Increased somatosensory amplification is associated with decreased pressure pain thresholds at both trigeminal and extra-trigeminal locations in healthy individuals.

BACKGROUND: The diagnosis of temporomandibular disorders (TMD) is based on patient history and physical examination, and may require medical imaging. Masticatory muscle palpation is essential to make a diagnosis of TMD. However, the response of masticatory muscles to mechanical pressure stimuli depends on many physical and psychological factors. OBJECTIVE: This study aimed at determining the impact of somatosensory amplification (SSA)-an estimate of somatic awareness and bodily hypervigilance-on pressure pain thresholds (PPTs) measured at both trigeminal and extra-trigeminal locations in healthy individuals. METHODS: PPTs were measured at the right anterior temporalis and superficial masseter, and the thenar eminence of the right hand in one hundred healhty individuals (69F, 31M), divided in three groups based on their SSA scores: low (N = 32), intermediate (N = 34) and high (N = 34). General linear models were used to test between-group differences in PPTs including sex as a covariate. The level of significance was set at P < .05. RESULTS: Individuals with high SSA had lower PPTs at the anterior temporalis than individuals with low (P = .006) and intermediate (P = .001) SSA. No significant between-group differences were found in PPTs measured at the masseter (P = .372). PPTs measured at the thenar eminence were significantly lower in the high than the low SSA group (P = .009). Females had lower PPTs at the masseter than males (P = .021) but not at other muscle locations (all P > .05). CONCLUSION: Increased somatosensory amplification is associated with decreased pressure pain thresholds at both trigeminal and extra-trigeminal locations in healthy individuals. SSA could be a potential confounder while diagnosing TMD and evaluating treatment outcomes.

Music Modulates Awake Bruxism in Chronic Painful Temporomandibular Disorders.

OBJECTIVE: In this experimental study, we aimed to determine whether guided music listening (GML) - a music intervention based on models of mood mediation and attention modulation - modulates masticatory muscle activity and awake bruxism in subjects with chronic painful muscular temporomandibular disorders (TMD myalgia, mTMD), a condition causing a significant burden to patients, their families, and healthcare systems. BACKGROUND: Awake bruxism - a stress behavior characterized by clenching of the teeth - is a strong contributor to chronic mTMD. GML modulates psychological stress and motor responses and could thus reduce muscle activity in chronic musculoskeletal conditions, including mTMD. METHODS: We recorded the electromyographic (EMG) activity in the right masseter of 14 women with chronic (>6 months) mTMD (median [IQR] = 39.5.3 [24.3] years) and 15 pain-free women (median [IQR] = 30.0 [3.5] years) during a GML session, including 3 music (stressful, relaxing, and participants' favorite music) and a no-music (pink noise) control blocks, each lasting 15 minutes. We measured the motor effort of the right masseter relative to the participants' maximum voluntary contraction (MVC), the muscular effort to maintain mandibular posture (EMGposture ), and to produce spontaneous awake bruxism episodes (EMGbruxism ), and the duration and frequency of spontaneous awake bruxism episodes. We tested between-group and within-group (between blocks) differences, as well as the effect of the interaction group by experimental block on these outcome measures. RESULTS: In both groups, EMGposture was significantly affected by the interaction group by experimental block (P < .001). Compared to pink noise [mean (95% CI); mTMD: 2.2 (1.6-2.8) %MVC; Controls: 1.1 (0.5-1.7) %MVC], EMGposture increased during the stressful music block [contrast estimate (95% CI); mTMD: +0.8 (0.7-0.8) %MVC; Controls: +0.3 (0.3-0.4) %MVC; both P < .001], and decreased during the relaxing [mTMD: -0.4 (-0.5 to -0.4) %MVC; Controls: -0.3 (-0.4 to -0.3) %MVC; both P < .001] and favorite [mTMD: -0.5 (-0.6 to -0.5) %MVC; Controls: -0.5 (-0.5 to -0.4) %MVC; both P < .001] music blocks. EMGposture was greater in mTMD individuals than controls during the favorite music [contrast estimate (95% CI): +1.1 (0.2-1.9) %MVC; P = .019] and the pink noise [+1.1 (0.2-2.0) %MVC; P = .014] blocks. EMGbruxism was significantly affected by the interaction group by experimental block (P < .001). In mTMD participants, compared to the pink noise block [mean (95% CI); 23.8 (16.0-31.6) %MVC], EMGbruxism increased during the stressful music block [contrast estimate (95% CI); +10.2 (8.6-11.8) %MVC], and decreased during the relaxing [-6.2 (-8.1 to -4.3) %MVC; P < .001] and favorite [-10.2 (-12.2 to -9.1) %MVC; P < .001] music blocks. These effects were not observed in the control group [mean (95% CI); pink noise: 19.3 (10.9-27.6); stressful: 21.2 (12.9-29.4) %MVC; relaxing: 21.6 (13.3-29.9) %MVC; favorite: 24.2 (15.8-32.7) %MVC; all P > .05]. EMGbruxism was significantly greater in mTMD participants than controls during the stressful music block [contrast estimate (95% CI): +12.9 (1.6-24.2) %MVC; P = .026). GML did not affect the duration or the frequency of awake bruxism in either group (median [IQR], mTMD: 23.5 [96.7] s, range 1-1300 seconds; Controls: 5.5 [22.5], range 0-246 seconds; P = .108). The frequency of awake bruxism episodes was greater in the mTMD group compared to controls only during the pink noise block (median [IQR], mTMD: 5 [15.3] episodes, range 0-62 episodes; Controls: 1 [3] episode, range 0-27 episodes; P = .046). No significant between-group differences were found in either the overall time spent engaging in awake bruxism (median [IQR], mTMD: 23.5 [96.7] s, range 1-1300 seconds; Controls: 5.5 [22.5], range 0-246 seconds; P = .108), or during each block (all P > .05). CONCLUSIONS: In subjects with chronic mTMD, relaxing music and the individual's favorite music decreased the muscular effort during spontaneous awake bruxism episodes by 26% and 44% (relative changes), respectively. In contrast, stressful music increases it by about 43%. Because of its positive effects on awake bruxism, GML with selected music could be a promising and non-invasive component of a multimodal approach for the management of chronic mTMD.

Autophagy is associated with chemoresistance in neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is a frequent pediatric tumor characterized by a poor prognosis where a majority of tumors progress despite intensive multimodality treatments. Autophagy, a self-degradative process in cells, could be induced by chemotherapy and be associated with chemoresistance. The aim of this study was to determine whether: 1) autophagy is present in NB, 2) chemotherapy modified its levels, and 3) its inhibition decreased chemoresistance. METHODS: Immunohistochemical stainings were performed on samples from 184 NB patients in order to verify the expression of LC3B, a specific marker for autophagy, and Beclin 1, a positive regulator of autophagy. In addition, we performed an in vitro study with six NB cell lines and six drugs (vincristine, doxorubicin, cisplatin temozolomide, LY294002 and syrolimus). Inhibition of autophagy was performed using ATG5 knockdown cells or hydroxychloroquine (HCQ). Cell survival was measured using the MTT cell proliferation assay. Autophagy was detected by monodansylcadaverine, confocal microscopy and Western blot. In vivo study with tumor xenografts in NSG mice was performed. RESULTS: Our results have indicated that autophagy was present at low levels in NB and was not a prognostic factor, while Beclin 1 was highly expressed in children with poor NB prognosis. However, autophagy levels increased after chemotherapy in vitro and in vivo. Tumor progression was significantly decreased in mice treated with a combination of HCQ and vincristine. CONCLUSIONS: Taken together, autophagy is present in NB, induced by chemotherapy and associated with chemoresistance, which is significantly reduced by its inhibition. Therefore, targeting autophagy represents a very attractive approach to develop new therapeutic strategies in NB.

CD133 expression is associated with poor outcome in neuroblastoma via chemoresistance mediated by the AKT pathway.

AIMS: Neuroblastoma is a frequent childhood cancer with a heterogeneous prognosis. CD133 expression is an independent prognostic marker for a low survival rate in several cancers. The aim of this study was to determine the prognostic value of CD133 expression in a large cohort of neuroblastoma cases, to define the chemoresistance of neuroblastoma cells expressing CD133, and to determine whether this chemoresistance is regulated by activation of the AKT pathway. METHODS AND RESULTS: Two hundred and eighty samples of neuroblastoma were screened for CD133 expression. The sensitivity of purified CD133+ neuroblastoma cells isolated from two human cell lines to doxorubicin, vincristine and cisplatin, as single agents or in combination with LY294002, an AKT inhibitor, was evaluated in vitro. CD133 expression was found in 100 of 280 tumours. There was a significant association between CD133 expression and the following poor prognosis covariates: age, International Neuroblastoma Staging System stage, MYCN amplification, and phospho-AKT (pAKT) expression. Patients with CD133- tumours had significantly better 3-year event-free and overall survival than patients with CD133+ tumours. In a multivariate model, CD133 expression was independently associated with decreased overall survival. CD133(high) neuroblastoma cells were significantly resistant to chemotherapy as compared with CD133(low) cells. Treatment of unsorted neuroblastoma cells with the three anticancer drugs significantly enriched the CD133+ subpopulation. CD133(high) cells expressed significantly higher levels of pAKT than CD133(low) cells. LY294002 treatment abolished the preferential survival of CD133(high) cells. CONCLUSIONS: CD133 is associated with in-vitro resistance to chemotherapy involving activation of the AKT pathway.