Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system.

OBJECTIVE: The enteric nervous system (ENS) undergoes neuronal loss and degenerative changes with age. The cause of this neurodegeneration is poorly understood. Muscularis macrophages residing in close proximity to enteric ganglia maintain neuromuscular function via direct crosstalk with enteric neurons and have been implicated in the pathogenesis of GI motility disorders like gastroparesis and postoperative ileus. The aim of this study was to assess whether ageing causes alterations in macrophage phenotype that contributes to age-related degeneration of the ENS. DESIGN: Longitudinal muscle and myenteric plexus from small intestine of young, mid-aged and old mice were dissected and prepared for whole mount immunostaining, flow cytometry, Luminex immunoassays, western blot analysis, enteric neural stem cell (ENSC) isolation or conditioned media. Bone marrow derived macrophages were prepared and polarised to classic (M1) or alternative (M2) activation states. Markers for macrophage phenotype were measured using quantitative RT-PCR. RESULTS: Ageing causes a shift in macrophage polarisation from anti-inflammatory 'M2' to proinflammatory 'M1' that is associated with a rise in cytokines and immune cells in the ENS. This phenotypic shift is associated with a neural response to inflammatory signals, increase in apoptosis and loss of enteric neurons and ENSCs, and delayed intestinal transit. An age-dependent decrease in expression of the transcription factor FoxO3, a known longevity gene, contributes to the loss of anti-inflammatory behaviour in macrophages of old mice, and FoxO3-deficient mice demonstrate signs of premature ageing of the ENS. CONCLUSIONS: A shift by macrophages towards a proinflammatory phenotype with ageing causes inflammation-mediated degeneration of the ENS.

Assessment of Lipid Peroxidation Levels and Total Antioxidant Status in Chronic and Aggressive Periodontitis Patients: An in vivo Study.

INTRODUCTION: Periodontitis is a common problem affecting a significant population of the world. For the assessment of oxidative stress of an individual, total oxidation status (TOS) and total antioxidant capacity (TAOC) are the significant biomarkers. Hence, we planned the present study to assess malondialde-hyde (MDA), TOS, TAOC levels, and oxidative stress index (OSI) in generalized aggressive periodontitis (GP) and chronic periodontitis (CP) patients. MATERIALS AND METHODS: The present study included assessment of 40 CP patients, 40 GP patients, and 40 healthy controls. Clinical assessment of all the subjects was done by measuring the probing depth (PD), clinical attachment (CL), gingival index (GI), gingival bleeding index (GBI), and plaque index (PI). Salivary and serum samples were taken and assessed by standard procedures as described previously in the literature. All the values were assessed and compared. RESULTS: Significant results were obtained while comparing all the periodontal parameters in between various study groups. Mean serum MDA levels in the CP, GP, and control group were found to be 0.68, 0.65, and 0.61 µM respectively. Statistically nonsignificant results were obtained while comparing the serum MDA levels in between the three study groups. Significant results were obtained while comparing the mean serum and salivary TOS values, TAOC values, and OSI in between various study groups. CONCLUSION: In periodontitis patients, oxidative stress was significantly higher in comparison with healthy subjects. CLINICAL SIGNIFICANCE: Oxidative parameters do play a significant role in the pathologic profile of periodontitis.

Cellular thermotolerance is independent of HSF 1 expression in zebu and crossbred non-lactating cattle.

Heat stress is an important domain of research in livestock due to its negative impact on production and disease resistance. The augmentation of stress in the body stimulates the antioxidative activity comprising various enzymes (viz., catalase, superoxide dismutase), metabolites (reduced glutathione, etc.), vitamins, minerals, etc. to combat the situation. The major key players involved in regulation of heat shock response in eukaryotes are the transcription factors, called as heat shock factors (HSF). They activate the heat shock protein (HSP) genes by binding to their promoters. Lymphocytes are considered to be the best model to evaluate the immunity in any living body as it contains plethora of white blood cells (WBCs).In this study, the peripheral blood mononuclear cells (PBMC) obtained from non-lactating Sahiwal vis-à-vis crossbred (Holstein Friesian × Sahiwal) cattle with 75% or more exotic inheritance were subjected to heat shock at 39, 41, and 43 °C in three different incubators, in vitro. The cell count and viability test of pre and post heat stress of concerned PBMCs indicated that the crossbreeds are more prone to heat stress as compared to Sahiwal. The reverse transcription PCR (qRT-PCR) expression data revealed an increment in HSF1 expression at 41 °C which subsequently declined (non-significantly) at 43 °C in both breeds post 1 h heat shock. However, the association between the HSF 1 expression and antioxidative activity through correlation analysis was found to be non-significant (P < 0.05), though enzymatic activity appeared to behave in a similar fashion in both breeds at 5% level of significance (P < 0.05). This rule out the role of HSF1 expression level on the activity of enzymes involved in oxidative stress in vitro in zebu and crossbred cattle.

Repetitive transcranial magnetic stimulation: Course and early prediction of response in depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression, yet few studies have mapped the trajectories of symptom change over treatment. Tracking clinical response during early treatment may be helpful to predict outcome, particularly non-response. METHODS: We used naturalistic data (N = 117) to examine changes in the Daily Symptom Index (DI-5) scores of adult patients with unipolar or bipolar depression who underwent ≥16 treatment sessions of left dorsolateral prefrontal cortex rTMS at a private psychiatric facility in Western Australia, between 2016 and 2019. RESULTS: Two response trajectories were charted: non-response (N = 71, 61%) and response (N = 46, 39%). Both trajectories diverged at 99% confidence interval at session 10, which was used as the point to predict treatment response at session 20. The response group showed a reduction of 4.21 in the mean DI-5 score from baseline at session 10. On this basis, a 4-point reduction in the DI-5 score at session 10 was defined as predictor of responder status at session 20. If the improvement is < 4 points at session 10, the probability of non-response at session 20 is 75%. If the improvement is ≥ 4 points, the probability of response at session 20 is 66%. LIMITATIONS: The DI-5 scores were not examined beyond 20 treatment sessions, which may have shown delayed responders in the non-response group. CONCLUSIONS: In this study of depression response trajectories with rTMS treatment, prediction of response at session 20 can be made at session 10 of treatment. Further research is required to generalise the current findings.

TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy.

One of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not well-understood. Here we show that GBM cells secrete IL-8 and CCL2 which stimulate GAMs to produce TNFα. Subsequently, TNFα induces a distinct gene expression signature of activated ECs including VCAM-1, ICAM-1, CXCL5, and CXCL10. Inhibition of TNFα blocks GAM-induced EC activation both in vitro and in vivo and improve survival in mouse glioma models. Importantly we show that high TNFα expression predicts worse response to Bevacizumab in GBM patients. We further demonstrated in mouse model that treatment with B20.4.1.1, the mouse analog of Bevacizumab, increased macrophage recruitment to the tumor area and correlated with upregulated TNFα expression in GAMs and increased EC activation, which may be responsible for the failure of AATx in GBMs. These results suggest TNFα is a novel therapeutic that may reverse resistance to AATx. Future clinical studies should be aimed at inhibiting TNFα as a concurrent therapy in GBMs.

Five year clinical outcomes and evaluation following implantation of the Oticon™ wide bone anchored hearing system in 47 children.

OBJECTIVES: The Oticon™ wide implant system was launched in 2009 and used at Birmingham Children's Hospital from 2014. To evaluate clinical outcomes of the Oticon™ wide implant (Oticon Medical), with a focus on skin complication rates and fixture loss over a 5-year period in a tertiary paediatric hospital in the UK. METHODS: Retrospective 5-year longitudinal case record review of 47 children who were implanted with the Oticon™ wide implant system at Birmingham Children's Hospital (BCH) between January 2014 and January 2016. RESULTS: 47 children (27 M:20F) were implanted with 70 Oticon wide implants 23 bilateral, 27 unilateral. Mean age at the time of implantation was 9y 6 m. The follow up was for a mean of 5.4 years. Significant soft tissue complications requiring treatment was found in 11% (n = 8) of loaded fixtures, abutment tightening on two patients, abutment exchange 6% (n = 4) and a 10% (n = 7) fixture failure. CONCLUSION: The Oticon™ wide implant system produces favourable results with regards to peri-abutment skin complications, fixture stability and revision surgery rates when compared to similar cohorts of children studied at Birmingham Children's Hospital.

First Pediatric Experience With a Novel, Adhesive Adapter Retained, Bone Conduction Hearing Aid System.

OBJECTIVES: To assess the audiological outcomes, practicalities, and impact on quality of life of a new, nonimplantable, adhesive retained bone conduction hearing aid in children. STUDY DESIGN: A prospective, single-subject repeat measure, cohort study. SETTING: Community and in pediatric assessment center. PATIENTS: Twenty-one children aged between 5 and 15 years with a conductive hearing loss of >/=25 dB HL in the better hearing ear. INTERVENTION: Audiological comparisons were made using pure-tone thresholds; unaided, with a softband aid, and with the new adhesive retained bone conducting system. MAIN OUTCOME MEASURES: Comparison of hearing threshold levels. Data analysis via paired t-testing, significance set at p value <0.01. Quality of life was assessed via the Glasgow Children's Benefit Inventory and a 10 cm linear analogue scale. A hearing aid review questionnaire provided insight into practical use. RESULTS: Statistically significant improvement in thresholds of 7.3 dB HL (p=0.0001) was demonstrated with the adhesive system as compared with softband aids. After 4 weeks of usage, the mean hearing thresholds for the adhesive hearing system improved from 55 dB HL ±â€Š2.4 to 31 dB HL± 7.9 in unaided and aided conditions.Improvements in QOL were demonstrated with LAS and GCBI. Four children reported mild skin reactions. Eighty-six percent reported improved self-confidence. CONCLUSION: The adhesive aid produces comparable audiological results to the commercial softband hearing aids. It provides an excellent alternative in the treatment of conductive hearing loss without the possible complications and costs of a surgical intervention. Furthermore, it preserves skin envelope over the mastoid for those who wish to proceed with an autologous pinna reconstruction in the future.

Clinical outcomes following Cochlear™ BIA300 bone anchored hearing aid implantation in children.

OBJECTIVE: Bone anchored hearing implants (BAHI) have been in use for over 30 years, and are commonly implanted in children for a range of indications. The Cochlear™ BIA300 system was launched in 2010 and used at The Birmingham Children's Hospital from 2011. Here we report the long-term outcomes of children implanted with the Cochlear™ BIA300 BAHI system in our centre. METHODS: A retrospective case note analysis was performed to identify outcomes in all children who underwent BIA300 implantation between 2011 and 2013. RESULTS: 52 children with a total of 78 implants were included. Mean age at implantation was 8.7 years. Mean follow-up was 43.5 months. Overall, 60 (77%) implants developed soft tissue complications requiring treatment. Forty-eight (62%) required topical treatment; 27 (35%) required systemic treatment; and 27 (35%) required surgical soft tissue revision under general anaesthesia. CONCLUSIONS: The Cochlear™ BIA300 system appears to be associated with higher than expected rates of soft tissue reaction in children, with late as well as early soft tissue complications requiring both medical and surgical treatment.

Oral haemangioma.

Vascular anomalies comprise a widely heterogeneous group of tumours and malformations. Haemangioma is the most common benign tumour of vascular origin of the head and neck region. The possible sites of occurrence in oral cavity are lips, tongue, buccal mucosa, and palate. Despite its benign origin and behaviour, it is always of clinical importance to the dental profession and requires appropriate management. This case study reports a rare case of capillary haemangioma on the palatal gingiva in a 14-year-old female.