Lysophosphatidic acid receptor 1 antagonist (EPGN2154) causes regression of NASH in preclinical NASH models.

BACKGROUND: NASH causes a tremendous health care burden in the United States. A glucagon-like peptide-1 agonist, semaglutide (Sema), treatment resulted in hepatic steatosis reduction in clinical trials of NASH. Lysophosphatidic acid receptor 1 antagonists are known to have antifibrotic effects in several organs. We tested Sema and a novel lysophosphatidic acid receptor 1 antagonist, EPGN2154, individually and in combination to evaluate their efficacy for NASH remission in preclinical models. METHODS: In the present study, we used (1) C57Bl6/J wild-type mice fed on a high-fat, high-carbohydrate (HFHC) diet for 16 weeks and (2) leptin-deficient mice (ob/ob) fed on an Amylin liver NASH diet for 16 weeks. After 16 weeks, the mice were randomly distributed in equal numbers in (1) no-drug, (2) EPGN2154, (3) Sema, and (4) EPGN2154+Sema treatment groups for 8 additional weeks at a dosage of 10 mg/kg body weight for EPGN2154 (oral gavage, 5 days a week) and 6.17 µg/kg body weight of Sema (subcutaneous injection every alternate day, 3 days a week). RESULTS: In the wild-type-high-fat, high-carbohydrate model, we observed the most body weight loss in the EPGN2154+Sema combination group compared to the other treatment groups. All groups led to a significant reduction in alanine transaminase levels when compared to high-fat, high-carbohydrate-fed wild type. However, no significant difference in alanine transaminase levels was observed among the treatment groups. In the ob/ob mice study, Sema did not cause body weight loss. Moreover, the EPGN2154 and the combination groups had a lower NAFLD Activity Score and incidence of advanced-stage hepatic fibrosis than the Sema group. CONCLUSIONS: EPGN2154 demonstrated a hepato-protective effect independent of body weight loss in preclinical NASH models.

Topographical Analysis of Pacinian Corpuscle in the Pulp of Human Cadaver Finger Tip Pulp: A Pilot Cadaver Study.

Background: The human hand is a specialised organ for fine motion and sensation and has a relatively large representation in the homunculus. The pathway of sensation starts from information sent by mechanoreceptors in the hand. This study reports the topography of the Pacinian corpuscle in the fingertips of a human cadaver. Methods: All 10 digits from both hands of a fresh-frozen cadaver were examined. Glabrous skin distal to the distal interphalangeal joint was harvested superficial to the periosteum including fat and subcutaneous tissue. The glabrous skin were divided into 10 sections that included five distal and five proximal sections. Modified gold chloride staining was performed. Sectioned specimens were observed under a light microscope and the density of Pacinian corpuscles was determined in each segment. The density of the corpuscles was compared between the radial/ulnar and proximal/distal segments and also between digits from the right hand versus those from the left hand. Results: Pacinian corpuscles were observed only in the subcutaneous tissue. There was no significant difference in density of the corpuscles between the distal and proximal segments or between the right and left hands. There was a statistically significant greater density of Pacinian corpuscles on the radial segments of all digits except the thumb. Conclusions: There is a greater density of Pacinian corpuscles on the radial side of the human fingertip in all digits except the thumb.

Photothermally Active Core-Shell Catalyst Based on UiO-66 and Polydopamine for Highly Effective Detoxification of Nerve Agents.

A new, photothermally active, catalytic composite (Fe3O4@PD@UiO-66) based on UiO-66 and polydopamine (PD) was prepared for the decomposition of chemical warfare agents (CWAs). An iron oxide nanoparticle was introduced to enable rapid recovery after the reaction. The PD layer enabled conversion of the absorbed light into heat under infrared (IR) irradiation and increased the reaction temperature, thereby increasing the reaction rate. Dendrimer-functionalized silica particles (NH2-DS) were used as heterogeneous catalyst regenerators instead of N-ethylmorpholine. Under IR irradiation, a mixture of Fe3O4@PD@UiO-66 and NH2-DS was effective as a heterogeneous catalyst for degrading DMNP, with a 5 min half-life in water. Without IR irradiation, the half-life of DMNP was 45 min using the same catalyst mixture. Various bases including arginine, histidine, and D4 were directly modified on the surface of Fe3O4@PD@UiO-66 and used without NH2-DS or N-ethylmorpholine in order to compare their reactivities. Furthermore, a mixture of Fe3O4@PD@UiO-66 and NH2-DS was used for the decomposition of nerve agents, including sarin (GB), soman (GD), and VX, under IR-LED irradiation. Remarkably, GB was effectively decomposed with a half-life of 4.2 min, and GD demonstrated a half-life of 8.7 min. VX was hydrolyzed with a half-life of 14.0 min.

N-doped porous carbons derived from Zn-porphyrin-MOF.

N-doped porous metal-organic framework (MOF)-derived carbons (MDCs) were directly synthesized from a new Zn-DpyDtolP-MOF (ZnDpyDtolP·1/2DMF, H2DpyDtolP = 5,15-di(4-pyridyl)-10,20-di(4-methylphenyl)porphyrin) containing a 3D hexagonal network through a self-templated carbonization method. KOH-activated MDC derivatives denoted as MDC-700-nKOH were also prepared with different weight ratios of KOH activator to MDC (MDC : KOH = 1 : n, where n = 1, 2). Compared to bare MDC, MDC-700-nKOH showed effective improvements of both gas sorption and electrochemical capacitive properties. More developed microporosity by KOH activation might induce great enhancement of high operating capacitive performances. The N-doped MDC-700-2KOH had high maximum gravimetric specific capacitance (555.6 F g-1) and specific energy (40.4 W h kg-1) at 0.1 A g-1 in 1 M H2SO4. Even at a high current density of 190 A g-1 in 6 M KOH, it exhibited high capacitive performance with a large specific power of 80 423 W kg-1. MDC-700-nKOH electrodes also showed good recycling properties of electrochemical capacitance up to 30 000 cycles.

Pullout strength of pedicle screws using cadaveric vertebrae with or without artificial demineralization.

OBJECTIVES: To evaluate the differences in the pullout strength and displacement of pedicle screws in cadaveric thoracolumbar vertebrae with or without artificial demineralization. METHODS: Five human lumbar and five thoracic vertebrae from one cadaver were divided into two hemivertebrae. The left-side specimens were included in the simulated osteopenic model group and the right-side bones in a control group. In the model group, we immersed each specimen in HCl (1 N) solution for 40 minutes. We measured bone mineral density (BMD) using dual-energy X-ray absorptiometry and quantitative computerized tomography. We inserted polyaxial pedicle screws into the 20 pedicles of the cadaveric lumbar and thoracic spine after measuring the BMD of the 2 hemivertebrae of each specimen. We measured the pullout strength and displacement of the screws before failure in each specimen using an Instron system. RESULTS: The average pullout strength of the simulated osteopenic model group was 76% that of the control group. In the control and model groups, the pullout strength was 1678.87±358.96 N and 1283.83±341.97 N, respectively, and the displacement was 2.07±0.34 mm and 2.65±0.50 mm, respectively (p<.05). We detected positive correlations between pullout strength and BMD in the control group and observed a negative correlation between displacement and BMD in the model group. CONCLUSIONS: By providing an anatomically symmetric counterpart, the human cadaveric model with or without demineralization can be used as a test bed for pullout tests of the spine. In the simulated osteopenic model group, pullout strength was significantly decreased compared with the untreated control group. CLINICAL SIGNIFICANCE: Decreased bone mineral density may significantly reduce the pullout strength of a pedicle screw, even though the range is osteopenic rather than osoteoporotic.

Retained Foreign Body Which Should be Suspected as a Cause of Retractable Chronic Hand Inflammation and Diagnostic Capacity of Ultrasonography.

Background: Foreign bodies in the hand are common but easily and often missed in the initial evaluation of injury. Diagnosing retained foreign bodies is difficult due to radiolucent foreign bodies. Purpose of this study is to emphasize the need of consideration of foreign bodies in patients with chronic synovitis in hand. Methods: Twenty-five patients who had retained foreign body in soft tissue of hand with chronic inflammation symptoms were included. Ultrasonography was conducted in all of the patients. Patient age, sex, localization of foreign body, duration of symptom, history of injury, follow up period, complication, and biopsy results were recorded and reviewed. Also, patients' demographics and clinical results were retrospectively reviewed. Results: Nine of the 25 patients diagnosed with a foreign body in the hand did not remember the initial presentation of injury. The average symptom duration (from injury to hospitalization) was 10.5 months (range 1-96 months). The middle finger and the proximal interphalangeal joint were the most common site of a retained foreign body (10 patients). All patients were diagnosed via ultrasonography and underwent surgery. Biopsy results showed mainly chronic inflammation, fibrosis, granuloma, and foreign bodies. Conclusions: Patient with symptoms of cellulitis, osteomyelitis, and palpable mass in hand for over a month without a diagnosis should be suspected of retained FBs.

Spinal Stenosis Grading in Magnetic Resonance Imaging Using Deep Convolutional Neural Networks.

STUDY DESIGN: Retrospective magnetic resonance imaging grading with comparison between experts and deep convolutional neural networks (CNNs). OBJECTIVE: This study aims to verify the feasibility of a computer-assisted spine stenosis grading system by comparing the diagnostic agreement between two experts and the agreement between the experts and trained artificial CNN classifiers. SUMMARY OF BACKGROUND DATA: Spinal stenosis grading is important; however, it is tedious job to check the MR images slide by slide to classify patient grades often having different opinions regarding the final diagnosis. METHODS: For 542 L4-5 axial MR images, two experts independently localized the center position of the spine canal and graded the status. Two CNN classifiers each trained with the grading label made by the two experts were validated using 10-fold cross-validation. Each classifier consisted of a CNN detection model responsible for the localization of patches near the canal and a classification CNN model to predict the spinal stenosis status in the localized patches. Faster R-CNN was used for the detection model whereas VGG network was used for the classification model. A comparison in grading agreement was carried out between the two experts as well as that of the experts and the prediction results generated by the CNN models. RESULTS: Grading agreement between the experts was 77.5% and 75% in terms of accuracy and F1 scores. The agreement between the first expert and the model trained with the labels of the first expert was 83% and 75.4%, respectively. The agreement between the second expert and the model trained with the labels of the second expert was 77.9% and 74.9%. The differences between the two experts were significant, whereas the differences between each expert and the trained models were not significant. CONCLUSION: We indeed confirmed that automatic diagnosis using deep learning may be feasible for spinal stenosis grading. LEVEL OF EVIDENCE: 4.

Neuroanatomical distribution of sensory receptors in the human elbow joint capsule.

BACKGROUND: The topographic arrangement of sensory receptors in the human elbow joint capsule is pertinent to their role in the transmission of neural signals. The signals from stimuli in the joint are concisely delivered via afferent pathways to allow recognition of pain and proprioception. Sensory receptors in the elbow joint include mechanoreceptors and free nerve endings acting as nociceptors, although the distribution of each of the structures has not been determined, despite their importance for the integrity of the joint. We therefore aimed to investigate the neuroanatomical distribution and densities of mechanoreceptors and free nerve endings in the capsule of the elbow, at the same time as considering surgical approaches that would result in the minimum insult to them. METHODS: Four elbow joint capsules were harvested from fresh cadavers. The specimens were carefully separated from adjacent osteoligamentous attachments and the capsular complex was stained with a modified gold chloride method. Evaluations of free nerve endings, and Golgi, Ruffini and Pacinian corpuscles were performed under an inverted light microscope. The number and density of each structure were recorded. RESULTS: Ruffini corpuscles observed to be the dominant mechanoreceptor type. No Golgi corpuscle was observed. Free nerve endings were found at the highest density at posterodistal sites, whereas mechanoreceptors were most frequent at bony attachment sites. CONCLUSIONS: A consistent distribution pattern of articular sensory receptors was observed, which allows further understanding of elbow pathology. An awareness of the neuroanatomical distribution of sensory receptors in the elbow joint capsule may allow their preservation during surgical procedures for elbow joint pathology.

Modified Transosseous Wiring Technique for Neglected Fracture-Dislocation of the Proximal Interphalangeal Joint.

BACKGROUND: Fracture-dislocation of the proximal interphalangeal (PIP) joint of the finger is challenging due to the high risk of stiffness. The purpose of this study is to evaluate the clinical and radiological results of a modified transosseous wiring technique for the management of chronic fracture-dislocations of the PIP joint. METHODS: Ten patients (nine men and one woman; mean age, 38.3 years; range, 21 to 69 years) with neglected fracture-dislocation of the PIP joint were included. The mean duration from injury to operation was 14.7 weeks (range, 3 to 66 weeks). The dorsolateral approach and extension block pinning were used to reduce dislocation. After thorough debridement of the scar tissues in the dorsal dead space and the fracture site, the reduction was maintained with transosseous wiring. Radiologic evaluations of bone union and arthritic changes and clinical evaluations (range of motion of the PIP joint and Disabilities of the Arm, Shoulder and Hand [DASH] score) were performed. The mean follow-up period was 12.9 months (range, 12 to 19 months). RESULTS: All patients demonstrated evidence of radiographic healing within a mean healing time of 6 weeks (range, 4 to 10 weeks); however, one had a widened gap and one had an early arthritic change. The mean range of motion in the PIP joint was 81° (range, 50° to 105°). The mean DASH score was 21.6 (range, 7.5 to 35.8). CONCLUSIONS: For chronic fracture-dislocation of the PIP joint, transosseous wiring with direct curettage and optimal bone purchase can provide satisfying outcome.

Mechanoreceptor profile of the lateral collateral ligament complex in the human elbow.

BACKGROUND: Active restraint for the elbow joint is provided by the soft tissue component, which consists of a musculoligamentous complex. A lesion of the lateral collateral ligament complex (LCLC) is thought to be the primary cause of posterolateral rotatory instability in the elbow. Its role as a protective reflexogenic structure is supported by the existence of ultrastructural mechanoreceptors. The aim of this study was to describe the existence and distribution of LCLC mechanoreceptors in the human elbow joint and to determine their role in providing joint stability. METHODS: Eight LCLCs were harvested from fresh frozen cadaver elbows. Specimens were carefully separated from the lateral epicondyle and ulna. The ligament complex was divided into 7 regions of interest and stained with modified gold chloride. Microscopic evaluation was performed for Golgi, Ruffini, and Pacinian corpuscles. The number, distribution, and density of each structure were recorded. RESULTS: Golgi, Ruffini, and Pacinian corpuscles were observed in LCLCs, with variable distribution in each region of interest. Ruffini corpuscles showed the highest total mechanoreceptor density. Mechanoreceptor density was higher at bony attachment sites. CONCLUSION: The existence and role of each mechanoreceptor defined the purpose of each region of interest. Mechanoreceptors are beneficial for its proprioceptive feature towards a successful elbow ligament reconstruction.

Clenching Reduction Technique for Osteosynthesis of Atypical C2 Fractures with the Combining Use of Laminar and Pedicle Screw: A Technical Note.

Atypical C2 fractures refer to all fracture types of the C2 body excluding odontoid fractures and traumatic spondylolisthesis of C2. A 55-year-old male patient presented with neck pain after a vehicular accident. Computed tomography (CT) showed an oblique fracture line of the C2 vertebral body through the pedicle and lamina with fracture gap and posterior displacement. We used a clenching reduction technique to treat this fracture by using an ipsilateral laminar screw and contralateral pedicle screw. The final follow-up CT scan showed complete bone union. Neck motion was preserved including rotation. For this unstable atypical C2 fracture, the clenching reduction technique proved to be a safe and effective technique while salvaging neck motion.

Synthesis, Characterization, and Efficient Catalytic Activities of a Nickel(II) Porphyrin: Remarkable Solvent and Substrate Effects on Participation of Multiple Active Oxidants.

A new nickel(II) porphyrin complex, [NiII (porp)] (1), has been synthesized and characterized by 1 H NMR, 13 C NMR and mass spectrometry analysis. This NiII porphyrin complex 1 quantitatively catalyzed the epoxidation reaction of a wide range of olefins with meta-chloroperoxybenzoic acid (m-CPBA) under mild conditions. Reactivity and Hammett studies, H218 O-exchange experiments, and the use of PPAA (peroxyphenylacetic acid) as a mechanistic probe suggested that participation of multiple active oxidants NiII -OOC(O)R 2, NiIV -Oxo 3, and NiIII -Oxo 4 within olefin epoxidation reactions by the nickel porphyrin complex is markedly affected by solvent polarity, concentration, and type of substrate. In aprotic solvent systems, such as toluene, CH2 Cl2 , and CH3 CN, multiple oxidants, NiII -(O)R 2, NiIV -Oxo 3, and NiIII -Oxo 4, operate simultaneously as the key active intermediates responsible for epoxidation reactions of easy-to-oxidize substrate cyclohexene, whereas NiIV -Oxo 3 and NiIII -Oxo 4 species become the common reactive oxidant for the difficult-to-oxidize substrate 1-octene. In a protic solvent system, a mixture of CH3 CN and H2 O (95:5), the NiII -OOC(O)R 2 undergoes heterolytic or homolytic O-O bond cleavage to afford NiIV -Oxo 3 and NiIII -Oxo 4 species by general acid catalysis prior to direct interaction between 2 and olefin, regardless of the type of substrate. In this case, only NiIV -Oxo 3 and NiIII -Oxo 4 species were the common reactive oxidant responsible for olefin epoxidation reactions.

Results of Abductor Pollicis Longus Suspension Ligamentoplasty for Treatment of Advanced First Carpometacarpal Arthritis.

BACKGROUND: Suspension ligamentoplasty using abductor pollicis longus (APL) tendon without bone tunneling, was introduced as one of the techniques for treatment of advanced first carpometacarpal (CMC) arthritis. The purpose of this study was to evaluate the radiologic and clinical results of APL suspension ligamentoplasty. METHODS: The medical records of 19 patients who underwent APL suspension ligamentoplasty for advanced first CMC arthritis between January 2008 and May 2012 were reviewed retrospectively. The study included 13 female and 6 male patients, whose mean age was 62 years (range, 43 to 82 years). For clinical evaluation, we assessed the grip and pinch power, radial and volar abduction angle, thumb adduction (modified Kapandji index), including visual analogue scale (VAS) and Disabilities of the Arm, Shoulder and Hand (DASH) scores. Radiologic evaluation was performed using simple radiographs. RESULTS: The mean follow-up was 36 months (range, 19 to 73.7 months). Mean power improved from 18.3 to 27 kg for grip power, from 2.8 to 3.5 kg for tip pinch, and from 4.3 to 5.4 kg for power pinch. All patients showed decreased VAS from 7.2 to 1.7. Radial abduction improved from 71° preoperatively to 82° postoperatively. The modified Kapandji index showed improvement from 6 to 7.3, and mean DASH was improved from 41 to 17.8. The height of the space decreased from 10.8 to 7.1 mm. Only one case had a complication involving temporary sensory loss of the first dorsal web space, which resolved spontaneously. CONCLUSIONS: The APL suspension ligamentoplasty for treatment of advanced first CMC arthritis yielded satisfactory functional results.

Efficacy of intra-articular injection of thrombin-based hemostatic agent in the control of bleeding after primary total knee arthroplasty.

PURPOSE: To evaluate the hemostatic effect of intraarticular injection of a thrombin-based hemostatic agent in total knee arthroplasty (TKA). MATERIALS AND METHODS: We performed a prospective randomized controlled trial on the use of a thrombin-based hemostatic agent in patients undergoing unilateral TKA. A total of 100 TKA patients were enrolled, with 50 patients randomized into the study group and the other 50 patients into the controlled group. Drain output, hemoglobin level, total red blood cell loss for 24 hours after surgery, transfusion rates, and complications were assessed. RESULTS: Postoperative drain output was 525 mL in the study group and 667 mL in the control group (p=0.01). Nine patients in the study group and eighteen in the control group received blood transfusion (p=0.043). But, there was no significant difference between two groups in terms of hemoglobin level change and total red blood cell loss (p>0.05). CONCLUSIONS: The thrombin-based hemostatic agent demonstrated efficacy in reducing drain output and blood transfusion rates. Thus, we believe the use of a thrombin-based hemostatic agent should be considered as an option in orthopedic surgery that involves massive bleeding.

Transtendinous wiring of mallet finger fractures presenting late.

PURPOSE: To determine if transtendinous wiring was an effective late treatment for bony mallet injuries. METHODS: Between 2005 and 2011, 19 consecutive patients (13 men, 6 women) with a mean age of 29 years (range, 13-52 y) were treated late for mallet finger fractures. The mean interval from injury to initial operation was 57 days (range, 28-141 d). RESULTS: Fifteen of 18 mallet fractures demonstrated evidence of radiographic healing after an average of 6 weeks (range, 5-10 wk). One patient developed ankylosis, and 3 patients failed to achieve bone union at the final follow-up. The mean motion of the distal interphalangeal joint was 73° (range, 35°-95°), and the mean extension lag was 7° (range, 0°-25°). CONCLUSIONS: Transtendinous wiring was an effective late treatment for mallet fractures, demonstrating satisfactory fixation, allowing early mobilization, and showing good functional results while avoiding salvage operations. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

CO(2) selective 1D double chain dipyridyl-porphyrin based porous coordination polymers.

Thermal reactions of MnCl(DPyP) (DPyP = 5,15-di(4-pyridyl)-10,20-diphenylporphyrin) as a metalloligand with Co(II) and Zn(II) ions in dimethylformamide led to neutral one-dimensional (1D) double chain dipyridyl-porphyrin-based porous coordination polymers (PCPs), Co3(DPyP)3·4DMF (I) and Zn3(DPyP)3·2DMF·4H2O (II). Both PCPs were structurally characterized by X-ray crystallography. Particularly, the central Mn(III) ion in MnCl(DPyP) was transmetallated with Co(II) or Zn(II) ions and the central Co(II) or Zn(II) ions were further coordinated to pyridyl groups of neighboring M(DPyP) (M = Co or Zn) porphyrin complexes. PCPs I and II are isostructural and each 1D double chain interacts with another 1D double chain by multiple hydrogen bonding to stabilize the resulting framework. Therefore, solvent-free 1D double chain PCPs have permanent porosity, and the void volumes of the solvent-free I and II are calculated to be 22.6% and 23.0%, respectively. Gas sorption analysis indicated that I and II exhibited selective adsorption of CO2 at 196 K. Both PCPs exhibited much smaller sorption abilities for N2 (77 K), H2 (77 K), and CH4 (196 K) than CO2 (196 K). Both PCPs exhibited different PXRD patterns when dried at 373 K, which indicated that the framework transformation of the isostructural M3(DPyP)3 type of PCPs strongly depended on the type of central metal ions.

Dramatic enhancement of carrier mobility via effective secondary structural arrangement resulting from the substituents in a porphyrin transistor.

OFET devices based on single-crystals of two different porphyrin derivatives display excellent mobilities of 2.57 and 0.48 cm(2) V(-1) s(-1). Although they generate similar J-aggregations, the dramatic enhancement of mobility obtained using porphyrin 1 is due to the well-confined secondary structural arrangement caused by substituents on the porphyrin ring.

An unsymmetrically π-extended porphyrin-based single-crystal field-effect transistor and its anisotropic carrier-transport behavior.

Anisotropic charge transport: Single-crystal organic field-effect transistor devices derived from aggregates of thiophene-appended porphyrins display very high mobility (0.27 cm(2) V(-1) s(-1)). This behavior is due to staircase stacking of the porphyrins with distances between layers of 3.17(7) Å. Furthermore, the charge-transport behavior is anisotropic owing to an anisotropic molecular arrangement in the single-crystal microplates.

Tricyclic GyrB/ParE (TriBE) inhibitors: a new class of broad-spectrum dual-targeting antibacterial agents.

Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.

Remarkable solvent, porphyrin ligand, and substrate effects on participation of multiple active oxidants in manganese(III) porphyrin catalyzed oxidation reactions.

The participation of multiple active oxidants generated from the reactions of two manganese(III) porphyrin complexes containing electron-withdrawing and -donating substituents with peroxyphenylacetic acid (PPAA) as a mechanistic probe was studied by carrying out catalytic oxidations of cyclohexene, 1-octene, and ethylbenzene in various solvent systems, namely, toluene, CH(2) Cl(2) , CH(3) CN, and H(2) O/CH(3) CN (1:4). With an increase in the concentration of the easy-to-oxidize substrate cyclohexene in the presence of [(TMP)MnCl] (1a) with electron-donating substituents, the ratio of heterolysis to homolysis increased gradually in all solvent systems, suggesting that [(TMP)Mn-OOC(O)R] species 2a is the major active species. When the substrate was changed from the easy-to-oxidize one (cyclohexene) to difficult-to-oxidize ones (1-octene and ethylbenzene), the ratio of heterolysis to homolysis increased a little or did not change. [(F(20) TPP)Mn-OOC(O)R] species 2b generated from the reaction of [(F(20) TPP)MnCl] (1b) with electron-withdrawing substituents and PPAA also gradually becomes involved in olefin epoxidation (although to a much lesser degree than with [(TMP)Mn-OOR] 2a) depending on the concentration of the easy-to-oxidize substrate cyclohexene in all aprotic solvent systems except for CH(3) CN, whereas Mn(V)=O species is the major active oxidant in the protic solvent system. With difficult-to-oxidize substrates, the ratio of heterolysis to homolysis did not vary except for 1-octene in toluene, indicating that a Mn(V)=O intermediate generated from the heterolytic cleavage of 2b becomes a major reactive species. We also studied the competitive epoxidations of cis-2-octene and trans-2-octene with two manganese(III) porphyrin complexes by meta-chloroperbenzoic acid (MCPBA) in various solvents under catalytic reaction conditions. The ratios of cis- to trans-2-octene oxide formed in the reactions of MCPBA varied depending on the substrate concentration, further supporting the contention that the reactions of manganese porphyrin complexes with peracids generate multiple reactive oxidizing intermediates.