The Volar Cortical Hinge: An Independent Risk Factor for Distal Radius Fracture Displacement.

Background Displaced distal radius fractures are prone to redisplacement after manipulation. This can result in the need for delayed surgery. Several criteria have been studied to predict the likelihood of redisplacement. We hypothesized that reduction in the volar cortex would be an additional predictive factor. Purpose The aim of this study was to assess whether the quality of the volar cortex reduction predicts the subsequent need for further intervention (surgery or remanipulation). As a secondary outcome, we assessed whether the quality of the reduction predicts the rate of malunion. Methods A retrospective review was performed of displaced adult distal radius fractures over a 2-year period that had undergone closed reduction at presentation. We identified 105 patients and a review of their electronic notes and radiographs was then performed. The volar cortex reduction was defined as "anatomical," "opposed," or "displaced." We assessed the radial height, radial inclination, radial/ulnar translation, volar/dorsal angulation, teardrop angle, presence of dorsal comminution, quality of the cast (molding, cast index), and volar cortex reduction. These measurements were taken at five time points (prereduction, postreduction, 1 week, 2 weeks, and 6 weeks). All patients that subsequently required surgical fixation or repeat reduction were identified as the primary outcome measure. The 6-week radiographs were assessed for radiographic malunion as our secondary outcome measure. A statistical analysis was then performed to assess the factors that influenced a loss of position and the need for delayed surgical intervention. Results Of the 105 patients, 22 patients required delayed surgery, 3 patients underwent a repeat manipulation, and 12 patients had a radiographic malunion at 6 weeks. During the study period, the proportion of patients requiring surgery or repeat manipulation in the displaced group was 10/21 (47.6%), in the opposed group it was 11/50 (23.4%), and in the anatomic group it was 4/36 (11.1%; p = 0.008). We then included the patients with a radiographic malunion and found the proportion of patients with an adverse outcome in the displaced group was 14/21 (66.7%), in the opposed group it was 17/47 (36.2%), and in the anatomic group it was 6/36 (16.7%; p = 0.001). At the 1-week time point, this association was equally significant, as the proportion in the displaced group was 17/33 (51.5%), in the opposed group it was 15/45 (33.3%) and in the anatomic group it was 1/22 (4.5%; p = 0.001). The patients' age, quality of cast, presence of dorsal comminution, and degree of initial displacement did not predict the subsequent need for surgery or remanipulation. Conclusion The most important factor in our study for significant redisplacement of an initially dorsally displaced distal radius fracture is the association of the volar cortex. This parameter maintains significance at the 1-week time point. This data shows that volar cortex reduction is a useful clinical measurement in assessing which distal radius fractures will undergo delayed displacement requiring intervention. Level of evidence Level 3-Retrospective comparative study.

Lunate Fracture Morphology in Kienbock's Disease-A Computed Tomography Study.

Background The pathogenesis of Kienbock's disease is poorly understood. The coronal fracture line is acknowledged as a poor prognostic marker in the disease. Other fracture types in the Kienbock's wrist have subsequently been identified. Questions/Purposes The aim is to study the fracture morphology of the lunate in a cohort of patients using computed tomography. Methods Patient images were acquired using a set protocol with four-dimensional computed tomography scanning. Images were reviewed by two orthopaedic surgeons and a consultant radiologist. Static and dynamic images were assessed and a fracture map created. The relationship of fracture type to other parameters was then analyzed. Results Twenty-three patients were included in the study, including 11 males and 12 females, with a mean age of 43 years. Total frequency of fracture lines in the cohort was coronal - 26, proximal subchondral bone plate type - 24, avulsion - 19, sagittal - 16, and distal subchondral bone plate type - 11. There were statistically significantly more proximal than distal subchondral bone plate fractures ( p = 0.03), and more coronal fractures than distal subchondral bone plate fractures ( p = 0.01). There were statistically significantly more radiolunate ligament-avulsion types ( p <0.001) than other types. The sagittal fracture line through the lunate approximated closely to the ulnar edge of the capitate and the ulnar edge of the radius. Conclusion Study on the fracture morphology in the Kienbock's wrist has improved our understanding of the disease pathogenesis. Fracture lines may correspond to loading points, intrinsic and extrinsic ligament avulsions. These fracture types may play a role in disease progression and are important to identify when considering lunate salvage surgery.

The Pathoanatomy and Biomechanics of Kienböck Disease.

Kienböck disease (KD) involves osseous, vascular, and chondral aspects of the lunate and wrist. We present our theories on the etiology and pathogenesis of the condition based on basic science models, seminal literature, personal case experience, and kinematic observations of the Kienböck wrist. Three phenotypes of Kienböck disease occur, and each tends to have different morphology, rates of progression, and disease pattern. The lunate fracture in KD is well-recognized but different fracture types can occur. Dynamic assessment of the Kienböck wrist allows assessment of the complex kinematics of KD. Disease onset and progression require a "perfect storm" of risk factors.

Preiser's Disease-Current Concepts of Etiology and Management.

The term Preiser's disease typically is used to describe idiopathic avascular necrosis of the scaphoid, but there have been a number of putative etiologies considered. It is rare and the natural history is not fully understood. Management of the condition should be based on patient factors as well as the stage of disease with regard to the scaphoid and the surrounding wrist. This chapter appraises the available evidence and aims to provide the reader with a framework to manage this rare condition.

Volar Marginal Rim Fractures of the Distal Radius Have a Higher Rate of Associated Carpal Injuries-A Comparative Cohort Study.

Background Volar marginal rim distal radius fractures can be challenging due to volar instability of the carpus. The associated carpal injuries, however, have not previously been reported. Purpose The aim of this study was to compare volar marginal rim fractures to other distal radius fractures to determine if there is any association with other carpal injuries. If so, do these injuries lead to further instability and fixation failure? Materials and Methods A retrospective radiological review of 25 volar marginal rim fractures was conducted. This was compared with a comparison cohort of 25 consecutive intra-articular distal radius fractures not involving the volar marginal rim. All radiographs were reviewed for associated carpal injuries, including carpal and ulnar styloid fractures, scapholunate instability, and carpal translocation. Results Volar marginal rim fractures had a significantly higher incidence of associated carpal injuries per patient (2.52 vs. 1.64), scapholunate diastasis (36 vs. 12%), and carpal dislocation (80 vs. 48%). The fixation chosen was more likely to involve a volar rim-specific plate (44 vs. 0%). Following surgical fixation, the volar marginal rim fractures had a significantly higher incidence of carpal instability (56 vs. 24%), failure of fixation (24 vs. 0%), and revision surgery (12 vs. 0%). Conclusions Volar marginal rim fractures have significantly more carpal injuries, scapholunate instability, and volar carpal instability, compared with other distal radius fractures. Despite the use of volar rim-specific plating, volar marginal rim fractures have a significantly higher incidence of persistent carpal instability, including scapholunate instability, ulnar translocation, volar subluxation, failure of fixation, and revision surgery. Level of Evidence This is a level III, retrospective review.

Anatomic factors associated with partial distal biceps tendon tears: a comparative control study.

BACKGROUND: There is minimal literature on the anatomic factors associated with partial distal biceps tendon (DBT) tears. It has been proposed that a larger radial tuberosity size-and, therefore, a smaller radioulnar space during pronation-may cause mechanical impingement of the DBT predisposing to tears. We sought to investigate the anatomic factors that may be associated with partial DBT tears by retrospectively reviewing the DBT anatomy using 3-T magnetic resonance imaging (MRI) scans of elbows with partial DBT tears and a comparison group of normal elbows. METHODS: Two independent observers retrospectively reviewed 3-T MRI scans of elbows with partial DBT tears and elbows without visible pathology. Basic demographic data were collected, and measurements of radial tuberosity length, radial tuberosity thickness, radioulnar space, and radial tuberosity-ulnar space were made using simultaneous tracker lines and a standardized technique. The ratio of radial tuberosity thickness to radial diameter and the ratio of radioulnar space to radial tuberosity-ulnar space were calculated. The presence or absence of enthesophytes and the presence of a single DBT vs. double DBTs were noted. RESULTS: This study included twenty-six 3-T MRI scans of 26 elbows with partial DBT tears and thirty 3-T MRI scans of 30 elbows without pathology. Basic demographic data were comparable between the 2 groups. The tear group showed statistically significantly larger mean measurements for radial tuberosity length (24.3 mm vs. 21.3 mm, P = .002) and radial tuberosity thickness (5.5 mm vs. 3.7 mm, P < .0001). The tear group also showed statistically significantly smaller measurements for radioulnar space (8.2 mm vs. 10.0 mm, P = .010) and radial tuberosity-ulnar space (7.2 mm vs. 9.1 mm, P = .013). The ratio of radial tuberosity thickness to radial diameter was statistically significantly larger in the tear group (0.389 vs. 0.267, P < .0001). There was a statistically significant positive correlation between partial DBT tears and the presence of enthesophytes (P = .007), as well as between partial DBT tears and the presence of 2 discrete DBTs rather than a single tendon or 2 DBTs that interdigitated prior to insertion (P < .0001). CONCLUSION: Larger radial tuberosities and smaller radioulnar and radial tuberosity-ulnar spaces are associated with partial DBT tears. Larger tuberosities and a smaller functional space for the DBT may lead to chronic impingement, tendon delamination, and consequent weakness, which ultimately lead to tears. Enthesophytes may be associated with tears for the same reason. The presence of 2 discrete DBTs that do not interdigitate prior to insertion is also associated with partial tears. This study will help clinicians understand the pathogenesis of partial DBT tears.

Anatomy of the distal biceps tendon: an in vivo 3-T magnetic resonance imaging study.

BACKGROUND: On the basis of the current literature, the optimal surgical technique for distal biceps tendon tears remains controversial. Cadaveric studies have investigated distal biceps anatomy but are limited by cohort size and tissue factors. We sought to investigate distal biceps anatomy in vivo by retrospectively reviewing magnetic resonance imaging (MRI) scans. An improved understanding of the anatomy of the distal biceps tendon will lead to better definition of the optimal anatomic surgical repair. METHODS: Two independent observers retrospectively reviewed 3-T MRI scans of elbows. Basic demographic data were collected, and measurements of tendon length, footprint width, footprint length, and footprint angle were taken using simultaneous tracker lines and a standardized technique. From the biceps muscle belly distally, the presence of a single tendon or double tendons was recorded and the tendon interdigitation point was measured if relevant. RESULTS: A total of 106 3-T MRI scans of 106 elbows of 103 patients were included. There were 71 male and 32 female patients, and the mean age was 44.7 years. Most distal biceps tendons exited the biceps muscle belly as separate entities (91%, 96 of 106 elbows) and then coalesced prior to insertion on the radial tuberosity (91%, 87 of 96 elbows). There was a positive correlation between tendon length and footprint length (P < .05), as well as between tendon length and footprint width (P < .05). The mean tendon length was 65.2 mm (95% confidence interval [CI], 63.3-66.8 mm; range, 44.3-86.8 mm), the mean distance from the musculotendinous junction to the interdigitation point was 38.3 mm (95% CI, 35.8-40.9 mm; range, 8.9-64.8 mm), the mean footprint width was 10.3 mm (95% CI, 9.9-10.7 mm; range, 5.9-16.3 mm), the mean footprint length was 16.2 mm (95% CI, 15.6-16.9; range, 7.3-25.4 mm), and the mean footprint angle was 32.1° (95% CI, 29.5°-34.6°; range, 8.5°-84.3°). CONCLUSION: An in vivo, high-resolution study of the anatomy of the distal biceps tendon improves our understanding of its complex morphology and hence our ability to perform an anatomic "footprint repair."

Long-Term Outcome of Surgical Treatment for Kienböck Disease Using an Articular-Based Classification.

PURPOSE: The aim of this study was to report the outcomes of surgery using the Bain and Begg articular-based classification for the treatment of Kienböck disease. METHODS: We identified and followed patients who had surgery for Kienböck disease between 1995 and 2014. Assessment included functional scoring using a modification of the Gartland and Werley score, pain levels, and grip strength. RESULTS: Thirty-one patients were operated on for Kienböck disease between 1995 and 2014. Twenty-seven patients were assessed (12 men and 15 women). Mean age at the index procedure was 45.1 years (range, 20-82 years). Median follow-up after the index procedure was 10 years (range, 2-18 years). On the Bain and Begg classification, 5 patients had grade 0, 4 had grade 1, 5 had grade 2a, 10 had grade 2b, 1 had grade 3, and 1 had grade 4. The median pain visual analog scale improved from a preoperative score of 5 (interquartile range [IQR], 5-6) to a postoperative score of 2 (IQR, 0-3). The median functional scores from the modified Gartland and Werley score improved from 67 (IQR, 57.0-78.5) to 97 (IQR, 90.0-97.0). Eighteen out of 20 working patients returned to the same level of work. There was a significant improvement in power grip and tip pinch following surgery. One patient required a secondary salvage procedure. No patient required a full wrist fusion or arthroplasty. CONCLUSIONS: This study confirms that the Bain and Begg arthroscopic classification and an articular-based approach to Kienböck disease provide a high probability of good long-term relief of pain and a minimal chance of requiring a salvage procedure. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Kinematics of the wrist in Kienböck's disease: a four-dimensional computed tomography study.

We studied the kinematics of 20 wrists affected by Kienböck's disease using four-dimensional computed tomography (4-D-CT) scanning. Degenerative changes progressed from the lunate facet to the scaphoid fossa at the radiocarpal articulation, then involved the midcarpal joint. Lunate fracture types included coronal (14/20), sagittal (10/20) and ligament attachment-types (8/20). Findings specific to dynamic scanning included the nutcracker phenomenon (12/20), anterior radiolunate impingement (7/20), internal instability of the lunate (6/20), ulnar styloid triquetral impingement (3/20) and dynamic proximal row instability (2/20). Ulnocarpal translocation was found in 4/20 cases. Dynamic 4-D-CT has helped us to identify a subset of pathology in Kienböck's disease on assessment of static imaging. Better understanding of these phenomena can improve our understanding of symptoms and may help direct surgical treatment.Level of evidence: IV.

Defining the proximity of the axillary nerve from defined anatomic landmarks: an in vivo magnetic resonance imaging study.

BACKGROUND: The location of the axillary nerve in the shoulder makes it vulnerable to traumatic or iatrogenic injury. Cadaveric studies have reported the location of the axillary nerve but are limited because of tissue compression, dehydration, and decay. Three-Tesla (T) magnetic resonance imaging (MRI) allows high anatomic resolution of neural structures. The aim of our study was to better define the location of the axillary nerve from defined bony surgical landmarks in vivo, using MRI scan. METHODS: Using MRI, we defined a number of anatomic points and measured the distance from these to the perineural fat surrounding the axillary nerve using simultaneous tracker lines on both images. Two observers were used. RESULTS: A total of 187 consecutive 3-T MRI shoulder scans were included. Mean age was 57.9 years (range 18-86). The axillary nerve was located at a mean of 14.1 mm inferior from the bony glenoid at the anterior border, 11.9 mm from the midpoint, and 12.0 mm from the posterior border. There was a significant difference between distance at the anterior border and midpoint (P < .001), and between the anterior and posterior borders (P < .001). The axillary nerve was located at a mean of 12.6 mm medial to the humeral shaft at the anterior border, 9.9 mm at the midpoint, and 8.6 mm from the posterior border. There was a significant difference between distance at the anterior border and midpoint (P = .008) and between the anterior and posterior borders (P = .002). The mean distance of the axillary nerve from the anterolateral edge of the acromion was 53.3 mm (95% confidence interval [CI] 52.3, 54.2; range 33.9-76.3). The mean distance of the axillary nerve from the inferior edge of the capsule was 2.7 mm (95% CI 2.9, 3.1; range 0.3-9.9). There was a positive correlation between humeral head diameter and axillary nerve distance from the inferior glenoid (R2 = 0.061, P < .001). There was a positive correlation between humeral head diameter and distance from the anterolateral edge of the acromion (R2 = 0.140, P < .001). CONCLUSION: Our study has defined the proximity of the axillary nerve from defined anatomic landmarks. The proximity of the axillary nerve to the inferior glenoid and medial humeral shaft changes as the axillary nerve passes from anterior to posterior. The distance of the axillary nerve from the anterolateral edge of the acromion remains relatively constant. Both sets of distances may be affected by humeral head size. The study has relevance to the shoulder surgeon when considering "safe zones" during arthroscopic or open surgery.

Design, Synthesis, and Structure-Activity Relationship Studies of Dual Inhibitors of Soluble Epoxide Hydrolase and 5-Lipoxygenase.

Inhibition of multiple enzymes of the arachidonic acid cascade leads to synergistic anti-inflammatory effects. Merging of 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) pharmacophores led to the discovery of a dual 5-LOX/sEH inhibitor, which was subsequently optimized in terms of potency toward both targets and metabolic stability. The optimized lead structure displayed cellular activity in human polymorphonuclear leukocytes, oral bioavailability, and target engagement in vivo and demonstrated profound anti-inflammatory and anti-fibrotic efficiency in a kidney injury model caused by unilateral ureteral obstruction in mice. These results pave the way for investigating the therapeutic potential of dual 5-LOX/sEH inhibitors in other inflammation- and fibrosis-related disease models.

Application of dermal chlorhexidine antisepsis is ineffective at reducing Proprionibacterium acnes colonization in shoulder surgery.

BACKGROUND: Chlorhexidine as a skin surface antiseptic has been shown to be ineffective with respect to reducing Proprionibacterium acnes colonization within the dermis. The purpose of the present study was to determine whether the application of aqueous chlorhexidine solution to the dermal layer decreased P. acnes colonization during open shoulder surgery. METHODS: The present study enrolled 50 patients who were undergoing open shoulder surgery. Patients received standard antimicrobial preparation. Three dermal swabs were taken from each patient: swab 1 following skin incision; swab taken 2 minutes to 5 minutes post-application of aqueous chlorhexidine to the dermis; and swab 3 taken 60 minutes post-application. RESULTS: Mean age was 57.5 years (22 males, 28 females). There were 21 patients (42%) with P. acnes present on any dermal swab. There were significantly more P. acnes positive cultures identified at swab 3 compared to swab 1 (p = 0.043). In nine patients with positive P. acnes at cultures swab 1, eight also isolated P. acnes after at swabs 2 or 3. Males were significantly more likely to have P. acnes on any swab (p < 0.001). Positive P. acnes cultures were significantly more common in patients ≤50 years (p < .001). None of the patients had any clinical signs of infection at a minimum of 1 year following surgery. CONCLUSIONS: Dermal application of aqueous chlorhexidine during open shoulder surgery fails to eradicate or reduce P. acnes on deep cultures.

Association of scapholunate dissociation and two-part articular fractures of the distal radius.

Scapholunate dissociation may occur in association with distal radial fractures and is easily missed at initial presentation. The aim of this study was to examine variances in the scapholunate distance with respect to subtypes of two-part partial articular distal radial fractures. Axial computed tomography (CT) scans of acute two-part intra-articular radial fractures were assessed retrospectively from 80 patients and compared to 20 controls. From each scan, two images were analysed to identify the scaphoid, lunate and articular fracture line in the distal radius for fracture type categorization. The images were overlaid on a standardized distal radius template and the scapholunate distance measured. Significant increase in the scapholunate distance was noted in fracture subtypes: radial styloid oblique; dorsal ulnar column; sagittal ulnar column; and volar coronal. We conclude that these findings support the need for a higher index of suspicion for scapholunate dissociation in these distal radial fracture subtypes. Level of evidence: III.

PAX4 R192H is associated with younger onset of Type 2 diabetes in East Asians in Singapore.

AIMS: Young-onset T2D (YT2D) is associated with a more fulminant course and greater propensity for diabetic complications. The association of PAX4 R192H (rs2233580) variation with YT2D was inconsistent partly because of its Asian-specificity and under-representation of Asians in international consortiums. Interestingly, in our preliminary YT2D (mean = 25 years old) cohort, the prevalence of PAX4 R192H variant was remarkably higher (21.4%) than the general population. Therefore, we sought to determine whether PAX4 R192H is associated with younger onset of T2D in our East Asian (Chinese) population. METHODS: Genotyping of PAX4 R192H was carried out using Illumina OmniExpress BeadChips as part of a genome-wide association study. Data analysis was performed using SPSS Ver. 22. RESULTS: PAX4 R192H genotype was associated with younger onset age (CC: 47.1, CT: 46.0, TT: 42.6) after adjusting for gender, F = 5.402, p = 0.005. Independently, onset of diabetes was younger among males by 2.52 years, 95% CI [-3.45, -1.59], p < 0.0001. HOMA-IR and HOMA-%B were not significantly different across genotypes for a subset (n = 1045) of the cohort. CONCLUSIONS: Minor allele (T) of PAX4 R192H is associated with younger onset diabetes among Chinese in Singapore. Determining this genotype is important for identifying at-risk individuals for earlier onset diabetes and diabetic complications.

Radioscapholunate fusion with triquetrum and distal pole of scaphoid excision: long-term follow-up.

The purpose of this study was to assess the long-term outcomes of radioscapholunate fusion, with and without distal pole of scaphoid excision and excision of the triquetrum. These compromised three operative groups. Seventeen patients were identified with a minimum of 10 years follow-up, with a mean of 15 years (range 10-19). Fifteen of the 17 patients were satisfied with their outcome. Two were converted to total wrist fusion. The mean outcomes scores were; pain visual analogue scale score 2.1/10, Quick Disabilities of the Arm, Shoulder, and Hand 29 and Modified Mayo Wrist score 60. Patients with excision of the triquetrum had a mean radial-ulnar arc increase of 10° compared with the other two groups, but this was not statistically significant. The mean space for the scaphocapitate joint was 1.7 mm and lunocapitate joint was 1.3 mm at latest follow-up. Close adherence to the indications and surgical technique provided a sustainable good clinical outcome. Patients who obtained a good result at 2 years were likely to achieve a good long-term outcome. LEVEL OF EVIDENCE: IV.

The Role of Wrist Arthroscopy in Kienbock Disease.

Kienbock disease (KD) is a disease of uncertain etiology, leading to chondral and osseous change in the lunate and wrist. Traditionally, Lichtman's classification of KD, based on radiographic appearances, has been used to direct treatment. Diagnostic wrist arthroscopy allows direct assessment of the lunate and surrounding articulations. Wrist arthroscopy can also serve as a therapeutic tool for performing debridement, resection, or arthrodesis procedures. The new Lichtman-Bain algorithm takes into consideration the status of the lunate, the effect on the wrist, and surgical and patient factors to guide management.

Characterization of the molecular mechanism of 5-lipoxygenase inhibition by 2-aminothiazoles.

5-Lipoxygenase (5-LO, EC1.13.11.34) has been implicated in the pathogenesis of inflammatory and immune diseases. Recently, aminothiazole comprising inhibitors have been discovered for this valuable target. Yet, the molecular mode of action of this class of substances is only poorly understood. Here, we present the detailed molecular mechanism of action of the compound class and the in vitro pharmacological profile of two lead compounds ST-1853 and ST-1906. Mechanistic studies with recombinant proteins as well as intact cell assays enabled us to define this class as a novel type of 5-LO inhibitors with unique characteristics. The parent compounds herein presented a certain reactivity concerning oxidation and thiol binding: Unsubstituted aminophenols bound covalently to C159 and C418 of human 5-LO. Yet, dimethyl substitution of the aminophenol prevented this reactivity and slowed down phase II metabolism. Both ST-1853 and ST-1906 confirmed their lead likeness by retaining their high potency in physiologically relevant 5-LO activity assays, high metabolic stability, high specificity and non-cytotoxicity.

Michael acceptor containing drugs are a novel class of 5-lipoxygenase inhibitor targeting the surface cysteines C416 and C418.

Recently, we published that nitro-fatty acids (NFA) are potent electrophilic molecules which inhibit 5-lipoxygenase (5-LO) by interacting catalytically with cysteine residues next to a substrate entry channel. The electrophilicity is derived from an intramolecular Michael acceptor moiety consisting of an electron-withdrawing group in close proximity to a double bond. The potential of the Michael acceptor moiety to interact with functionally relevant cysteines of proteins potentially renders them effective and sustained enzyme activity modulators. We screened a large library of naturally derived and synthetic electrophilic compounds to investigate whether other types of Michael acceptor containing drugs suppress 5-LO enzyme activity. The activity was measured by assessing the effect on the 5-LO product formation of intact human polymorphonuclear leukocytes. We demonstrated that a number of structurally different compounds were suppressive in the activity assays and showed that Michael acceptors of the quinone and nitro-alkene group produced the strongest inhibition of 5-LO product formation. Reactivity with the catalytically relevant cysteines 416 and 418 was confirmed using mutated recombinant 5-LO and mass spectrometric analysis (MALDI-MS). In the present study, we show for the first time that a number of well-recognized naturally occurring or synthetic anti-inflammatory compounds carrying a Michael acceptor, such as thymoquinone (TQ), the paracetamol metabolite NAPQI, the 5-LO inhibitor AA-861, and bardoxolone methyl (also known as RTA 402 or CDDO-methyl ester) are direct covalent 5-LO enzyme inhibitors that target the catalytically relevant cysteines 416 and 418.