Murine IRF8 Mutation Offers New Insight into Osteoclast and Root Resorption.

Interferon regulatory factor 8 (IRF8), a transcription factor expressed in immune cells, functions as a negative regulator of osteoclasts and helps maintain dental and skeletal homeostasis. Previously, we reported that a novel mutation in the IRF8 gene increases susceptibility to multiple idiopathic cervical root resorption (MICRR), a form of tooth root resorption mediated by increased osteoclast activity. The IRF8 G388S variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. To investigate the molecular basis of MICRR and IRF8 function in osteoclastogenesis, we generated Irf8 knock-in (KI) mice using CRISPR/Cas9 technique modeling the human IRF8G388S mutation. The heterozygous (Het) and homozygous (Homo) Irf8 KI mice showed no gross morphological defects, and the development of hematopoietic cells was unaffected and similar to wild-type (WT) mice. The Irf8 KI Het and Homo mice showed no difference in macrophage gene signatures important for antimicrobial defenses and inflammatory cytokine production. Consistent with the phenotype observed in MICRR patients, Irf8 KI Het and Homo mice demonstrated significantly increased osteoclast formation and resorption activity in vivo and in vitro when compared to WT mice. The oral ligature-inserted Het and Homo mice displayed significantly increased root resorption and osteoclast-mediated alveolar bone loss compared to WT mice. The increased osteoclastogenesis noted in KI mice is due to the inability of IRF8G388S mutation to inhibit NFATc1-dependent transcriptional activation and downstream osteoclast specific transcripts, as well as its impact on autophagy-related pathways of osteoclast differentiation. This translational study delineates the IRF8 domain important for osteoclast function and provides novel insights into the IRF8 mutation associated with MICRR. IRF8G388S mutation mainly affects osteoclastogenesis while sparing immune cell development and function. These insights extend beyond oral health and significantly advance our understanding of skeletal disorders mediated by increased osteoclast activity and IRF8's role in osteoclastogenesis.

Preventative strategies for low anterior resection syndrome.

BACKGROUND: A common and debilitating complication of low anterior resection for rectal cancer is low anterior resection syndrome (LARS). As a multifactorial entity, LARS is poorly understood and challenging to treat. Despite this, prevention strategies are commonly overlooked. Our aim was to review the pathophysiology of LARS and explore current evidence on the efficacy and feasibility of prophylactic techniques. METHODS: A literature review was performed between [1st January 2000 to 1st October 2023] for studies which investigated preventative interventions for LARS. Mechanisms by which LARS develop are described, followed by a review of prophylactic strategies to prevent LARS. Medline, Cochrane, and PubMed databases were searched, 189 articles screened, 8 duplicates removed and 18 studies reviewed. RESULTS: Colonic dysmotility, anal sphincter dysfunction and neorectal dysfunction all contribute to the development of LARS, with the complex mechanism of defecation interrupted by surgery. Transanal irrigation (TAI) and pelvic floor rehabilitation (PFR) have shown benefits in preventing LARS, but may be limited by patient compliance. Intraoperative nerve monitoring (IONM) and robotic-assisted surgery have shown some promise in surgically preventing LARS. Nerve stimulation and other novel strategies currently used in treatment of LARS have yet to be investigated in their roles prophylactically. CONCLUSIONS: To date, there is a limited evidence base for all preventative strategies including IONM, RAS, PFP and TAI. These strategies are limited by either access (IONM, RAS and PFP) or acceptability (PFP and TAI), which are both key to the success of any intervention. The results of ongoing trials will serve to assess acceptability, while technological advancement may improve access to some of the aforementioned strategies.

Detection of Oncogenic Human Papillomavirus (HPV-16 and HPV-18) from Bacterial Vaginosis Positive Patient Attending at Tertiary Care Hospital in Mymensingh.

Cervical cancer is the fourth most common cancer in women in the world and is the second leading malignancy among Bangladeshi women. Persistent infection with high risk human papillomavirus (HPV) is an important cause of development of cervical intraepithelial neoplasia (CIN) followed by cancer. Bacterial vaginosis (BV), a common treatable vaginal infection which can disrupt the balanced vaginal ecosystem and its innate protective mechanisms against infection, can play an essential role in the acquisition and persistence of high risk human papillomavirus (HR-HPV) infection. This cross sectional study was conducted to detect the HR-HPV (HPV-16 and HPV-18) infection among bacterial vaginosis positive patient in the Department of Microbiology, Mymensingh Medical College (MMC), Bangladesh, from March 2018 to February 2019. A total of 300 endocervical swabs and high vaginal swabs were collected from the VIA (Visual inspection with acetic acid) outdoor clinic of Obstetrics and Gynaecology Department of Mymensingh Medical college Hospital. HPV DNA was tested among all 300 cases by nested PCR. Typing of HPV 16 and HPV 18 was done among HPV DNA positive cases with BV and intermediate flora by multiplex PCR. BV was diagnosed according to Nugent criteria by using the gram stained smear of high vaginal swab. A total of 57/300 (19.0%) samples were positive for HPV DNA by nested PCR. Of the total 300 cases 78(26.0%) had BV, 38(13.0%) had intermediate flora and 184(61.0%) had normal vaginal flora. HPV DNA was more positive in patients having intermediate flora 08/38 (21.05%) followed by the patients having normal vaginal flora 37/184 (20.11%) and BV 12/78 (15.38%). Among the 12 BV patients who were also HPV DNA positive (83.33%) were belong to high risk HPV (type 16 and 18) group and among them 08(66.67%) were HPV-16 and 02(16.67%) were HPV-18. But among 08 HPV DNA positive intermediate flora containing patients only 01(12.5%) were belong to HR-HPV (type 16 and no type 18 was detected).

Food environment index and preterm birth rate in the counties of the United States.

OBJECTIVES: To determine the relationship between Food Environment Index (FEI) and Preterm Birth (PTB) rate at the county level of the United States of America (USA) (primary), while evaluating the interaction of multiple factors within a framework of sociodemographic, maternal health, maternal behavioral, and environmental factors. METHODS: This is a population-based retrospective cohort ecological study from 2015-2018. The study compares the characteristics of the population of the counties of the USA. All counties with complete data on their PTB rate and the independent variables were included in the study. Independent variables with greater than 20% missing data were excluded from the study. Purposive sampling technique was applied. A total of 2983/3142 counties were included in the study. RESULTS: The median PTB rate of all counties was 9.90%. The highest PTB rate (23.3%) was in Tallapoosa County, Alabama and the lowest (3.4%) in San Juan County, Washington State. After adjusting for variables, PTB rate had a significant association with FEI (coefficient of correlation - 0.36, p < 0.01, 95% CI - 0.19 to - 0.04). Increase in the rate of unemployment, African American race, adult smoking, obesity, uninsured rate, sexually transmitted diseases (STD), high school education and air pollution was associated with an increase in PTB rate, while an increase in FEI and alcohol abuse rates was associated with a decrease in PTB rate. CONCLUSIONS: FEI can predict the PTB rate in USA counties after adjusting for sociodemographic, health, behavioral and environmental factors. Future studies are needed to confirm these associations and consider them when making policies to reduce PTBs.

Role of four-dimensional computer tomography (4D-CT) in non-localising and discordant first-line imaging in primary hyperparathyroidism.

BACKGROUND: Accurate preoperative localisation of parathyroid adenoma is imperative for the success of minimally invasive parathyroidectomy (MIP). OBJECTIVE: Our study aimed to evaluate the role of four-dimensional computer tomography (4D-CT) scan as an imaging modality in patients with failed and discordant localisation reported in the first-line imaging modalities (ultrasonography and 99mTc-MIBI-SPECT/CT). METHODS: This is a prospective cohort study performed at a university teaching centre from March 2013 to July 2021. All patients with primary hyperparathyroidism who had failed localisation by ultrasonography and 99mTc-MIBI-SPECT/CT (SpCT), or discordance between them, had 4D-CT performed in this study. RESULTS: One hundred and two sporadic cases of pHPT with failed/discordant first-line imaging had 4D-CT imaging prior to parathyroidectomy. In 102 patients, 105 parathyroid adenomas were reported on histopathology. 4D-CT was able to localise 78% of them to the correct side and 64% to the correct quadrant in 102 patients, as compared with US (correct side 21%, correct quadrant 16%) and 99mTc-MIBI-SPECT/CT (correct side 36%, correct quadrant 31%). 4D-CT had a sensitivity, precision, accuracy and F1 score for correct quadrant localisation as 79%, 81%, 66% and 80%; and for correct side localisation as 82%, 98%, 80% and 89%, respectively. 4D-CT was able to identify three ectopic adenomas (two in superior mediastinum and one in the oesophageal wall) which were not detected on US or SpCT. CONCLUSION: 4D-CT was found to be sensitive and accurate in preoperative localising of the diseased parathyroid glands after failed/discordant US and SpCT. This led to more patients being offered MIP as the primary surgery and improved operative outcomes.

Ocular involvement in facial nerve paralysis: risk factors for severe visual impairment and ocular surface exposure in 1870 patients.

PURPOSE: To identify the risk factors associated with the development of ocular surface exposure and severe visual impairment (SVI) in patients with facial nerve palsy (FNP). METHODS: Ocular data of all consecutive FNP patients (N = 1870) presenting to an eye-care network over the past 10 years were reviewed. Risk factors associated with SVI (best-corrected visual acuity <20/200) and ocular surface exposure at presentation were evaluated using multivariate analysis and odds ratios (OR). RESULTS: The prevalence of SVI was 15%, and 47% had ocular surface exposure at the first presentation. The presence of corneal scar (28% vs. 10.2%, p < .001; OR 3.05), corneal ulcer (12.9% vs. 2.3%, p < .001; OR 4.67), older age at presentation (p < .001; OR 1.02), >10 mm lagophthalmos (p < .001; OR 8.7), male sex, and duration of FNP (p = .021; OR 1) were independent risk factors for developing SVI. Of the 893 eyes with ocular surface exposure, 75 (3.9%) had a corneal ulcer, and 11 (0.6%) were perforated, with the rest having epithelial defects and punctate keratopathy. Patients with neoplastic etiology (15.9% vs. 5.7%; p < .001; OR 2.39), lagophthalmos (49% vs. 29.7%; p < .001; OR 2.25) and poor Bell's phenomenon (9.4% vs. 4.2%; p = .005; OR 1.8) had twofold risk for developing ocular surface exposure. CONCLUSION: Eyes with lagophthalmos, poor Bell's phenomenon, and FNP of neoplastic etiology have a higher risk of developing ocular surface exposure. Male sex, increasing age, longer duration of FNP, and >10 mm lagophthalmos are associated with SVI in FNP patients; hence, early and timely intervention is necessary.

Using Real-world Data to Define a Validated Nomogram for Advanced Bladder Cancer Patients Who Respond to Immunotherapy.

AIMS: Immune checkpoint inhibitors (ICIs) are used in incurable urothelial cancers, both in chemo-naïve and platinum-refractory patients. Efficacy and toxicity data published outside controlled clinical trials are limited. We report overall survival, progression-free survival and toxicities of ICIs in locally advanced (LABC) or metastatic bladder cancer (MBC). We aimed to develop and validate a prognostic model for these patients. MATERIALS AND METHODS: A multicentre real-world individual patient-level data study (n = 272) evaluating ICIs in the first-line platinum-ineligible or platinum-refractory setting for LABC/MBC between March 2017 and February 2020 was undertaken. Cox regression analyses evaluated the association of prognostic factors with overall survival. Data were split to create a training (n = 208) and validation (n = 64) cohort. The backward elimination method with a P-value cut-off of 0.05 was used to develop a reduced prognostic model using the training data set. The concordance index and assessment of observed versus predicted survival probabilities were used to evaluate the final model. RESULTS: The median follow-up was 18.9 (15.8-21.5) months. The median overall survival and progression-free survival in the training cohort were 9.2 (95% confidence interval 7.4-10.5) and 4.5 months (3.5-5.7), respectively. The most common grade 1/2 adverse events recorded were fatigue (47.8%) and infection (19.9%). Five key prognostic factors found in the training set were low haemoglobin, high neutrophil count, choice of immunotherapy favouring pembrolizumab, presence of liver metastasis and steroid use within 30 days of treatment. The concordance index for the training and validation cohorts was 0.66 (standard error = 0.05) and 0.64 (standard error = 0.04), respectively, for the final model. A nomogram was developed to calculate the expected survival probabilities based on risk factors. CONCLUSIONS: Real-world data were used to produce a validated prognostic model for overall survival in LABC/MBC treated with ICIs. This model could assist in patient stratification, interpreting and framing future trials incorporating PD-1/PD-L1 inhibitors in LABC/MBC.

A high-resolution computed tomography based scoring system to predict ease of electrode insertion in cochlear implantation.

OBJECTIVE: This study aimed to formulate a scoring system based on high-resolution computed tomography scans to predict ease of electrode insertion during cochlear implantation via posterior tympanotomy in paediatric patients. METHOD: A scoring system Cochlear Implantation Radiological Assessment Score (CIRAS) was formulated based on six parameters. This score was correlated with intra-operative findings, and receiver operating characteristic analysis was performed to determine the optimal cut-off score to predict difficulty of surgery and to establish the inherent validity of the scoring system by area under curve. RESULTS: Receiver operating characteristic analysis showed that optimal cut-off score was 8 (93.1 per cent specificity and 56.52 per cent sensitivity), and area under the curve was 0.828. Patients with CIRAS of more than 8 had significantly higher time for surgery (p < 0.05). CONCLUSION: CIRAS is an easy to administer tool by utilising classical axial and coronal sections, without any numerical measures. Pre-operative assessment by this score gives a good idea of intra-operative challenges.

Impact of the COVID-19 pandemic on the management of surgical patients presenting in an emergency setting -Report from a tertiary referral centre.

Introduction: At the onset of the first wave of COVID-19 pandemic, the publications on managing surgical emergencies were sparse. Health care personnel were facing an unprecedented problem with limited information. On this background, we have reviewed the operational challenges faced and the protocols followed by us while managing emergency surgical patients. The clinical presentations, RT-PCR testing rates, trend of COVID-19 positivity in emergency surgical patients and its comparison to the general population, swab positivity among screen positive and negative patients, grade of COVID-19 affection, the outcomes in emergency surgical patients, and COVID-19 affection in treating personnel is studied. Patients and Methods: A protocol for triaging patients at presentation into screen positive or negative for COVID-19 was instituted. A proforma for all admitted patients over the period of March 2020 to August 2020 was maintained. A retrospective review of this data was carried out after Institutional Ethics Committee permission. Results: A total of 222 patients presented to the surgical emergency, of which 110 required admission. Of the admitted patients, 28 were COVID-19 positive. The positivity amongst admitted and operated patients increased to 50% and 66.67%, respectively in August. The difference in mortality rate amongst the operated COVID-19 positive (11.1%) and negative (14.28%) patients was nonsignificant. None of the treating doctors had to be quarantined during this period. Conclusions: The number of COVID-19 positive patients rose serially over the study period. The outcome was not affected by the COVID-19 status in mild cases. A high rate of COVID-19 positivity was seen in patients requiring emergency surgery. Universal precautions ensured delivering treatment to emergency patients in standard time. Testing should continue for all as screening alone is not effective as the virus spreads into the population. Proper protocols helped us to protect the health care workers.

Clinical effectiveness of Lactobacillus reuteri in the treatment of peri-implant diseases: a systematic review and meta-analysis.

In the last decades, the presence of peri-implant diseases (PD) has increased. One of the therapies currently used is probiotics with Lactobacillus reuteri (LR). The aim of this article is to determinate, through a systematic review and meta-analysis, the clinical effectiveness of LR in the treatment of PD. We searched the literature until January 2021, in the biomedical databases: Pubmed, Embase, Scielo, Science Direct, Scopus, SIGLE, LILACS, Google Scholar and Cochrane Central Registry of Clinical Trials. The selection criteria of the studies were: randomized controlled clinical trials, without language and time restriction, reporting the clinical effects (depth to probing, plaque index and bleeding index) of the LR in the PD treatment. The risk of study bias was analyzed through the Cochrane tool for randomized studies using Review Manager software. The search strategy resulted in 6 articles of which four investigated peri-implantitis and three peri-implant mucositis. All studies reported that there was a difference in the depth of the probing in the treatment of PD, in favor of the group using LR, though not always achieving significance. The use of LR can be clinically effective in terms of pocket depth reduction in the treatment of PD.

Clinical efficacy of grape seed extract as an adjuvant to scaling and root planing in treatment of periodontal pockets.

Grape seed extract (GSE), a naturally producing polyphenolic compound, is found to be a potent hostmodulatory agent and considered for management of periodontal disease. Its anti-bacterial, antioxidant, and anti-inflammatory property may aid in achieving periodontal health. To assess the clinical efficacy of GSE in adjunct to scaling and root planing (SRP) in healing of periodontal pockets. The present study was a longitudinal, parallel design, randomized clinical trial. Seventy-two patients (mean age 39.2±8.6 years) with periodontal pockets were randomly divided into two groups; Test group received intra-pocket delivery of GSE with SRP and Control group received SRP alone. The clinical parameters like Plaque Index (PI), Gingival Index (GI), Probing Depth (PD) and Relative Attachment Level (RAL) were recorded at baseline and 3 months. 64 patients completed the study. Test group at the end of 3 months had statistically significant reduced PD (p=0.002) and RAL (p=0.01). No significant difference was observed for PI and GI at the end of 3 months. Intra-pocket application of GSE with SRP could be beneficial in management of periodontal pockets.

Linear lesions in dermatology: a clinicoaetiopathological study.

BACKGROUND: Linear lesions are fairly common in our daily practice. However, the appearance of these lesions can vary, thus complicating the diagnosis. AIMS: To study the various clinical presentations, the demographic profile of patients and the clinicopathological correlations of dermatoses presenting with a linear distribution. METHODS: We conducted an institution-based, cross-sectional, descriptive study of 281 consecutive patients with linear lesions attending dermatology clinics. MedCalc software (V11.6) was used for statistical analysis. RESULTS: Patients were divided into eight groups: lesions along the lines of Blaschko (n = 136), lesions along blood vessels (n = 3), lesions along lymphatics (n = 3), Koebner phenomenon (n = 24), autoinoculation (n = 24), external factors (n = 45), infestations (n = 2) and 'other' (n = 44). The mean age at presentation was 24.50 ± 18.82 years and the male/female ratio was 1.32 : 1. The commonest symptom was itching/burning (56.94% of patients), while the commonest site was the arm (44.48%); followed by the leg (30.60%), trunk and abdomen (22.42%), head and neck (19.20%), and genitalia (0.35%). Apart from the common cases, there was a wide gamut of rare conditions (e.g. angiokeratoma circumscriptum naeviforme, porokeratotic eccrine ostial and dermal duct naevus, Blaschko-linear syringocystadenoma papilliferum, progressive cribriform and zosteriform hyperpigmentation, unilateral naevoid acanthosis nigricans, fixed drug eruption, discoid lupus erythematosus). CONCLUSION: Linear lesions act as diagnostic clues to many dermatological conditions, therefore, the importance of meticulous examination in clinical dermatology cannot be overemphasized.

Label free, electric field mediated ultrasensitive electrochemical point-of-care device for CEA detection.

Developing point-of-care (PoC) diagnostic platforms for carcinoembryonic antigen detection is essential. However, thefew implementations of transferring the signal amplification strategies in electrochemical sensing on paper-based platforms are not satisfactory in terms of detection limit (LOD). In the quest for pushing down LOD, majority of the research has been targeted towards development of improved nanostructured substrates for entrapping more analyte molecules and augmenting the electron transfer rate to the working electrode. But, such approaches have reached saturation. This paper focuses on enhancing the mass transport of the analyte towards the sensor surface through the application of an electric field, in graphene-ZnO nanorods heterostructure. These hybrid nanostructures have been deposited on flexible polyethylene terephthalate substrates with screen printed electrodes for PoC application. The ZnO nanorods have been functionalized with aptamers and the working sensor has been integrated with smartphone interfaced indigenously developed low cost potentiostat. The performance of the system, requiring only 50 µl analyte has been evaluated using electrochemical impedance spectroscopy and validated against commercially available ELISA kit. Limit of detection of 1 fg/ml in human serum with 6.5% coefficient of variation has been demonstrated, which is more than three orders of magnitude lower than the existing attempts on PoC device.

A systematic review of the primary squamous cell carcinoma of the external auditory canal: survival outcome based on T-staging and proposal of a new classification.

OBJECTIVE: This study aimed to provide a systematic review on survival outcome based on Pittsburgh T-staging for patients with primary external auditory canal squamous cell carcinoma. METHOD: This study was a systematic review in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines performed until January 2018; pertinent studies were screened. Quality of evidence was assessed using the grading of recommendation, assessment, development and evaluation working group system. RESULTS: Eight articles were chosen that reported on 437 patients with external auditory carcinoma. The 5-year overall survival rate was 53.0 per cent. The pooled proportion of survivors at 5 years for T1 tumours was 88.4 per cent and for T2 tumours was 88.6 per cent. For the combined population of T1 and T2 cancer patients, it was 84.5 per cent. For T3 and T4 tumours, it was 53.3 per cent and 26.8 per cent, respectively, whereas for T3 and T4 tumours combined, it was 40.4 per cent. Individual analysis of 61 patients with presence of cervical nodes showed a poor survival rate. CONCLUSION: From this review, there was not any significant difference found in the survival outcome between T1 and T2 tumours. A practical classification incorporating nodal status that accurately stratifies patients was proposed.

MGMT-inhibitor in combination with TGF-ßRI inhibitor or CDK 4/6 inhibitor increases temozolomide sensitivity in temozolomide-resistant glioblastoma cells.

BACKGROUND: Glioblastoma (GB) remains an incurable and deadly brain malignancy that often proves resistant to upfront treatment with temozolomide. Nevertheless, temozolomide remains the most commonly prescribed FDA-approved chemotherapy for GB. The DNA repair protein methylguanine-DNA methyl transferase (MGMT) confers resistance to temozolomide. Unsurprisingly temozolomide-resistant tumors tend to possess elevated MGMT protein levels or lack inhibitory MGMT promotor methylation. In this study, cultured human temozolomide resistance GB (43RG) cells were introduced to the MGMT inhibitor O6-benzylguanine combined with temozolomide and either LY2835219 (CDK 4/6 inhibitor) or LY2157299 (TGF-ßRI inhibitor) seeking to overcome GB treatment resistance. METHODS: Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot, cell viability, and cell cycle progression. RESULTS: Our in vitro study demonstrated that sequential treatment of O6-Benzylguanine with either LY2385219 or LY2157299-enhanced temozolomide enhanced sensitivity in MGMT+ 43RG cells. Importantly, normal human neurons and astrocytes remained impervious to the drug therapies under these conditions. Furthermore, LY2835219 has additional anti-proliferative effects on cell cycling, including induction of an RB-associated G (1) arrest via suppression of cyclin D-CDK4/6-Rb pathway. LY2157299 enhances anti-tumor effect by disrupting TGF-ß-dependent HIF-1α signaling and by activating both Smad and PI3K-AKT pathways towards transcription of S/G2 checkpoints. CONCLUSION: This study establishes the groundwork for the development of a combinatorial pharmacologic approach by using either LY2385219 or LY2157299 inhibitor plus O6-Benzylguanine to augment temozolomide response in temozolomide-resistant GB cells.

Design, characterization and in vitro evaluation of thin films enriched by tannic acid complexed by Fe(III) ions.

Materials based on carbohydrate polymers may be used for biomedical application. However, materials based on natural polymers have weak physicochemical properties. Thereby, there is a challenge to improve their properties without initiation of toxicity. The alternative method compared to toxic chemical agents' addition is the use of metal complexation method. In this study, chitosan/tannic acid mixtures modified by Fe(III) complexation are proposed and tested for potential applications as wound dressings. Thereby, surface properties, blood compatibility as well as platelet adhesion was tested. In addition, the periodontal ligament stromal cells compatibility studies were carried out. The results showed that the iron(III) addition to chitosan/tannic acid mixture improves properties due to a decrease in the surface free energy and exhibited a reduction in the hemolysis rate (below 5%). Moreover, cells cultured on the surface of films with Fe(III) showed higher metabolic activity. The current findings allow for the medical application of the proposed materials as wound dressings.

Prolonged intra-operative thermal exposure in endoscopic ear surgery: is it really safe?

OBJECTIVE: The aim of this study was to assess change in temperature, audiometric outcomes and post-operative complications following exposure to different light sources during endoscopic ear surgery. METHOD: A total of 64 patients diagnosed with chronic otitis media with central perforation and pure conductive hearing loss underwent endoscopic type 1 tympanoplasty. The patients were randomised into two groups based on the light source used: xenon or light-emitting diode. Temperature was measured using a K type thermocouple at the promontory and round window niche. Mean temperature change with respect to operating time, mean audiometric change, incidence of vomiting in the first 24 hours, vertigo and tinnitus at the end of the first week were observed. RESULTS: Mean temperature change showed a statistically significant difference with increasing length of operating time with the xenon light source and when the two light sources were compared for a particular time interval. Mean audiometric change showed statistically significant deterioration at higher frequencies (4, 6 and 8 kHz) with the xenon light source but only at 8 kHz for the light emitting diode source. When the mean audiometric change was compared between light sources for a particular frequency, statistical significance was found at 4, 6 and 8 kHz. Post-operative complications were vomiting, vertigo and tinnitus (p-values of 0.042, 0.099 and 0.147, respectively, between two groups). CONCLUSION: Light emitting diodes are associated with less significant middle-ear temperature rises and audiometric changes at higher frequencies when compared to xenon light sources. Hence, xenon should be replaced with cooler light sources.

Evaluating anti-tumor activity of palbociclib plus radiation in anaplastic and radiation-induced meningiomas: pre-clinical investigations.

PURPOSE: Meningiomas are common brain tumors, the majority of which are considered benign. Despite surgery and/or radiation therapy, recurrence rates are approximately 8-10%. One likely cause is the dysregulation of cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway, which controls the cell cycle restriction point. This pathway is commonly dysregulated in anaplastic meningioma cell lines (AM) and radiation-induced meningioma cells (RIM), making it a rational target for anti-meningioma therapy. In this study, we investigate the effect of a CDK4/6 inhibitor, palbociclib, with radiation in relevant pre-clinical models. METHODS: In vitro cell culture, ex vivo slice culture and in vivo cell line-derived orthotopic xenograft animal models of AM/RIM were utilized to assess treatment efficacy with palbociclib plus radiation. Treatment effects were examined by immunoblot, cell viability, apoptosis, and cell cycle progression. RESULTS: The in vitro and ex vivo studies demonstrate that palbociclib plus radiation treatment reduced proliferation and has additional effects on cell cycling, including induction of an RB-associated G (1) arrest in Rb+ AM and RIM cells, but not in Rb- cells. Our results also demonstrated reduced CDK4 and CDK6 expression as well as reduced E2F target gene expression (CCNA2 and CCNE2) with the combination therapy. MRI results in vivo demonstrated reduced tumor size at 5 weeks when treated with 14 days palbociclib (10 mg/kg) plus 6 Gy radiation compared to saline-treated tumors. Finally, no hepatic toxicity was found after treatments. CONCLUSION: A pre-clinical murine model provides preclinical evidence for use of palbociclib plus radiation as a therapeutic agent for Rb+ meningiomas.