Tofacitinib and peficitinib inhibitors of Janus kinase for autoimmune disease treatment: a quantum biochemistry approach.

Autoimmune inflammatory diseases, such as rheumatoid arthritis (RA) and ulcerative colitis, are associated with an uncontrolled production of cytokines leading to the pronounced inflammatory response of these disorders. Their therapy is currently focused on the inhibition of cytokine receptors, such as the Janus kinase (JAK) protein family. Tofacitinib and peficitinib are JAK inhibitors that have been recently approved to treat rheumatoid arthritis. In this study, an in-depth analysis was carried out through quantum biochemistry to understand the interactions involved in the complexes formed by JAK1 and tofacitinib or peficitinib. Computational analyses provided new insights into the binding mechanisms between tofacitinib or peficitinib and JAK1. The essential amino acid residues that support the complex are also identified and reported. Additionally, we report new interactions, such as van der Waals; hydrogen bonds; and alkyl, pi-alkyl, and pi-sulfur forces, that stabilize the complexes. The computational results revealed that peficitinib presents a similar affinity to JAK1 compared to tofacitinib based on their interaction energies.

Phytanic acid, an inconclusive phytol metabolite: A review.

Phytanic acid (PA: 3,7,11,15-tetramethylhexadecanoic acid) is an important biometabolite of the chlorophyll-derived diterpenoid phytol. Its biological sources (occurrence) and ADME (absorption, distribution, metabolism, and elimination) profile are well-discussed in the literature. Cumulative literature suggests that PA has beneficial as well as harmful biological roles in humans and other animals. This study aimed to sketch a brief summary of PA's beneficial and harmful pharmacological effects in test systems on the basis of existing literature reports. Literature findings propose that PA has anti-inflammatory and immunomodulatory, antidiabetic, anti-obesity, anticancer, and oocyte maturation effects. Although a high plasma PA-level mediated SLS remains controversial, it is evident to link it with Refsum's disease and other peroxisomal enzyme deficiency diseases in humans, including RCDP and LD; ZHDA and Alzheimer's disease; progressive ataxia and dysarthria; and an increased risk of some lymphomas such as LBL, FL, and NHL. PA exerts toxic effects on different kinds of cells, including neuronal, cardiac, and renal cells, through diverse pathways such as oxidative stress, mitochondrial disturbance, apoptosis, disruption of Na+/K+-ATPase activity, Ca2+ homeostasis, alteration of AChE and MAO activities, etc. PA is considered a cardiac biomarker in humans. In conclusion, PA may be one of the most important biometabolites in humans.

Graphene Nano-Optics in the Terahertz Gap.

Graphene nano-optics at terahertz (THz) frequencies (ν) is theoretically anticipated to feature extraordinary effects. However, interrogating such phenomena is nontrivial, since the atomically thin graphene dimensionally mismatches the THz radiation wavelength reaching hundreds of micrometers. Greater challenges happen in the THz gap (0.1-10 THz) wherein light sources are scarce. To surpass these barriers, we use a nanoscope illuminated by a highly brilliant and tunable free-electron laser to image the graphene nano-optical response from 1.5 to 6.0 THz. For ν < 2 THz, we observe a metal-like behavior of graphene, which screens optical fields akin to noble metals, since this excitation range approaches its charge relaxation frequency. At 3.8 THz, plasmonic resonances cause a field-enhancement effect (FEE) that improves the graphene imaging power. Moreover, we show that the metallic behavior and the FEE are tunable upon electrical doping, thus providing further control of these graphene nano-optical properties in the THz gap.

Effect of the quality of orthodontic finishing on the stability of anterior tooth alignment.

OBJECTIVES: To evaluate whether the quality of orthodontic finishing influences long-term stability of anterior tooth alignment. MATERIALS AND METHODS: This retrospective study evaluated 38 patients. Data were obtained at the beginning of treatment (T0), at the end (T1), and at least 5 years after T1 (T2). At this point, the individuals were no longer wearing retainers. Anterior tooth alignment was measured using Little's index (LI). Effect on alignment stability was tested with multiple linear regression using LI-T0, LI-T1, intercanine width difference T1-T0, overbite (T1), overjet (T1), age, gender, time without retention, and presence of third molars as predictor variables. Well-aligned (LI < 1.5 mm) and misaligned (LI > 1.5 mm) cases were compared at T2. RESULTS: At T2, the alignment stability in the upper arch was inversely associated with the alignment quality (R2 = 0.378, P < .001) and directly associated with overbite (R2 = 0.113, P = .008) at T1. Posttreatment changes caused cases finished with poor alignment to become similar to those finished with excellent alignment (P = .917). In the mandible, posttreatment changes were directly associated only with overjet (R2 = 0.152, P = .015) and well-finished cases displayed better alignment than poorly finished cases (P = .011). Other variables showed no significant association. CONCLUSIONS: In arches without retention, better quality of orthodontic finishing does not guarantee the stability of anterior alignment. In the maxilla, long-term changes were more significant the greater the overbite and the better the quality of alignment at end of treatment. In the mandible, changes were not dependent on the quality of finishing but were associated with greater overbite at T2.

Effect of Lippia alba (Mill.) N.E. Brown Essential Oil on the Human Umbilical Artery.

Lippia alba is popularly known as lemon balm, with its essential oil (EO) cited for displaying antimicrobial, sedative, and vasorelaxant effects. Yet, its action on isolated human vessels has not been described in the literature. Thus, we evaluated the vasorelaxant effect of essential oil of L. alba (EOLa) on human umbilical arteries (HUA) isolated in organ baths. HUA rings were isolated, subjected to contractions induced by potassium chloride (KCl), serotonin (5-HT), or histamine (HIST) to record the isometric tension, and then treated with EOLa (30-1000 µg/mL). The EOLa showed a more prominent inhibitory effect on the pharmacomechanical coupling contraction via HIST with an EC50 value of 277.1 ± 8.5 µg/mL and maximum relaxant effect at 600 µg/mL. The addition of tetraethylammonium (TEA) or 4-aminopyridine (4-AP) in HUA preparations did not inhibit EOLa total relaxant effect at 1000 µg/mL. In the presence of gliblenclamide (GLI), the oil relaxed the HUA rings by 90.8% at maximum concentration. The EOLa was also investigated for its effects on voltage-operated calcium channels (VOCCs), where the HUA preincubation with this oil at 1000 µg/mL inhibited BaCl2 (0.1-30 mM)-induced contractions. This study demonstrates for the first time that EOla has a vasorelaxant effect on HUA and its particular blockade of VOCCs.

Evaluation of the antibacterial and inhibitory activity of NorA and MepA efflux pumps from Staphylococcus aureus by diosgenin.

The increase in bacterial resistance to available antibiotics has driven several researchers to search for new agents with therapeutic properties. Diosgenin is a naturally occurring steroidal saponin that has demonstrated several pharmacological properties. In the present study, we report the antimicrobial activity of diosgenin against the standard and multidrug-resistant bacteria of Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus, in addition to the efflux pump inhibitory activity against Staphylococcus aureus strains carrying NorA and MepA pumps. For this purpose, the broth microdilution method was used, from which the value of the Minimum Inhibitory Concentration (MIC) was obtained, and this was associated with subinhibitory concentration (MIC/8) with antibiotic of clinical use and ethidium bromide for strains carrier by efflux pump. Diosgenin showed antimicrobial activity for standard S. aureus bacteria and potentiating activity in association with gentamicin and ampicillin for P. aeruginosa multidrug-resistant bacteria, it also showed potentiation in association with norfloxacin against the E. coli strain and gentamicin against the S. aureus strain. Antimicrobial activity against efflux pump-bearing strains revealed that saponin did not interfere with the efflux pump mechanism or intervened antagonistically. Thus, saponin has shown to be very promising against bacterial resistance in association with aminoglycoside, fluoroquinolones and beta-lactam, however additional studies should be carried out to better elucidate the mechanism of action of diosgenin.

Analysis of gunshot residues from nontoxic ammunition: a contribution to health and environmental analysis.

This study's aim was to determine the presence, as well as to evaluate the health and environmental impacts, of chemical elements from firearm shots during shooter practice at outdoor shooting ranges, both in the environment and on the shooters' hands. Two high-precision devices were used for measuring suspended particles that are released during discharge of Taurus PT 100 .40 caliber pistols. The analysis of collected data allowed the identification of specific distribution patterns of samples that were adsorbed. Moreover, samples were collected from the opisthenar area of the hand to investigate both the occurrence and deposition of particles and chemical elements through scanning electron microscopy coupled with energy dispersive spectroscopy (SEM-EDS). The results indicate that copper, lead, and zinc concentration profiles will be able to delimit and reveal more precise details regarding shots made with nontoxic ammunition (NTA). In particular, the residual graphic analysis indicated that the majority of metal deposited in the shooter's hand is zinc. Further, the metals barium and lead also were detected. Due to the exposure to these elements, it could be concluded that engineering controls and administrative management should be sought in order to avoid human overexposure and environmental release of these airborne toxic metals.

Practical approach for lateral canal benign paroxysmal positional vertigo.

Benign paroxysmal positional vertigo (BPPV) of the lateral semicircular canal is a well-recognized condition, even though there are controversies about the repositioning maneuvers and their efficacy. In recent decades, several maneuvers have been proposed for treating both apogeotropic and geotropic variants of lateral canal BPPV. Our purpose is to discuss a practical approach to this pathology with the Zuma maneuver. In a single session, this maneuver may be useful to treat patients with canalithiasis of the ampullary and non-ampullary arms, and cupulolithiasis with the otoliths in the canal and utricular side of the lateral canal.

Bacterial volatile organic compounds induce adverse ultrastructural changes and DNA damage to the sugarcane pathogenic fungus Thielaviopsis ethacetica.

Due to an increasing demand for sustainable agricultural practices, the adoption of microbial volatile organic compounds (VOCs) as antagonists against phytopathogens has emerged as an eco-friendly alternative to the use of agrochemicals. Here, we identified three Pseudomonas strains that were able to inhibit, in vitro, up to 80% of mycelial growth of the phytopathogenic fungus Thielaviopsis ethacetica, the causal agent of pineapple sett rot disease in sugarcane. Using GC/MS, we found that these bacteria produced 62 different VOCs, and further functional validation revealed compounds with high antagonistic activity to T. ethacetica. Transcriptomic analysis of the fungal response to VOCs indicated that these metabolites downregulated genes related to fungal central metabolism, such as those involved in carbohydrate metabolism. Interestingly, genes related to the DNA damage response were upregulated, and micro-FTIR analysis corroborated our hypothesis that VOCs triggered DNA damage. Electron microscopy analysis showed critical morphological changes in mycelia treated with VOCs. Altogether, these results indicated that VOCs hampered fungal growth and could lead to cell death. This study represents the first demonstration of the molecular mechanisms involved in the antagonism of sugarcane phytopathogens by VOCs and reinforces that VOCs can be a sustainable alternative for use in phytopathogen biocontrol.

The role of the reversed nystagmus during Zuma maneuver in patients treated for geotropic lateral canal benign paroxysmal positional vertigo.

INTRODUCTION: The geotropic variant of lateral canal BPPV occurs due to free floating otoconia in the non ampullary arm of this canal. Several repositioning maneuvers were effective to treat patients with this variant. We have previously proposed that the Zuma maneuver, first described for apogeotropic lateral canal BPPV, could also be effective for the geotropic variant as we believe that adopting a single maneuver may help the neurotological clinical practice. MATERIAL AND METHODS: Fifteen patients with geotropic lateral canal BPPV were enrolled and treated with Zuma maneuver. Patients were reevaluated 1 h after a single maneuver. RESULTS: All patients showed a nystagmus beating to the affected side in step I of Zuma maneuver that reversed its direction in step II. Besides, all patients achieved immediate resolution of vertigo and positional nystagmus after the application of the maneuver. CONCLUSIONS: The reversal of the nystagmus in step II of Zuma maneuver could be considered as a good prognostic indicator of the successful of this maneuver in patients with geotropic lateral canal BPPV. Moreover, despite the small sample of patients, Zuma maneuver was effective on short-term follow up for geotropic LC-BPPV after a single application.

Three-dimensional simulations of six treatment maneuvers for horizontal canal benign paroxysmal positional vertigo canalithiasis.

BACKGROUND AND PURPOSE: Horizontal canal benign paroxysmal positional vertigo (BPPV) is the second most common variant of BPPV after posterior canal BPPV. Various liberatory maneuvers are recommended for the treatment of horizontal canal BPPV canalithiasis (hc-BPPV-ca). The aim of this study was to show how three-dimensional (3D) dynamic simulation models visualize the movement of the clot of otoconia within the canal for a better understanding of the theoretical efficacy. METHODS: Based on reconstructed magnetic resonance imaging and fluid dynamics, a 3D dynamic simulation model (as a function of time) was developed and applied. Thereby, six treatment maneuvers for hc-BPPV-ca were simulated: two types of the roll maneuver (the original 270° and the modified 360°) as well as two Gufoni and Zuma maneuvers (for geotropic and apogeotropic nystagmus). RESULTS: The simulations showed that the 360° roll maneuver and Zuma maneuver are effective treatment options for hc-BPPV-ca for debris in all locations within the canal. However, the original 270° roll maneuver will not be effective if the clot is in the ampullary arm of the horizontal canal. The Gufoni maneuver for geotropic hc-BPPV-ca is effective, whereas for apogeotropic hc-BPPV-ca there is a risk of treatment failure due to insufficient repositioning of the debris. CONCLUSIONS: The 3D simulations for movement of the otoconia clots can be used to test the mechanism of action and the theoretical efficacy of existing maneuvers for the different BPPV variants. For hc-BPPV-ca, the modified 360° roll maneuver and Zuma maneuver are theoretically efficient for all subtypes, whereas Gufoni maneuver is effective for geotropic nystagmus only.

Zuma Modified Maneuver as a Treatment to Geotropic Lateral Semicircular Canal Benign Paroxysmal Positional Vertigo.

Introduction Benign Paroxysmal Positional Vertigo (BPPV) is the most common vestibular disorder, resulting from detached otoliths that migrate to one of the semicircular canals - canalolithiasis - or one of the cupulas - cupulolithiasis. The present study is related to lateral canal BPPVs, which may be either geotropic or apogeotropic. The geotropic variant of lateral semicircular canal benign paroxysmal positional vertigo (LC-BPPV) is attributed to free floating particles in the posterior arm of the lateral semicircular canal. Objectives To verify the possibility of employing the Zuma repositioning maneuver, with a brief modification, as an alternative treatment for geotropic LC-BPPV. Methods Seven patients with geotropic LC-BPPV were enrolled and treated with the Zuma modified maneuver. Patients were reevaluated 1 hour after a single maneuver, to confirm the resolution of vertigo and positional nystagmus. Results All seven patients achieved immediate resolution of vertigo and positional nystagmus as measured 1 hour after the application of the maneuver. Conclusion The Zuma modified maneuver was effective for geotropic LC-BPPV after a single application. The use of the Zuma maneuver for both apogeotropic and geotropic LC-BPPV may simplify the treatment of these patients.

Sub-diffractional cavity modes of terahertz hyperbolic phonon polaritons in tin oxide.

Hyperbolic phonon polaritons have recently attracted considerable attention in nanophotonics mostly due to their intrinsic strong electromagnetic field confinement, ultraslow polariton group velocities, and long lifetimes. Here we introduce tin oxide (SnO2) nanobelts as a photonic platform for the transport of surface and volume phonon polaritons in the mid- to far-infrared frequency range. This report brings a comprehensive description of the polaritonic properties of SnO2 as a nanometer-sized dielectric and also as an engineered material in the form of a waveguide. By combining accelerator-based IR-THz sources (synchrotron and free-electron laser) with s-SNOM, we employed nanoscale far-infrared hyper-spectral-imaging to uncover a Fabry-Perot cavity mechanism in SnO2 nanobelts via direct detection of phonon-polariton standing waves. Our experimental findings are accurately supported by notable convergence between theory and numerical simulations. Thus, the SnO2 is confirmed as a natural hyperbolic material with unique photonic properties essential for future applications involving subdiffractional light traffic and detection in the far-infrared range.

Zuma Modified Maneuver as a Treatment to Geotropic Lateral Semicircular Canal Benign Paroxysmal Positional Vertigo

Abstract Introduction Benign Paroxysmal Positional Vertigo (BPPV) is the most common vestibular disorder, resulting from detached otoliths that migrate to one of the semicircular canals - canalolithiasis - or one of the cupulas - cupulolithiasis. The present study is related to lateral canal BPPVs, which may be either geotropic or apogeotropic. The geotropic variant of lateral semicircular canal benign paroxysmal positional vertigo (LC-BPPV) is attributed to free floating particles in the posterior arm of the lateral semicircular canal. Objectives To verify the possibility of employing the Zuma repositioning maneuver, with a brief modification, as an alternative treatment for geotropic LC-BPPV. Methods Seven patients with geotropic LC-BPPV were enrolled and treated with the Zuma modified maneuver. Patients were reevaluated 1 hour after a single maneuver, to confirm the resolution of vertigo and positional nystagmus. Results All seven patients achieved immediate resolution of vertigo and positional nystagmus as measured 1 hour after the application of the maneuver. Conclusion The Zuma modified maneuver was effective for geotropic LC-BPPV after a single application. The use of the Zuma maneuver for both apogeotropic and geotropic LC-BPPV may simplify the treatment of these patients.

Graphene: Insights on Biological, Radiochemical and Ecotoxicological Aspects.

Graphene, including graphene quantum dots, its oxide and unoxidized forms (pure graphene) have several properties, like fluorescence, electrical conductivity, theoretical surface area, low toxicity, and high biocompatibility. In this study, we evaluated genotoxicity (in silico analysis using the functional density theory-FDT), cytotoxicity (human glioblastoma cell line), in vivo pharmacokinetics, in vivo impact on microcirculation and cell internalization assay. It was also radiolabeled with lutetium 177 (177Lu), a beta emitter radioisotope to explore its therapeutic use as nanodrug. Finally, the impact of its disposal in the environment was analyzed using ecotoxicological evaluation. FDT analysis demonstrated that graphene can construct covalent and non-covalent bonds with different nucleobases, and graphene oxide is responsible for generation of reactive oxygen species (ROS), corroborating its genotoxicity. On the other hand, non-cytotoxic effect on glioblastoma cells could be demonstrated. The pharmacokinetics analysis showed high plasmatic concentration and clearance. Topical application of 0.1 and 1 mg/kg of graphene nanoparticles on the hamster skinfold preparation did not show inflammatory effect. The cell internalization assay showed that 1-hour post contact with cells, graphene can cross the plasmatic membrane and accumulate in the cytoplasm. Radio labeling with 177Lu is possible and its use as therapeutic nanosystem is viable. Finally, the ecotoxicity analysis showed that A. silina exposed to graphene showed pronounced uptake and absorption in the nauplii gut and formation of ROS. The data obtained showed that although being formed exclusively of carbon and carbon-oxygen, graphene and graphene oxide respectively generate somewhat contradictory results and more studies should be performed to certify the safety use of this nanoplatform.

Corrective Saccades in Unilateral and Bilateral Vestibular Hypofunction During Slow Rotation Expressed by Visually Enhanced VOR and VOR Suppression: Role of the Cerebellum.

In clinical practice, the head impulse test paradigm (HIMP) and the suppression head impulse paradigm (SHIMP) stimulate high-frequency head movements so that the visual system is temporarily suppressed. The two tests could also be useful tools for vestibular assessment at low frequencies: VVOR (visually enhanced vestibulo-ocular reflex) and VORS (vestibulo-ocular reflex suppression). The aim of this study is to analyze the eye movements typically found during VVOR and VORS testing in patients with unilateral and bilateral vestibular hypofunction. Twenty patients with unilateral vestibular hypofunction, three patients with bilateral vestibular hypofunction, and ten patients with normal vestibular function (control group) were analyzed through VVOR and VORS testing with an Otometrics ICS Impulse system. During the VVOR test, patients with unilateral vestibular hypofunction exhibited corrective saccades to the same direction of the nystagmus fast phase toward the healthy side when the head rotates toward the affected side, while patients with bilateral vestibular hypofunction exhibited corrective saccades to the opposite side of head movements to each side. During the VORS test, patients with unilateral vestibular hypofunction seem to exhibit larger corrective saccades to the healthy side when the head was moved to this side, while patients with bilateral vestibular hypofunction did not exhibit corrective saccades during head movements to either side. Our data suggest that the VVOR and VORS tests yield the same diagnostic information as the HIMP and SHIMP tests in unilateral and bilateral vestibular hypofunction, and can contribute to the diagnosis of a peripheral vestibular loss as well as the affected side.

An Algorithm for the Diagnosis of Vestibular, Cerebellar, and Oculomotor Disorders Using a Systematized Clinical Bedside Examination.

The bedside examination associated with their clinical history remains the most critical means to accurately diagnose the cause for most of the signs and symptoms related to pathology of the cerebellum and vestibular system in patients presenting with dizziness and imbalance. This paper focuses on those critical bedside examinations, suggests when laboratory testing might be useful to confirm the clinical suspicion, and considers the shared neural circuitry within the visual and vestibular systems to offer an algorithmic approach in conducting the clinical bedside examination.

Galactomannan of Delonix regia seeds reduces nociception and morphological damage in the rat model of osteoarthritis induced by sodium monoiodoacetate.

This study investigated the effects of the protein-free galactomannan obtained from Delonix regia seeds (GM-DR) in an experimental osteoarthritis (OA) model. GM-DR was obtained from water-homogenized endosperms by collection of the supernatant and precipitation with ethanol. The remaining proteins in the galactomannan were removed by alkaline hydrolysis. Weight average molar mass (Mw) of the galactomannan was estimated in 5.8 × 105 g mol-1, presenting mannose:galactose ratio of 2.39:1. Rats received sodium monoiodoacetate (OA groups, 1 mg/25 µL) or saline (sham group) in the right tibio-tarsal joint. GM-DR (30-300 µg) was administered by intra-articular route at days 14 and 21 after OA induction. Hypernociception was evaluated daily by the measurement of the mechanical threshold required to cause joint flexion and paw withdrawal reflex. The 56-day animal groups were euthanized for joint histopahological analysis using the OARSI score system. Lower doses of GM-DR (30 and 100 µg) promoted antinociception from day 15 until the endpoint at day 56. Joint damage was reduced by GM-DR administration (100 µg) in OA-subjected animals, compared to the vehicle-treated OA group (5.9 ± 1.8 vs 19.0 ± 1.8, respectively, p < 0.05). Conclusion: Both antinociception and damage reduction suggest that Delonix regia galactomannan is a promising approach for osteoarthritis therapy.

Management of Lateral Semicircular Canal Benign Paroxysmal Positional Vertigo.

Benign paroxysmal positional vertigo (BPPV) is the most common cause of peripheral vestibular vertigo. It is caused by free-floating otoconia moving freely in one of the semicircular canals (canalolithiasis) or by otoliths adhered to the cupula (cupulolithiasis). The posterior canal is the most common canal affected, followed by the lateral canal. Diagnosis of the side affected is critical for successful treatment; therefore, suppressing visual fixation is essential to examination of these patients' eye movement. On the basis of our experience, we have adopted the Zuma maneuver and the modified Zuma maneuver for both apogeotropic and geotropic variants of lateral canal BPPV. Knowledge of the anatomy and pathophysiologic mechanisms of the semicircular canals is essential for correct management of these patients. Hence, using a single maneuver and its modification may facilitate daily neurotological practice.