The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation.

Potassium (K+) efflux across the plasma membrane is thought to be an essential mechanism for ATP-induced NLRP3 inflammasome activation, yet the identity of the efflux channel has remained elusive. Here we identified the two-pore domain K+ channel (K2P) TWIK2 as the K+ efflux channel triggering NLRP3 inflammasome activation. Deletion of Kcnk6 (encoding TWIK2) prevented NLRP3 activation in macrophages and suppressed sepsis-induced lung inflammation. Adoptive transfer of Kcnk6-/- macrophages into mouse airways after macrophage depletion also prevented inflammatory lung injury. The K+ efflux channel TWIK2 in macrophages has a fundamental role in activating the NLRP3 inflammasome and consequently mediates inflammation, pointing to TWIK2 as a potential target for anti-inflammatory therapies.

CD38-mediated Inhibition of Bruton's Tyrosine Kinase in Macrophages Prevents Endotoxemic Lung Injury.

TLR4 signaling via endotoxemia in macrophages promotes macrophage transition to the inflammatory phenotype through NLRP3 inflammasome activation. This transition event has the potential to trigger acute lung injury (ALI). However, relatively little is known about the regulation of NLRP3 and its role in the pathogenesis of ALI. Here we interrogated the signaling pathway activated by CD38, an ectoenzyme expressed in macrophages, in preventing ALI through suppressing NLRP3 activation. Wild-type and Cd38-knockout (Cd38-/-) mice were used to assess inflammatory lung injury, and isolated macrophages were used to delineate underlying TLR4 signaling pathway. We showed that CD38 suppressed TLR4 signaling in macrophages by inhibiting Bruton's tyrosine kinase (Btk) through the recruitment of Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) and resulting in the dephosphorylation of activated Btk. Cd38-/- mice show enhanced lung polymorphonuclear leukocyte extravasation and severe lung injury. LPS- or polymicrobial sepsis-induced mortality in Cd38-/- mice were markedly augmented compared with wild types. CD38 in macrophages functioned by inhibiting Btk activation through activation of SHP2 and resulting dephosphorylation of Btk, and thereby preventing activation of downstream targets NF-κB and NLRP3. Cd38-/- macrophages displayed markedly increased activation of Btk, NF-κB, and NLRP3, whereas in vivo administration of the Btk inhibitor ibrutinib (a Food and Drug Administration-approved drug) prevented augmented TLR4-induced inflammatory lung injury seen in Cd38-/- mice. Our findings together show upregulation of CD38 activity and inhibition of Btk activation downstream of TLR4 activation as potential strategies to prevent endotoxemic ALI.

STAT6 induces expression of Gas6 in macrophages to clear apoptotic neutrophils and resolve inflammation.

Efferocytosis of apoptotic neutrophils (PMNs) by alveolar macrophages (AMФs) is vital for resolution of inflammation and tissue injury. Here, we investigated the role of AMФ polarization and expression of the efferocytic ligand Gas6 in restoring homeostasis. In the murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI), we observed augmented temporal generation of cytokines IL-4 and TSG6 in bronchoalveolar fluid (BALF). Interestingly, we also observed increased expression of antiinflammatory markers consistent with a phenotype shift in AMФs. In particular, AMФs expressed the efferocytic ligand Gas6. In vitro priming of bone marrow-derived macrophages (BMMФs) with IL-4 or TSG6 also induced MФ transition and expression of Gas6. TSG6- or IL-4-primed BMMФs induced efferocytosis of apoptotic PMNs compared with control BMMФs. Adoptive transfer of TSG6- or IL-4-primed BMMФs i.t. into LPS-challenged mice more rapidly and effectively cleared PMNs in lungs compared with control BMMФs. We demonstrated that expression of Gas6 during AMФ transition was due to activation of the transcription factor signal transducer and activator of transcription-6 (STAT6) downstream of IL-4 or TSG6 signaling. Adoptive transfer of Gas6-depleted BMMФs failed to clear PMNs in lungs following LPS challenge and mice showed severely defective resolution of lung injury. Thus, activation of STAT6-mediated Gas6 expression during macrophage phenotype transition resulting in efferocytosis of PMNs plays a crucial role in the resolution of inflammatory lung injury.

Neutrophil Activation of Endothelial Cell-Expressed TRPM2 Mediates Transendothelial Neutrophil Migration and Vascular Injury.

RATIONALE: TRPM2 (transient receptor potential melastatin-2) expressed in endothelial cells (ECs) is a cation channel mediating Ca2+ entry in response to intracellular generation of adenosine diphosphoribose-the TRPM2 ligand. OBJECTIVE: Because polymorphonuclear neutrophils (PMN) interaction with ECs generates reactive oxygen species, we addressed the possible role of TRPM2 expressed in ECs in the mechanism of transendothelial migration of PMNs. METHODS AND RESULTS: We observed defective PMN transmigration in response to lipopolysaccharide challenge in adult mice in which the EC expressed TRPM2 is conditionally deleted (Trpm2iΔEC ). PMN interaction with ECs induced the entry of Ca2+ in ECs via the EC-expressed TRPM2. Prevention of generation of adenosine diphosphoribose in ECs significantly reduced Ca2+ entry in response to PMN activation of TRPM2 in ECs. PMNs isolated from gp91phox-/- mice significantly reduced Ca2+ entry in ECs via TRPM2 as compared with wild-type PMNs and failed to induce PMN transmigration. Overexpression of the adenosine diphosphoribose insensitive TRPM2 mutant channel (C1008→A) in ECs suppressed the Ca2+ entry response. Further, the forced expression of TRPM2 mutant channel (C1008→A) or silencing of poly ADP-ribose polymerase in ECs of mice prevented PMN transmigration. CONCLUSIONS: Thus, endotoxin-induced transmigration of PMNs was secondary to TRPM2-activated Ca2+ signaling and VE-cadherin phosphorylation resulting in the disassembly of adherens junctions and opening of the paracellular pathways. These results suggest blocking TRPM2 activation in ECs is a potentially important means of therapeutically modifying PMN-mediated vascular inflammation.

Short-term costs associated with non-medical switching in autoimmune conditions.

OBJECTIVES: To estimate short-term costs associated with non-medical switch (NMS) from originator biologics to biosimilars among stable patients with autoimmune conditions in rheumatology, gastroenterology, and dermatology from a US provider's and third-party payer's perspective. METHODS: An economic model was constructed to estimate switching costs related to physician time and healthcare resource utilisation (HRU) at the initial NMS visit and over 3 months. The proportion of patients with relevant conditions treated with originators and expected NMS rate, physician time, HRU, and payer reimbursement were derived from a physician survey. Switching costs were estimated for a practice of 1,000 patients with relevant conditions by therapeutic area and for an insurance plan with 1 million individuals by therapeutic area and all areas combined. Switching cost drivers were assessed with one-way sensitivity analyses. RESULTS: Physicians expected extra 6 minutes for the NMS visit and 22 minutes over 3 months; NMS rates of 14.4%, 15.5%, and 17.7%; and 11.3%, 16.2%, and 33.2% of time not reimbursed for gastroenterology, rheumatology, and dermatology, respectively. The total switching costs for payer's were $771,460 (for n = 3,609 patients with an NMS rate of 16.6%), mostly due to follow-up visits and additional laboratory tests/procedures. In sensitivity analyses, the NMS rate was the main cost driver. Increasing the NMS rate to 25% and 50% increased payer's total switching costs to $1.19 and $2.39 million, respectively. CONCLUSIONS: Originator-to-biosimilar NMS in stable patients with autoimmune conditions could result in considerable switching costs for both providers and payers.

TNFα-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury.

TNFα-stimulated gene-6 (TSG6), a 30-kDa protein generated by activated macrophages, modulates inflammation; however, its mechanism of action and role in the activation of macrophages are not fully understood. Here we observed markedly augmented LPS-induced inflammatory lung injury and mortality in TSG6-/- mice compared with WT (TSG6+/+) mice. Treatment of mice with intratracheal instillation of TSG6 prevented LPS-induced lung injury and neutrophil sequestration, and increased survival in mice. We found that TSG6 inhibited the association of TLR4 with MyD88, thereby suppressing NF-κB activation. TSG6 also prevented the expression of proinflammatory proteins (iNOS, IL-6, TNFα, IL-1ß, and CXCL1) while increasing the expression of anti-inflammatory proteins (CD206, Chi3l3, IL-4, and IL-10) in macrophages. This shift was associated with suppressed activation of proinflammatory transcription factors STAT1 and STAT3. In addition, we observed that LPS itself up-regulated the expression of TSG6 in TSG6+/+ mice, suggesting an autocrine role for TSG6 in transitioning macrophages. Thus, TSG6 functions by converting macrophages from a proinflammatory to an anti-inflammatory phenotype secondary to suppression of TLR4/NF-κB signaling and STAT1 and STAT3 activation.

Form, Function, and Esthetics in Prosthetically Rehabilitated Maxillary Defects.

PURPOSE: Patients with maxillofacial defects secondary to the removal of benign and malignant pathologies of midface have a profound impact on quality of life. The aim of this study was to collect and analyze the data pertaining to 4 designs of obturator by assessment of the patient with obturator functioning scale (OFS) MATERIALS AND METHODS:: This retrospective analysis included all the patients who underwent prosthetic rehabilitation of maxillary defects using 4 different types (conventional, cast partial, hollow bulb, and magnet retained) of obturators from 2009 to 2016 with minimum 1 year of follow up. Demographics, number, size, location, type of pathology, postmorbid dentition, and the treatment rendered were recorded. Obturator functioning scale was used to subjectively assess the patient satisfaction. RESULTS: The mean score on OFS was 5.67 (standard deviation: 1.8). There was a fair and statistical improvement in chewing/eating, speech clarity in public/on phone, swallowing of foods and liquids, pronunciation of words, and social interaction (P < 0.05). The outcome was best in magnet retained followed by cast partial group. The least outcome was in conventional obturator group. CONCLUSION: Obturators of different designs do play an important role in rehabilitation of maxillary defects with a satisfactory outcome.

Corticosteroid-Related Adverse Events Systematically Increase with Corticosteroid Dose in Noninfectious Intermediate, Posterior, or Panuveitis: Post Hoc Analyses from the VISUAL-1 and VISUAL-2 Trials.

PURPOSE: Chronic use of corticosteroids for the treatment of uveitis has been linked with drug-associated toxicity and adverse events (AEs). This study examines the association between corticosteroid dosage and incidence rates of corticosteroid-related AEs. DESIGN: A post hoc analysis of the VISUAL-1 and VISUAL-2 placebo-controlled clinical trials. PARTICIPANTS: The clinical trials consisted of adults with active (VISUAL-1) and inactive (VISUAL-2) noninfectious intermediate, posterior, and panuveitis. Patients were randomized to receive adalimumab or placebo and underwent a protocol-defined mandatory taper to discontinue their oral corticosteroids. METHODS: Adverse event data were collected at each visit and included an assessment of the corticosteroid relationship by the investigator. A longitudinal Poisson regression model was estimated controlling for time-dependent corticosteroid dose, age, sex, prior oral corticosteroid dose, prior topical corticosteroid use, and concomitant immunosuppressive drug use. Only patients randomized to placebo were considered. MAIN OUTCOME MEASURES: The primary outcome measure was the frequency of AEs. RESULTS: The incidence rates of corticosteroid-related AEs among placebo patients during the prednisone treatment period in VISUAL-1 was statistically higher than after discontinuation (454.2 per 100 patient-years [PY] vs. 36.1 per 100 PY, incident rate ratio = 12.6, P < 0.001). Incidence rate ratios among VISUAL-2 patients were similarly high (317.5 per 100 PY vs. 41.1 per 100 PY, incident rate ratio = 7.7, P < 0.001). Based on the Poisson multivariate longitudinal Generalized Estimating Equation (GEE) model, each 10 mg increase in prednisone dose is associated with a 1.5- and 2.6-fold increase (P < 0.001 and P < 0.001) in the rate of corticosteroid-related AEs in VISUAL-1 and VISUAL-2, respectively. This implies in turn that a patient with active uveitis taking 60 mg/day of prednisone will experience, on average, an additional 10.1 (95% confidence interval (CI), 6.3-14.5; P < 0.001) corticosteroid-related AEs per year compared with a patient taking 10 mg/day, whereas a patient with inactive uveitis taking 35 mg/day of prednisone will experience, on average, an additional 23.5 (95% CI, 7.6-52.7; P = 0.05) corticosteroid-related AEs per year compared with a patient taking 10 mg/day. CONCLUSIONS: Evidence from VISUAL-1 and VISUAL-2 suggests that the incidence rates of corticosteroid-related AEs increase systematically with corticosteroid dose.

ASAS40 and ASDAS clinical responses in the ABILITY-1 clinical trial translate to meaningful improvements in physical function, health-related quality of life and work productivity in patients with non-radiographic axial spondyloarthritis.

OBJECTIVE: To assess the impact of achieving Assessment in SpondyloArthritis international Society 40% (ASAS40) response or an Ankylosing Spondylitis Disease Activity Score inactive disease (ASDAS-ID) state on patient-reported outcomes (PROs) among patients with non-radiographic axial SpA (nr-axSpA). METHODS: Data are from ABILITY-1, a phase 3 trial of adalimumab vs placebo in nr-axSpA patients. PROs included the HAQ for Spondyloarthropathies (HAQ-S), 36-item Short Form Health Survey (SF-36) physical component summary (PCS) score and Work Productivity and Activity Impairment Questionnaire. Patients were grouped by clinical response using ASAS40 response and ASDAS disease states at week 12. Changes in PROs from baseline to week 12 were compared between groups using analysis of covariance with adjustment for baseline scores. RESULTS: At week 12, 47 of 179 patients were ASAS40 responders and 26 of 176 patients achieved ASDAS-ID (ASDAS <1.3). Compared with non-responders (n = 132), ASAS40 responders (n = 47) had a significantly greater improvement in mean HAQ-S (-0.65 vs -0.05, P < 0.0001), SF-36 PCS (12.4 vs 0.7, P < 0.0001), presenteeism (-24.7 vs -2.2, P < 0.0001), overall work impairment (-23.9 vs -2.5, P < 0.0001) and activity impairment (-33.5 vs -0.9, P < 0.0001) at week 12. Similarly, ASDAS-ID, ASDAS clinically important improvement (ASDAS-CII; improvement >1.1) and major improvement (ASDAS-MI; improvement >2.0) were associated with significantly greater improvements from baseline in the majority of the PROs. CONCLUSION: Among nr-axSpA patients, ASAS40, ASDAS-CII and ASDAS-MI response and achievement of ASDAS-ID were associated with statistically significant and clinically meaningful improvements in physical function, health-related quality of life and work productivity in a higher percentage of patients.

Integrin α6ß1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells.

Adhesion of embryonic stem cells (ESCs) to the extracellular matrix may influence differentiation potential and cell fate decisions. Here, we investigated the inductive role of binding of integrin α6ß1 expressed in mouse (m)ESCs to laminin-1 (LN1) in mediating the differentiation of ESCs to endothelial cells (ECs). We observed that α6ß1 binding to LN1 was required for differentiation to ECs. α6ß1 functioned by recruiting the adaptor tetraspanin protein CD151, which activated FAK and Akt signaling and mediated the EC lineage-specifying transcription factor Er71. In contrast, association of the ESC-expressed α3ß1, another highly expressed LN1 binding integrin, with CD151, prevented α6ß1-mediated differentiation. CD151 thus functioned as a bifurcation router to direct ESCs toward ECs when α6ß1 associated with CD151, or prevented transition to ECs when α3ß1 associated with CD151. These observations were recapitulated in mice in which α6 integrin or CD151 knockdown reduced the expression of Er71-regulated angiogenesis genes and development of blood vessels. Thus, interaction of α6ß1 in ESCs with LN1 activates α6ß1/CD151 signaling which programs ESCs toward the EC lineage fate.

Cooperative interaction of trp melastatin channel transient receptor potential (TRPM2) with its splice variant TRPM2 short variant is essential for endothelial cell apoptosis.

RATIONALE: Oxidants generated by activated endothelial cells are known to induce apoptosis, a pathogenic feature of vascular injury and inflammation from multiple pathogeneses. The melastatin-family transient receptor potential 2 (TRPM2) channel is an oxidant-sensitive Ca2+ permeable channel implicated in mediating apoptosis; however, the mechanisms of gating of the supranormal Ca2+ influx required for initiating of apoptosis are not understood. OBJECTIVE: Here, we addressed the role of TRPM2 and its interaction with the short splice variant TRPM2 short variant (TRPM2-S) in mediating the Ca2+ entry burst required for induction of endothelial cell apoptosis. METHODS AND RESULTS: We observed that TRPM2-S was basally associated with TRPM2 in the endothelial plasmalemma, and this interaction functioned to suppress TRPM2-dependent Ca2+ gating constitutively. Reactive oxygen species production in endothelial cells or directly applying reactive oxygen species induced protein kinase C-α activation and phosphorylation of TRPM2 at Ser 39. This in turn stimulated a large entry of Ca2+ and activated the apoptosis pathway. A similar TRPM2-dependent endothelial apoptosis mechanism was seen in intact vessels. The protein kinase C-α-activated phosphoswitch opened the TRPM2 channel to allow large Ca2+ influx by releasing TRPM2-S inhibition of TRPM2, which in turn activated caspase-3 and cleaved the caspase substrate poly(ADP-ribose) polymerase. CONCLUSIONS: Here, we describe a fundamental mechanism by which activation of the trp superfamily TRPM2 channel induces apoptosis of endothelial cells. The signaling mechanism involves reactive oxygen species-induced protein kinase C-α activation resulting in phosphorylation of TRPM2-S that allows enhanced TRPM2-mediated gating of Ca2+ and activation of the apoptosis program. Strategies aimed at preventing the uncoupling of TRPM2-S from TRPM2 and subsequent Ca2+ gating during oxidative stress may mitigate endothelial apoptosis and its consequences in mediating vascular injury and inflammation.

Novel role of reactive oxygen species-activated Trp melastatin channel-2 in mediating angiogenesis and postischemic neovascularization.

OBJECTIVE: Transient receptor potential melastatin-2 (TRPM2) channel is a nonselective cation channel that mediates influx of Ca(2+) and Na(+) with relative permeability of PCa:PNa ≈0.6 in response to cellular oxidative stress. As angiogenesis and ischemic neovascularization are both significantly dependent on oxidant signaling, here we investigated the possible role of vascular endothelial growth factor (VEGF)-induced reactive oxygen species production in activating TRPM2-dependent Ca(2+) signaling and in the mechanism of angiogenesis and ischemic neovascularization. APPROACH AND RESULTS: We observed that VEGF stimulation rapidly induced the association of TRPM2 and cellular Src kinase with vascular endothelial-cadherin forming a signalplex at vascular endothelial-cadherin junctions in endothelial cells. Using endothelial cells isolated from TRPM2(-/-) mice or after small interfering RNA depletion of TRPM2, we demonstrated that TRPM2-activated Ca(2+) signaling was required for cellular Src kinase-induced phosphorylation of vascular endothelial-cadherin at Y658 and Y731, the crucial sites involved in vascular endothelial-cadherin internalization in response to VEGF. VEGF-induced reactive oxygen species generation activated TRPM2-induced Ca(2+) entry, whereas the reactive oxygen species-insensitive TRPM2 mutant (C1008→A) showed impaired Ca(2+) entry. Endothelial cells depleted of TRPM2 also displayed significantly perturbed migratory phenotype and impaired activation of cellular Src in response to VEGF. TRPM2(-/-) mice reconstituted with wild-type myeloid cells demonstrated aberrant angiogenesis and neovascularization in the hindlimb ischemia model as compared with wild-type mice. CONCLUSIONS: VEGF-induced angiogenesis and postischemic neovascularization in mice required reactive oxygen species generation in endothelial cells and resultant TRPM2 activation. Thus, our findings provide novel insight into the role of TRPM2 in mechanism of angiogenesis and ischemic neovascularization.

Comparative evaluation of the tensile bond strength of two silicone based denture liners with denture base resins.

BACKGROUND: To evaluate and compare tensile bond strength of two silicone based liners with heat cure and heat cure high impact denture base resin at baseline and after storage in artificial saliva for 30 and 60 days. METHOD: Heat cure conventional and high impact acrylic blocks (120 blocks each) prepared with final test specimen of two blocks of each resin with a liner. The baseline samples and those tested after 30 and 60 days interval stored in artificial saliva in thermal incubator, all were pulled apart in UTM at 20 mm/min. The tensile bond strength and mode of failure (adhesive/cohesive) were assessed. Mean, SD determined and analysis using one way ANOVA and paired 't' test. RESULTS: The highest mean tensile bond strength (1.028 MPa) and the least i.e. 0.289 MPa was observed with Permaflex silicone liner against heat cure PMMA after storage in artificial saliva at 37 ± 1 °C. CONCLUSION: The study rejected the null hypothesis because storage time in artificial saliva affected the bond strength of the resilient liners examined. The results revealed a statistically significant difference (p < 0.05) of artificial saliva storage on the bond strength of both the liners. After storage in artificial saliva for 30 days and 60 days at 37 ± 1 °C, all the specimens showed a significant reduction in the tensile bond strength.

Comparison of articulating paper markings and T Scan III recordings to evaluate occlusal force in normal and rehabilitated maxillofacial trauma patients.

BACKGROUND: Prosthodontic Rehabilitation of Treated Maxillofacial Trauma Cases by Evaluating Occlusal Force Distribution Using Computerized Occlusal Analysis. METHOD: 30 patients were selected for the study. 15 normal and 15 treated trauma patients were subjected to T Scan analysis and evaluated for the occlusal force distribution. RESULTS: The results take into consideration the two parameters. Firstly the largest articulating paper mark (photographed) and secondly the T scan of the same patient. Comparison was made between the largest articulating paper mark and highest force tooth in the quadrant using T Scan. The matches and no matches were then tabulated for statistical analysis assessing the frequency of the matches to the no matches. CONCLUSION: The ultimate advantage of a T Scan III analysis is that it can detect the amount of force as well as location of the highest intensity contacts of a single tooth which is very specific.

Have antiepileptic drug prescription claims changed following the FDA suicidality warning? An evaluation in a state Medicaid program.

OBJECTIVE: In January 2008, the Food and Drug Administration (FDA) communicated concerns and, in May 2009, issued a warning about an increased risk of suicidality for all antiepileptic drugs (AEDs). This research evaluated the association between the FDA suicidality communications and the AED prescription claims among members with epilepsy and/or psychiatric disorder. METHODS: A longitudinal interrupted time-series design was utilized to evaluate Oklahoma Medicaid claims data from January 2006 through December 2009. The study included 9289 continuously eligible members with prevalent diagnoses of epilepsy and/or psychiatric disorder and at least one AED prescription claim. Trends, expressed as monthly changes in the log odds of AED prescription claims, were compared across three time periods: before (January 2006 to January 2008), during (February 2008 to May 2009), and after (June 2009 to December 2009) the FDA warning. RESULTS: Before the FDA warning period, a significant upward trend of AED prescription claims of 0.01% per month (99% CI: 0.008% to 0.013%, p<0.0001) was estimated. In comparison to the prewarning period, no significant change in trend was detected during (-20.0%, 99% CI: -70.0% to 30.0%, p=0.34) or after (80.0%, 99% CI: -20.0% to 200.0%, p=0.03) the FDA warning period. After stratification, no diagnostic group (i.e., epilepsy alone, epilepsy and comorbid psychiatric disorder, and psychiatric disorder alone) experienced a significant change in trend during the entire study period (p>0.01). CONCLUSIONS: During the time period considered, the FDA AED-related suicidality warning does not appear to have significantly affected prescription claims of AED medications for the study population.

Photocatalytic studies of crystal violet dye using mn doped and PVP capped ZnO nanoparticles.

Mn (0.5%, 1%, 1.5% and 2%) doped and undoped ZnO nanoparticles (NPs) capped with PVP (1.0%) were successfully synthesized via co-precipitation approach using zinc acetate, sodium hydroxide and manganese acetate as precursors. Structural analysis was performed by XRD confirming phase purity and crystalline wurtzite structure. TEM results show average particle size 15-20 nm and 22-25 nm for Mn (1%) and Mn (2%) doped ZnO NPs respectively. Manganese (Mn) doping has led to reduction in band gap which facilitate the absorption of radiation in visible region. The Photocatalytic activity of undoped and Mn (0.5%,1%,1.5% and 2%) doped NPs was analyzed via degradation of crystal violet (CV) dye. The crystal violet decomposition rate of undoped and Mn doped NPs were studied under UV-visible region. It is observed from degradation studies that the doping has a pronounced effect on the photocatalytic activity of ZnO NPs. Kinetic studies shows that photo degradation of CV follow a pseudo first-order kinetic law. Experiments for reusability of Mn (1%) doped with PVP (1%) capped ZnO were also performed to determine the stability of as prepared sample. It shows an increase in catalytic activity of NPs by small amount when exposed to UV irradiation for 3 h. Photoluminescence and UV-Visible absorption spectroscopy studies were also performed for studying the effect of UV irradiation on the surface of ZnO NPs.

Rehabilitation of a Patient with Central Giant Cell Granuloma of Mandible by Iliac Graft, Bone Distraction and Implant Retained Telescopic Prosthesis: a Two Year Follow Up.

Giant cell granulomas of the jaws are lesions that arise either peripherally in periodontal ligament, mucoperiosteum, or centrally in the bone. Histologically, both peripheral and central giant cell granuloma are characterized by the presence of numerous multinucleated giant cells in a prominent fibrous stroma. Traditional treatment has been local curettage, although aggressive sub-types have a high tendency to recur. This case report describes the rehabilitation procedure of a patient with central giant cell granuloma of left side of mandible. Marginal resection of the lesion was done followed by reconstruction of the resected mandible with iliac graft. Distraction of bone was done since there was partial uptake of the fibula graft. Five implants were placed once the distraction was complete. The patient was rehabilitated with implant retained removable telescopic prosthesis.

Endogenous defense mechanism-based neuroprotection in large-vessel acute ischemic stroke: A hope for future.

BACKGROUND: Stroke is a leading cause of morbidity and mortality worldwide and a leading cause of disability. None of the neuroprotective agents have been approved internationally except edaravone in Japanese guidelines in acute ischemic stroke. We here discuss that there are two types of endogenous defense mechanisms (EDMs) after acute stroke for neuromodulation and neuroregeneration, and if both can be activated simultaneously, then we can have better recovery in stroke. AIMS AND OBJECTIVES: We aimed to study the effect of combination of neuroprotection therapies acting on the two wings of EDM in acute large-vessel middle cerebral artery (LMCA) ischemic stroke. METHODS: Sixty patients of LMCA stroke were enrolled and randomized within 72 h into two groups of 30 patients each. The control group received standard medical care without any neuroprotective agents while the intervention group received standard medical care combined with oral citicoline with vinpocetine for 3 months with initial 1 week intravenous and edaravone and cerebrolysin injection, started within 72 h of onset of stroke. Patients were assessed on the basis of the National Institutes of Health Stroke Scale, Fugl-Meyer Assessment Score, Glasgow Coma Scale, and Mini-Mental Status Examination at admission, discharge, and after 90 days. RESULTS: The intervention group showed significant and early improvements in motor as well as cognitive recovery. CONCLUSION: Combination therapy for neuroprotection which is acting on two pathways of EDM can be useful in functional recovery after acute ischemic stroke.

Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration.

Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.