflammation and only mild cartilage destruction in all strains. We conclude that Fc gamma R expression on synovial macrophages may be related to the severity of synovial inflammation and cartilage destruction during ICA.

Animals↗

1-imidazolyl(alkyl)-substituted di- and tetrahydroquinolines and analogues: syntheses and evaluation of dual inhibitors of thromboxane A(2) synthase and aromatase.

A series of 1-imidazolyl(alkyl)-substituted quinoline, isoquinoline, naphthalene, benzo[b]furan, and benzo[b]thiophene derivatives was synthesized as dual inhibitors of thromboxane A(2) synthase (P450 TxA(2)) and aromatase (P450 arom). Dual inhibition of these enzymes could be a novel strategy for the treatment of mammary tumors and the prophylaxis of metastases. The most potent dual inhibitors, 5-(2-imidazol-1-ylethyl)-7,8-dihydroquinoline (31) (P450 TxA(2): IC(50) = 0.29 microM; P450 arom: IC(50) = 0.50 microM) and its 5, 6-saturated analogue 30 (P450 TxA(2): IC(50) = 0.68 microM; P450 arom: IC(50) = 0.38 microM), showed a stronger inhibition of both target enzymes than the reference compounds (dazoxiben: IC(50) = 1.1 microM; aminoglutethimide: IC(50) = 18.5 microM). For the determination of the in vivo activity, the influence of selected compounds on serum TxB(2) concentration was examined in rats. Compound 30 (8.5 mg/kg body weight) led to a reduction of the TxB(2) serum level of 78%, 71%, and 51% after 3, 5, and 8 h, respectively (dazoxiben: 60%, 34%, and 36%). Selectivity was studied toward some enzymes of the steroidogenic and eicosanoid pathways. P450 17 was inhibited by selected compounds only at high concentrations. Compound 30 inhibited P450 scc by 13% (25 microM). Compound 31 did not affect cyclooxygenase and lipoxygenase.

Animals↗