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Sounak Bagchi,1 Tanya Chhibber,1 Behnaz Lahooti,1 Angela Verma,1 Vivek Borse,2 Rahul Dev Jayant1 1Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; 2Centre for Nanotechnology, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, IndiaCorrespondence: Rahul Dev JayantDepartment of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1406 S. Coulter Street, Suite 1104, Amarillo, TX 79106, USATel +1 806 414 9154Fax +1 806 356 4034Email rd.jayant@ttuhsc.eduAbstract: The blood-brain barrier (BBB) is comprised of brain microvascular endothelial central nervous system (CNS) cells, which communicate with other CNS cells (astrocytes, pericytes) and behave according to the state of the CNS, by responding against pathological environments and modulating disease progression. The BBB plays a crucial role in maintaining homeostasis in the CNS by maintaining restricted transport of toxic or harmful molecules, transport of nutrients, and removal of metabolites from the brain. Neurological disorders, such as NeuroHIV, cerebral stroke, brain tumors, and other neurodegenerative diseases increase the permeability of the BBB. While on the other hand, semipermeable nature of BBB restricts the movement of bigger molecules i.e. drugs or proteins (>500 kDa) across it, leading to minimal bioavailability of drugs in the CNS. This poses the most significant shortcoming in the development of therapeutics for CNS neurodegenerative disorders. Although the complexity of the BBB (dynamic and adaptable barrier) affects approaches of CNS drug delivery and promotes disease progression, understanding the composition and functions of BBB provides a platform for novel innovative approaches towards drug delivery to CNS. The methodical and scientific interests in the physiology and pathology of the BBB led to the development and the advancement of numerous in vitro models of the BBB. This review discusses the fundamentals of BBB structure, permeation mechanisms, an overview of all the different in-vitro BBB models with their advantages and disadvantages, and rationale of selecting penetration prediction methods towards the critical role in the development of the CNS therapeutics.Keywords: blood-brain barrier, BBB, brain microvascular endothelial cells, BMECs, tight junctions, TJs, proteins, central nervous system, CNS, induced pluripotent cells, iPSCs, in-silico prediction methods

Abstract Introduction We report the case of a missed fracture through the body of the hamate bone, only detected on a later, mistakenly taken 30° oblique x-ray view. This case highlights some of the problems encountered with traditional x-ray views, and the need to consider oblique views as either standard procedure or as an adjunct where clinical suspicion remains high even in the presence of normal x-rays. Case presentation A healthy 26-year-old Caucasian male fell whilst jogging, suffering a low velocity injury to his right hand. Initial accident and emergency examination and x-rays failed to demonstrate a fracture. At clinic, anteroposterior and carpal tunnel radiographs showed no fracture, however a mistakenly taken oblique x-ray revealed a displaced hamate body fracture. Conclusion The authors believe that where a hamate fracture is suspected, an oblique x-ray view should be considered as part of the initial diagnostic investigations. Furthermore an oblique x-ray view is of particular use when clinical suspicion for hamate fracture remains high in the light of otherwise normal x-rays.

The sudden outbreak of the coronavirus disease 2019 (COVID-19) pandemic has brought to the fore the existing threat of disease-causing pathogens that affect public health all over the world. It has left the best healthcare systems struggling to contain the spread of disease and its consequences. Under challenging circumstances, several innovative technologies have emerged that facilitated quicker diagnosis and treatment. Nanodiagnostic devices are biosensing platforms developed using nanomaterials such as nanoparticles, nanotubes, nanowires, etc. These devices have the edge over conventional techniques such as reverse transcription-polymerase chain reaction (RT-PCR) because of their ease of use, quicker analysis, possible miniaturization, and scope for use in point-of-care (POC) treatment. This review discusses the techniques currently used for COVID-19 diagnosis, emphasizing nanotechnology-based diagnostic devices. The commercialized nanodiagnostic devices in various research and development stages are also reviewed. The advantages of nanodiagnostic devices over other techniques are discussed, along with their limitations. Additionally, the important implications of the utility of nanodiagnostic devices in COVID-19, their prospects for future development for use in clinical and POC settings, and personalized healthcare are also discussed., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Vivek Borse reports financial support was provided by 10.13039/501100006143Department of Science and Technology, Ministry of Science and Technology, Government of India., (© 2022 The Author(s).)

Programmed cell death (PCD) plays a critical role in the development and maturation of the cochlea. Significant remodeling occurs among cells of the greater epithelial ridge (GER) of Kölliker's organ, leading to tissue regression and formation of the inner sulcus. In mice, this event normally occurs between postnatal days 5-15 (P5-15) and is regulated by thyroid hormone (T3). During this developmental time period, the cochlea also contains a large population of macrophages. Macrophages are frequently involved in the phagocytic clearance of dead cells, both during development and after injury, but the role of macrophages in the developing cochlea is unknown. This study examined the link between developmental cell death in the GER and the recruitment of macrophages into this region. Cell death in the basal GER begins at P5 and enhanced numbers of macrophages were observed at P7. This pattern of macrophage recruitment was unchanged in mice that were genetically deficient for CX3CR1, the receptor for fractalkine (a known macrophage chemoattractant). We found that injection of T3 at P0 and P1 caused GER cell death to begin at P3, and this premature PCD was accompanied by earlier recruitment of macrophages. We further found that depletion of macrophages from the developing cochlea (using CX3CR1 DTR/+ mice and treatment with the CSF1R antagonist BLZ945) had no effect on the pattern of GER regression. Together, these findings suggest that macrophages are recruited into the GER region after initiation of developmental PCD, but that they are not essential for GER regression during cochlear remodeling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Borse, Kaur, Hinton, Ohlemiller and Warchol.)

Introduction Delivering bad news to patients is an essential skill for physicians, which is often developed through patient encounters. Residents in our program participate in objective structured clinical examinations (OSCEs) on an annual basis to evaluate their skills in these scenarios. Our objectives were to develop an educational video and determine if an educational video provided to residents prior to OSCEs would improve performance. Methods Previous OSCEs were reviewed to identify best practices and to create a four-minute video highlighting the "do's and don'ts" of delivering bad news. Residents in two post-graduate year (PGY) classes were randomized to watch the video prior to or after a standardized patient encounter. Three masked reviewers assessed resident empathy, attention, and understanding on 10 five-point Likert scales and assigned a total score (scale: 0-50). Hedges' g was used to assess mean scores and effect size. Results A total of 17 residents participated in the evaluation: nine in the pre-OSCE video group and eight in the control group. Residents randomized to the video prior to the patient encounter had a mean score of 37.01 (SD=3.6). Residents randomized to the control group had a mean score of 35.38 (SD=4.85). Hedges' g was 0.37 (95% CI: -0.59 to 1.33). Conclusion Residents randomized to the video group had a small increase in OSCE performance, which was not statistically significant. The novel video was helpful and addresses the need for a quick pre-assessment educational tool, though interns and graduating medical students may be a more appropriate target audience for instruction., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Shanks et al.)

Early-stage diagnosis is a crucial step in reducing the mortality rate in oral cancer cases. Point-of-care (POC) devices for oral cancer diagnosis hold great future potential in improving the survival rates as well as the quality of life of oral cancer patients. The conventional oral examination followed by needle biopsy and histopathological analysis have limited diagnostic accuracy. Besides, it involves patient discomfort and is not feasible in resource-limited settings. POC detection of biomarkers and diagnostic adjuncts has emerged as non- or minimally invasive tools for the diagnosis of oral cancer at an early stage. Various biosensors have been developed for the rapid detection of oral cancer biomarkers at the point-of-care. Several optical imaging methods have also been employed as adjuncts to detect alterations in oral tissue indicative of malignancy. This review summarizes the different POC platforms developed for the detection of oral cancer biomarkers, along with various POC imaging and cytological adjuncts that aid in oral cancer diagnosis, especially in low resource settings. Various immunosensors and nucleic acid biosensors developed to detect oral cancer biomarkers are summarized with examples. The different imaging methods used to detect oral tissue malignancy are also discussed herein. Additionally, the currently available commercial devices used as adjuncts in the POC detection of oral cancer are emphasized along with their characteristics. Finally, we discuss the limitations and challenges that persist in translating the developed POC techniques in the clinical settings for oral cancer diagnosis, along with future perspectives., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The Hippo signaling pathway is a key regulator of tissue development and regeneration. Activation of the Hippo pathway leads to nuclear translocation of the YAP1 transcriptional coactivator, resulting in changes in gene expression and cell cycle entry. Recent studies have demonstrated the nuclear translocation of YAP1 during the development of the sensory organs of the inner ear, but the possible role of YAP1 in sensory regeneration of the inner ear is unclear. The present study characterized the cellular localization of YAP1 in the utricles of mice and chicks, both under normal conditions and after HC injury. During neonatal development, YAP1 expression was observed in the cytoplasm of supporting cells, and was transiently expressed in the cytoplasm of some differentiating hair cells. We also observed temporary nuclear translocation of YAP1 in supporting cells of the mouse utricle after short periods in organotypic culture. However, little or no nuclear translocation of YAP1 was observed in the utricles of neonatal or mature mice after ototoxic injury. In contrast, substantial YAP1 nuclear translocation was observed in the chicken utricle after streptomycin treatment in vitro and in vivo. Together, these data suggest that differences in YAP1 signaling may partially account for the differing regenerative abilities of the avian vs. mammalian inner ear.

Background: The human enthesis conventional T cells are poorly characterised., Objectives: To study the biology of the conventional T cells in human enthesis., Methods: CD4+ and CD8+ T cells were investigated in 25 enthesis samples using immunofluorescence, cytometrically, bulk RNAseq and quantitative real-time PCR following anti-CD3/CD28 bead stimulation to determine interleukin (IL)-17A and tumour necrosis factor (TNF) levels. T-cell receptor (TCR) repertoires were characterised and a search for putative T-cell reactivity was carried out using TCR3 database. The impact of pharmacological antagonism with retinoic acid receptor-related orphan nuclear receptor gamma t inhibitor (RORγti), methotrexate and phosphodiesterase type 4 inhibitor (PDE4i) was investigated., Results: Immunofluorescence and cytometry suggested entheseal resident CD4+ and CD8+ T cells with a resident memory phenotype (CD69+/CD45RA-) and tissue residency gene transcripts (higher NR4A1/AhR and lower KLF2/T-bet transcripts). Both CD4+ and CD8+ T cells showed increased expression of immunomodulatory genes including IL-10 and TGF-β compared with peripheral blood T cells with entheseal CD8+ T cells having higher CD103, CD49a and lower SIPR1 transcript that matched CD4+ T cells. Following stimulation, CD4+ T cells produced more TNF than CD8+ T cells and IL-17A was produced exclusively by CD4+ T cells. RNAseq suggested both Cytomegalovirus and influenza A virus entheseal resident T-cell clonotype reactivity. TNF and IL-17A production from CD4+ T cells was effectively inhibited by PDE4i, while RORγti only reduced IL-17A secretion., Conclusions: Healthy human entheseal CD4+ and CD8+ T cells exhibit regulatory characteristics and are predicted to exhibit antiviral reactivity with CD8+ T cells expressing higher levels of transcripts suggestive of tissue residency. Inducible IL-17A and TNF production can be robustly inhibited in vitro., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Globally, oral cancer is the sixth most common type of cancer with India contributing to almost one-third of the total burden and the second country having the highest number of oral cancer cases. Oral squamous cell carcinoma (OSCC) dominates all the oral cancer cases with potentially malignant disorders, which is also recognized as a detectable pre-clinical phase of oral cancer. Tobacco consumption including smokeless tobacco, betel-quid chewing, excessive alcohol consumption, unhygienic oral condition, and sustained viral infections that include the human papillomavirus are some of the risk aspects for the incidence of oral cancer. Lack of knowledge, variations in exposure to the environment, and behavioral risk factors indicate a wide variation in the global incidence and increases the mortality rate. This review describes various risk factors related to the occurrence of oral cancer, the statistics of the distribution of oral cancer in India by various virtues, and the socio-economic positions. The various conventional diagnostic techniques used routinely for detection of the oral cancer are discussed along with advanced techniques. This review also focusses on the novel techniques developed by Indian researchers that have huge potential for application in oral cancer diagnosis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Antifungal drug resistance exhibits a major clinical challenge for treating nosocomial fungal infections. To find a possible solution, we synthesized and studied the antifungal activities of three different arginolipids (N α -acyl-arginine ethyl ester) against clinical drug-resistant isolates of Candida. The most active arginolipid, oleoyl arginine ethyl ester (OAEE) consisting of a long unsaturated hydrophobic chain, was tested for its mode of action, which revealed that it altered ergosterol biosynthesis and compromised the fungal cell membrane. Also, OAEE was found to exhibit synergistic interactions with fluconazole (FLU) or amphotericin B (AmB) against planktonic Candida cells, wherein it reduced the inhibitory concentrations of these drugs to their in vitro susceptible range. Studies conducted against the C. tropicalis biofilm revealed that the OAEE+AmB combination synergistically reduced the metabolic activity and hyphal density in biofilms, whereas OAEE+FLU was found to be additive against most cases. Finally, the evaluated selective toxicity of OAEE toward fungal cells over mammalian cells could establish it as an alternative treatment for combating drug-resistant Candida infections., (© 2019 Deutsche Pharmazeutische Gesellschaft.)

Point-of-care (POC) diagnostic device is an instrument that is used to acquire particular clinical information of patients in clinical as well as resource-limited settings. The conventional clinical diagnostic procedure requires high-end and costly instruments, an expert technician for operation and result interpretation, longer time, etc. that ultimately makes it exhausting and expensive. Although there are a lot of improvements in the medical facilities in the Indian healthcare system, the use of POC diagnostic devices is still in its nascent phase. This review illustrates the status of POC diagnostic devices currently used in clinical setups along with constraints in their use. The devices and technologies that are in the research and development phase across the country that has tremendous potential to elevate the clinical diagnostics scenario along with the diagnosis of ongoing COVID-19 pandemic are emphasized. The implications of using POC diagnostic devices and the future objectives for technological advancements that may eventually uplift the status of healthcare and related sectors in India are also discussed here., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: NA.The authors report no conflict of interest in this work., (© 2020 The Authors.)

The vestibular system of the inner ear contains Type I and Type II hair cells (HCs) generated from sensory progenitor cells; however, little is known about how the HC subtypes are formed. Sox2 (encoding SRY-box 2) is expressed in Type II, but not in Type I, HCs. The present study aimed to investigate the role of SOX2 in cell fate determination in Type I vs. Type II HCs. First, we confirmed that Type I HCs developed from Sox2-expressing cells through lineage tracing of Sox2-positive cells using a CAG-tdTomato reporter mouse crossed with a Sox2-CreER mouse. Then, Sox2 loss of function was induced in HCs, using Sox2 flox transgenic mice crossed with a Gfi1-Cre driver mouse. Knockout of Sox2 in HCs increased the number of Type I HCs and decreased the number of Type II HCs, while the total number of HCs and Sox2-positive supporting cells did not change. In addition, the effect of Sox2-knockout persisted into adulthood, resulting in an increased number of Type I HCs. These results demonstrate that SOX2 plays a critical role in the determination of Type II vs. Type I HC fate. The results suggested that Sox2 is a potential target for generating Type I HCs, which may be important for regenerative strategies for balance disorders., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Cervical collars are used after laminoplasty to protect the hinge opening, reduce risks of hinge fractures, and avoid spring-back phenomena. However, their use may lead to reduced range of motion and worse neck pain., Objective: To investigate the clinical, radiological, and functional outcomes of patients undergoing single-door laminoplasty with or without collar immobilization., Methods: This was a prospective, parallel, single-blinded randomized controlled trial. Patients underwent standardized single-door laminoplasty with mini-plates for cervical myelopathy and were randomly allocated into 2 groups based on the use of collar postoperatively. Clinical assessments included cervical range of motion, axial neck pain (VAS [visual analogue scale]), and objective scores (short-form 36-item, neck disability index, and modified Japanese Orthopaedic Association). All assessments were performed preoperatively and at postoperative 1, 2, 3, and 6 wk, and 3, 6, and 12 mo. Comparative analysis was performed via analysis of variance adjusted by baseline scores, sex, and age as covariates., Results: A total of 35 patients were recruited and randomized to collar use (n = 16) and without (n = 19). There were no dropouts or complications. There were no differences between groups at baseline. Subjects had comparable objective scores and range of motion at postoperative time-points. Patients without collar use had higher VAS at postoperative 1 wk (5.4 vs 3.5; P = .038) and 2 wk (3.5 vs 1.5; P = .028) but subsequently follow-up revealed no differences between the 2 groups., Conclusion: The use of a rigid collar after laminoplasty leads to less axial neck pain in the first 2 wk after surgery. However, there is no additional benefit with regards to range of motion, quality of life, and complication risk., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Capsaicin, the spicy component of hot chili peppers activates the TRPV1 pain receptors, and causes rapid desensitization. Capsaicin also ameliorates cisplatin-induced nephrotoxicity. Cisplatin, a commonly used anti-neoplastic agent for solid tumors causes significant hearing loss, nephrotoxicity and peripheral neuropathy. Upregulation of cochlear TRPV1 expression is related to cisplatin-mediated ototoxicity. Here we report that direct TRPV1 activation by localized trans-tympanic (TT) or oral administration of capsaicin (TRPV1 agonist) prevents cisplatin ototoxicity by sustained increased activation of pro-survival transcription factor signal transducer and activator of transcription (STAT3) in the Wistar rat. Cisplatin treatment produced prolonged activation of pro-apoptotic Ser 727 p-STAT1 and suppressed Tyr 705 -p-STAT3 for up to 72 h in the rat cochlea. Our data indicate that capsaicin causes a transient STAT1 activation via TRPV1 activation, responsible for the previously reported temporary threshold shift. Additionally, we found that capsaicin increased cannabinoid receptor (CB2) in the cochlea, which leads to pro-survival Tyr 705 -p-STAT3 activation. This tilts the delicate balance of p-STAT3/p-STAT1 towards survival. Furthermore, capsaicin mediated protection is lost when CB2 antagonist AM630 is administered prior to capsaicin treatment. In conclusion, capsaicin otoprotection appears to be mediated by activation of CB2 receptors in the cochlea which are coupled to both STAT1 and STAT3 activation.

Previous studies have demonstrated the presence of cannabinoid 2 receptor (CB2R) in the rat cochlea which was induced by cisplatin. In an organ of Corti-derived cell culture model, it was also shown that an agonist of the CB2R protected these cells against cisplatin-induced apoptosis. In the current study, we determined the distribution of CB2R in the mouse and rat cochleae and examined whether these receptors provide protection against cisplatin-induced hearing loss. In a knock-in mouse model expressing the CB2R tagged with green fluorescent protein, we show distribution of CB2R in the organ of Corti, stria vascularis, spiral ligament and spiral ganglion cells. A similar distribution of CB2R was observed in the rat cochlea using a polyclonal antibody against CB2R. Trans -tympanic administration of (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone (JWH015), a selective agonist of the CB2R, protected against cisplatin-induced hearing loss which was reversed by blockade of this receptor with 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone (AM630), an antagonist of CB2R. JWH015 also reduced the loss of outer hair cells (OHCs) in the organ of Corti, loss of inner hair cell (IHC) ribbon synapses and loss of Na + /K + -ATPase immunoreactivity in the stria vascularis. Administration of AM630 alone produced significant hearing loss (measured by auditory brainstem responses) which was not associated with loss of OHCs, but led to reductions in the levels of IHC ribbon synapses and strial Na + /K + -ATPase immunoreactivity. Furthermore, knock-down of CB2R by trans -tympanic administration of siRNA sensitized the cochlea to cisplatin-induced hearing loss at the low and middle frequencies. Hearing loss induced by cisplatin and AM630 in the rat was associated with increased expression of genes for oxidative stress and inflammatory proteins in the rat cochlea. In vitro studies indicate that JWH015 did not alter cisplatin-induced killing of cancer cells suggesting this agent could be safely used during cisplatin chemotherapy. These data unmask a protective role of the cochlear endocannabinoid/CB2R system which appears tonically active under normal conditions to preserve normal hearing. However, an exogenous agonist is needed to boost the activity of endocannabinoid/CB2R system for protection against a more traumatic cochlear insult, as observed with cisplatin administration.

Quantum dots are the semiconductor nanocrystals having unique optical and electronic properties. Quantum dots are category of fluorescent labels utilized for biological tagging, biosensing, bioassays, bioimaging and in vivo imaging as they exhibit very small size, signal brightness, photostability, tuning of light emission range, longer photoluminescence decay time as compared to organic dyes. In this work, we have synthesized and characterized mercaptopropionic acid capped cadmium telluride quantum dots (MPA-CdTe QDs) using hydrothermal method. The study further reports fluorescence intensity stability of quantum dots suspended in different buffers of varying concentration (1-100 mM), stored at various photophysical conditions. Fluorescence intensity values were reduced with increase in buffer concentration. When the samples were stored at room temperature in ambient light condition the quantum dots suspended in different buffers lost the fluorescence intensity after day 15 (except TRIS II). Fluorescence intensity values were found stable for more than 30 days when the samples were stored in dark condition. Samples stored in refrigerator displayed modest fluorescence intensity even after 300 days of storage. Thus, storage of MPA-CdTe QDs in refrigerator may be the suitable choice to maintain its fluorescence stability for longer time for further application.

Background: In situ gel formulations have been widely reported as a carrier for sustained release delivery systems due to certain advantages such as targeted drug delivery, minimal invasiveness and potent therapeutic activity., Objective: Herein, in situ gel system for sustained release of doxorubicin and ibuprofen for anti-cancer and anti-inflammatory activity is reported., Method: Doxorubicin-conjugated alginate (dox-alg) gel was prepared using EDC-NHS chemistry and loaded with ibuprofen encapsulated polycaprolactone (PCL) microparticles (dox-alg composite). PCL microparticles were prepared by a solvent evaporation method (size 50 - 100µm). The gel was characterized using SEM, FTIR, XRD and TGA analysis., Results: Dox-alg composite gel showed good syringeability and gel formation properties. Burst release was observed for both drugs within 24 h followed by sustained release till day 21. Doxorubicin released from composite showed considerable cytotoxic effect. Cell uptake was confirmed by confocal microscopy using MDA-MB-231 cells. Anti-inflammatory activity of ibuprofen released from composite gel was compared with the free drug. An injection of dox-alg composite gel in the tissue would fill the void created after tumor removal surgery, prevent the resuscitation of remnant cancerous cells and reduce inflammation., Conclusion: Thus, the dox-alg composite gel could be a potential agent for the dual anti-cancer and anti-inflammatory therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Cisplatin-induced ototoxicity is one of the major factors limiting cisplatin chemotherapy. Ototoxicity results from damage to outer hair cells (OHCs) and other regions of the cochlea. At the cellular level, cisplatin increases reactive oxygen species (ROS) leading to cochlear inflammation and apoptosis. Thus, ideal otoprotective drugs should target oxidative stress and inflammatory mechanisms without interfering with cisplatin's chemotherapeutic efficacy. In this study, we show that epigallocatechin-3-gallate (EGCG) is a prototypic agent exhibiting these properties of an effect otoprotective agent. Rats administered oral EGCG demonstrate reduced cisplatin-induced hearing loss, reduced loss of OHCs in the basal region of the cochlea and reduced oxidative stress and apoptotic markers. EGCG also protected against the loss of ribbon synapses associated with inner hair cells and Na + /K + ATPase α1 in the stria vascularis and spiral ligament. In vitro studies showed that EGCG reduced cisplatin-induced ROS generation and ERK1/2 and signal transducer and activator of transcription-1 (STAT1) activity, but preserved the activity of STAT3 and Bcl-xL. The increase in STAT3/STAT1 ratio appears critical for mediating its otoprotection. EGCG did not alter cisplatin-induced apoptosis of human-derived cancer cells or cisplatin antitumor efficacy in a xenograft tumor model in mice because of its inability to rescue the downregulation of STAT3 in these cells. These data suggest that EGCG is an ideal otoprotective agent for treating cisplatin-induced hearing loss without compromising its antitumor efficacy.

Prostate cancer (PCa) is the second leading cause of cancer deaths in men. A better understanding of the molecular basis of prostate cancer proliferation and metastasis should enable development of more effective treatments. In this study we focused on the lncRNA, prostate cancer associated transcript 29 (PCAT29), a putative tumor suppressive gene. Our data show that the expression of PCAT29 was reduced in prostate cancer tumors compared to paired perinormal prostate tissues. We also observed substantially lower levels of PCAT29 in DU145 and LNCaP cells compared to normal prostate (RWPE-1) cells. IL-6, a cytokine which is elevated in prostate tumors, reduced the expression of PCAT29 in both DU145 and LNCaP cells by activating signal transducer and activator of transcription 3 (STAT3). One downstream target of STAT3 is microRNA (miR)-21, inhibition of which enhanced basal PCAT29 expression. In addition, we show that resveratrol is a potent stimulator of PCAT29 expression under basal condition and reversed the down regulation of this lncRNA by IL-6. Furthermore, we show that knock down of PCAT29 expression by siRNA in DU145 and LNCaP cells increased cell viability while increasing PCAT29 expression with resveratrol decreased cell viability. Immunohistochemistry studies showed increased levels of STAT3 and IL-6, but low levels of programmed cell death protein 4 (PDCD4), in prostate tumor epithelial cells compared to adjacent perinormal prostate epithelial cells. These data show that the IL-6/STAT3/miR-21 pathway mediates tonic suppression of PCAT29 expression and function. Inhibition of this signaling pathway by resveratrol induces PCAT29 expression and tumor suppressor function.

Cisplatin is a commonly used antineoplastic agent that produces ototoxicity that is mediated in part by increasing levels of reactive oxygen species (ROS) via the NOX3 NADPH oxidase pathway in the cochlea. Recent studies implicate ROS generation in mediating inflammatory and apoptotic processes and hearing loss by activating signal transducer and activator of transcription (STAT1). In this study, we show that the adenosine A1 receptor (A1AR) protects against cisplatin ototoxicity by suppressing an inflammatory response initiated by ROS generation via NOX3 NADPH oxidase, leading to inhibition of STAT1. Trans-tympanic administration of the A1AR agonist R-phenylisopropyladenosine (R-PIA) inhibited cisplatin-induced ototoxicity, as measured by auditory brainstem responses and scanning electron microscopy in male Wistar rats. This was associated with reduced NOX3 expression, STAT1 activation, tumor necrosis factor-α (TNF-α) levels, and apoptosis in the cochlea. In vitro studies in UB/OC-1 cells, an organ of Corti immortalized cell line, showed that R-PIA reduced cisplatin-induced phosphorylation of STAT1 Ser(727) (but not Tyr(701)) and STAT1 luciferase activity by suppressing the ERK1/2, p38, and JNK mitogen-activated protein kinase (MAPK) pathways.R-PIA also decreased the expression of STAT1 target genes, such as TNF-α, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced cisplatin-mediated apoptosis. These data suggest that the A1AR provides otoprotection by suppressing NOX3 and inflammation in the cochlea and could serve as an ideal target for otoprotective drug therapy., Significance Statement: Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. Its use results in significant and permanent hearing loss, for which no US Food and Drug Administration-approved treatment is currently available. In this study, we targeted the cochlear adenosine A1 receptor (A1AR) by trans-tympanic injections of the agonist R-phenylisopropyladenosine (R-PIA) and showed that it reduced cisplatin-induced inflammation and apoptosis in the rat cochlea and preserved hearing. The mechanism of protection involves suppression of the NOX3 NADPH oxidase enzyme, a major target of cisplatin-induced reactive oxygen species (ROS) generation in the cochlea. ROS initiates an inflammatory and apoptotic cascade in the cochlea by activating STAT1 transcription factor, which is attenuated byR-PIA. Therefore, trans-tympanic delivery of A1AR agonists could effectively treat cisplatin ototoxicity., (Copyright © 2016 the authors 0270-6474/16/363962-16$15.00/0.)

Implants are an inevitable part of orthopaedic surgery. However, implant associated infection remains a major challenge for orthopaedic surgeons and researchers. This review focuses on current options available for prevention of implant associated infection, their drawbacks and future promising applications of nanotechnology-based approaches. Nanobiotechnology has shown remarkable progress in recent years especially in biomaterials, diagnostics, and drug delivery system. Although several applications of nanobiotechnology in orthopaedics have been described, few have elaborated their role in the prevention of implant related infection in orthopaedics. Novel "smart" drug delivery systems that release antibiotics locally in response to stimuli such as pH, temperature, enzymes or antigens; implant surface modification on a nanoscale to inhibit bacterial adhesion and propagation at the surgical site and biological approaches such as gene therapy to neutralize bacterial virulence and biomolecules to inhibit the quorum sensing adhesion of bacteria and disruption of biofilms can be used effectively to prevent orthopaedic implant related bacterial infection.

Background: Tibiotalocalcaneal arthrodesis is used to manage end stage arthritis, often associated with severe bone loss. The goal is to relieve pain through a stable, well-aligned hindfoot and ankle. We describe our initial results and outcome of ankle and tibiotalocalcaneal arthrodesis using a 90° blade plate., Methods: We retrospectively reviewed the records of patients managed at our institution between 2010 and 2014. Twenty cases were identified who had either talocrural (n = 9) or TTC fusion (n = 11) with 1 patient having both ankle and then TTC fusion in separate sittings., Results: Fusion occurred in 18 of the 20 cases (90%) with correction of angular deformity and restoration of hindfoot alignment. None of the 18 patients developed complications and all discharged to follow-up when independently mobile and satisfied with the outcome., Conclusions: This study demonstrated that using a 90° blade plate for ankle or TTC arthrodesis in a diverse group of complex primary and revision indications associated with severe deformity and bone loss resulted in a high rate of bony union and stable deformity correction., (Copyright © 2015 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

The high stiffness of bone cements used in vertebroplasty has been hypothesised to contribute to the propensity of adjacent vertebral fractures after treatment. Therefore, new low-modulus cements have been developed; however, there are currently no studies assessing the biomechanical aspects of vertebroplasty with these cements in an ex vivo non-prophylactic model. In this study, we induced wedge fractures through eccentric uniaxial compression to single whole-vertebrae, before and after augmentation with either standard or low-modulus cement. Compressive strength and stiffness of individual vertebrae were measured, on 19 samples from metastatic spines and 20 samples from elderly, osteopenic spines. While both cement types increased the strength of both the metastatic (+34% and +63% for standard and low-modulus cement, respectively) and the elderly vertebrae (+303% and +113%, respectively), none of them restored the initial stiffness of metastatic specimens (-51% and -46%, respectively). Furthermore, low-modulus cement gave a lower total stiffness (-13%) of elderly specimens whereas standard cement increased it above initial levels (+17%). Results show that vertebroplasty with low-modulus cement could provide restoration of the initial stiffness while increasing the strength of fractured elderly vertebrae and hence represent a treatment modality which is closer to pre-augmented behaviour. Also, this study indicates that stiffness-modified cement needs to be optimised for patient/pathology specific treatment., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Medial displacement calcaneal osteotomy is a common procedure often used as part of pes planovalgus deformity correction. Traditionally the osteotomy is performed using a direct lateral or extended lateral approach, which may carry the risk of wound problems, infection and neurovascular injury. The authors describe a minimally invasive technique to perform the osteotomy and achieve the desired correction. The article illustrates our experience and learning curve with the use of this technique as an option for calcaneal osteotomy., Methods: We retrospectively reviewed the records of a sequential series of patients since 2011 whose calcaneal osteotomies were performed by 2 surgeons, after cadaveric training using a minimally invasive operative approach. Prior to 2011, similar surgeries, performed by the senior authors, were undertaken using a direct lateral approach. Thirty cases were identified; 29 had tibialis posterior reconstruction coupled with calcaneal osteotomy for acquired flexible planovalgus deformity and 1 patient had surgery for a malunited calcaneal fracture., Results: Radiological and clinical union occurred in all 30 cases (100%). The radiographs of all cases were reviewed by a specialist musculoskeletal radiologist. There were no neurovascular or wound complications. All patients had restoration of neutral hindfoot alignment. One patient required screw removal after union, resolving all symptoms., Conclusion: This series suggests that minimally invasive calcaneal osteotomy surgery can achieve excellent union rates aiding correction of deformity with no observed neurovascular or soft tissue complications. For surgeons experienced in open surgery, there is a short learning curve after appropriate training., (© The Author(s) 2014.)

Introduction: Sensorineural hearing loss (HL) is becoming a global phenomenon at an alarming rate. Nearly 600 million people have been estimated to have significant HL in at least one ear. There are several different causes of sensorineural HL included in this review of new investigational drugs for HL. They are noise-induced, drug-induced, sudden sensorineural HL, presbycusis and HL due to cytomegalovirus infections., Areas Covered: This review presents trends in research for new investigational drugs encompassing a variety of causes of HL. The studies presented here are the latest developments either in the research laboratories or in preclinical, Phase 0, Phase I or Phase II clinical trials for drugs targeting HL., Expert Opinion: While it is important that prophylactic measures are developed, it is extremely crucial that rescue strategies for unexpected or unavoidable cochlear insult be established. To achieve this goal for the development of drugs for HL, innovative strategies and extensive testing are required for progress from the bench to bedside. However, although a great deal of research needs to be done to achieve the ultimate goal of protecting the ear against acquired sensorineural HL, we are likely to see exciting breakthroughs in the near future.

Aims: Oncogenic microRNAs (miRs) promote tumor growth and invasiveness. One of these, miR-21, contributes to carcinogenesis in prostate and other cancers. In the present study, we tested the hypothesis that NADPH oxidase-dependent reactive oxygen species (ROS) regulate the expression and function of miR-21 and its target proteins, maspin and programmed cell death 4 (PDCD4), in prostate cancer cells., Results: The highly aggressive androgen receptor negative PC-3M-MM2 prostate cancer cells demonstrated high expression of miR-21 and p47(phox) (an essential subunit of NADPH oxidase). Using loss-of-function strategy, we showed that transfection of PC-3M-MM2 cells with anti-miR-21- and p47(phox) siRNA (si-p47(phox)) led to reduced expression of miR-21 with concurrent increase in maspin and PDCD4, and decreased the invasiveness of the cells. Tail-vein injections of anti-miR-21- and si-p47(phox)-transfected PC-3M-MM2 cells in severe combined immunodeficient mice reduced lung metastases. Clinical samples from patients with advanced prostate cancer expressed high levels of miR-21 and p47(phox), and low expression of maspin and PDCD4. Finally, ROS activated Akt in these cells, the inhibition of which reduced miR-21 expression., Innovation: The levels of NADPH oxidase-derived ROS are high in prostate cancer cells, which have been shown to be involved in their growth and migration. This study demonstrates that ROS produced by this pathway is essential for the expression and function of an onco-miR, miR-21, in androgen receptor-negative prostate cancer cells., Conclusion: These data demonstrate that miR-21 is an important target of ROS, which contributes to the highly invasive and metastatic phenotype of prostate cancer cells.

Aim: The present study was undertaken to investigate a length polymorphism of (GT)n repeats of the heme oxygenase-1 (HMOX-1) gene and its association with serum bilirubin levels in apparently healthy adults., Methods: A total of 211 individuals (normal hematology and liver function test) with bilirubin levels of 1.7 to 22.2 μM were studied. The (GT)n repeats were analyzed by PCR and subsequent sizing by capillary electrophoresis on the ABI Prism 310 Genetic Analyzer., Results: Polymorphisms of the (GT)n repeats were grouped into three classes: short (S) alleles (<20 repeats), intermediate (M) alleles (20-28 repeats), and long (L) alleles (≥ 29 repeats). The frequencies of the S, M, and L allele groups were 0.10, 0.49, and 0.41, respectively. Carriers of short alleles had significantly higher mean bilirubin levels (13.8 ± 5.10 μM) compared with others (9.18 ± 3.73 μM, p < 0.001)., Conclusion: Short (GT)n alleles of the HMOX-1 gene promoter could be a genetic risk factor for hyperbilirubinemia.