Could transient hypoxia be associated with rhythmic masticatory muscle activity in sleep bruxism in the absence of sleep-disordered breathing? A preliminary report.

Sleep bruxism (SB) is a repetitive jaw-muscle activity characterised by clenching or grinding of the teeth during sleep. Sleep bruxism activity is characterised by rhythmic masticatory muscle activity (RMMA). Many but not all RMMA episodes are associated with sleep arousal. The aim of this study was to evaluate whether transient oxygen saturation level change can be temporally associated with genesis of RMMA/SB. Sleep laboratory or home recordings data from 22 SB (tooth grinding history in the absence of reported sleep-disordered breathing) and healthy subjects were analysed. A total of 143 RMMA/SB episodes were classified in four categories: (i) no arousal + no body movement; (ii) arousal + no body movement; (iii) no arousal + body movement; (iv) arousal + body movement. Blood oxygen levels (SaO2 ) were assessed from finger oximetry signal at the baseline (before RMMA), and during RMMA. Significant variation in SaO2 over time (P = 0·001) was found after RMMA onset (+7 to +9 s). No difference between categories (P = 0·91) and no interaction between categories and SaO2 variation over time (P = 0·10) were observed. SaO2 of six of 22 subjects (27%) remained equal or slight increase after the RMMA/SB onset (+8 s) compared to baseline; 10 subjects (45%) slightly decreased (drop 0·01-1%) and the remaining (27%) decreased between 1% and 2%. These preliminary findings suggest that a subgroup of SB subjects had (i) a minor transient hypoxia potentially associated with the onset of RMMA episodes, and this (ii) independently of concomitant sleep arousal or body movements.

Interactions between sleep disorders and oral diseases.

Dental sleep medicine is a rapidly growing field that is in close and direct interaction with sleep medicine and comprises many aspects of human health. As a result, dentists who encounter sleep health and sleep disorders may work with clinicians from many other disciplines and specialties. The main sleep and oral health issues that are covered in this review are obstructive sleep apnea, chronic mouth breathing, sleep-related gastroesophageal reflux, and sleep bruxism. In addition, edentulism and its impact on sleep disorders are discussed. Improving sleep quality and sleep characteristics, oral health, and oral function involves both pathophysiology and disease management. The multiple interactions between oral health and sleep underscore the need for an interdisciplinary clinical team to manage oral health-related sleep disorders that are commonly seen in dental practice.

Comparison of hypopnea definitions in lean patients with known obstructive sleep apnea hypopnea syndrome (OSAHS).

STUDY OBJECTIVES: In the interest of improving inter-rater reliability and standardization between sleep laboratories, hypopnea definitions were recently changed to place less emphasis on arousal scoring and more emphasis on oxygen desaturations. We sought to determine whether these changes would affect detection and treatment of OSAHS in lean patients-a group known to desaturate less-than-obese patients. METHODS: Thirty-five lean subjects (15 male, 20 women, five post-menopausal) diagnosed OSAHS and a documented benefit from treatment had diagnostic polysomnograms (PSG) originally scored using the American Academy of Sleep Medicine (AASM) rule from 1999 (referred to as "Rule C"). These patients had appropriate clinical care based on those results. PSG records were then re-scored in a randomized and blinded fashion utilizing hypopnea Rule A and B of the 2007 AASM guidelines. RESULTS: Baseline mean (SD) apnea hypopnea indices (AHI) for rules A, B, and C were 6.4 (3.1), 20.6 (8.2), and 26.9 (7.3), respectively (p < 0.0001). Mean (SD) BMI was 24.4 (1.0). By design, all subjects were treatment responders. Eighty-six percent with CPAP, 83% with oral appliance, and 100% with surgical intervention reported resolution of their initial daytime or sleep complaint. Post-treatment AHIs for rules A, B, and C were 0.8 (0.9), 1.8 (1.2) and 2.3 (1.6; p < 0.001). In all three scoring conditions, the AHI was reduced significantly with treatment (p < 0.001). A repeated measures ANOVA of the difference between scoring methods indicated statistically significant differences between all three strategies at both pre- and post-treatment (p < 0.001). Sleepiness on the Epworth sleepiness scale decreased from a mean of 10.9 (2.3) to 5.7 (1.3) with treatment (p < 0.001). This change in subjective rating of sleepiness was more strongly correlated with rules B and C (r = 0.6) and more modestly correlated with Rule A scoring (r = 0.4). CONCLUSION: Response to treatment was more tightly correlated with arousal based scoring rules B and C in this group of lean subjects. The1999 hypopnea rule was used at baseline to detect this cohort of patients with OSAHS that ultimately benefitted from treatment. Rule B detected OSAHS and correlated well with response to treatment, but many more were categorized as mild (5 < AHI < 15) at baseline. Since 40% of the subjects had an AHI less than 5 with Rule A, lack of sensitivity should be considered before applying Rule A to the scoring of sleep studies in lean patients.

Gene expression in the rat cerebral cortex: comparison of recovery sleep and hypnotic-induced sleep.

Most hypnotic medications currently on the market target some aspect of GABAergic neurotransmission. Although all such compounds increase sleep, these drugs differentially affect the activity of the cerebral cortex as measured by the electroencephalogram. Whereas benzodiazepine medications such as triazolam tend to suppress slow wave activity in the cortex, the GABA(B) ligand gamma-hydroxybutyrate greatly enhances slow wave activity and the non-benzodiazepine, zolpidem, which binds to the omega1 site on the GABA(A) receptor/Cl(-) ionophore complex, is intermediate in this regard. Our previous studies have demonstrated that a small number of genes exhibit increased expression in the cerebral cortex of the mouse and rat during recovery sleep after sleep deprivation: egr-3, fra-2, grp78, grp94, ngfi-b, and nr4a3. Using these genes as a panel of biomarkers associated with sleep, we asked whether hypnotic medications induce similar molecular changes in the rat cerebral cortex to those observed when both sleep continuity and slow wave activity are enhanced during recovery sleep. We find that, although each drug increases the expression of a subset of genes in the panel of biomarkers, no drug fully replicates the molecular changes in the cortex associated with recovery sleep. Furthermore, high levels of slow wave activity in the cortex are correlated with increased expression of fra-2 whereas the expression of grp94 is correlated with body temperature. These results demonstrate that sleep-related changes in gene expression may be affected by physiological covariates of sleep and wakefulness rather than by vigilance state per se.

Placenta growth factor gene expression is induced by hypoxia in fibroblasts: a central role for metal transcription factor-1.

Placenta growth factor (PlGF) is a mitogen for endothelial cells that can potentiate the growth and permeabilizing effects on endothelium of vascular endothelial growth factor. Here we report that hypoxia induces the expression of both PlGF mRNA and protein in immortalized/transformed mouse embryonic fibroblasts (mEFs) and in NIH 3T3 cells. Importantly, the magnitude of the induction of PlGF expression by hypoxia is enhanced by the presence of oncogenic Ras. To investigate the transcriptional component of hypoxia-inducible PlGF expression, we cloned and sequenced a 1350-bp fragment of the 5'-flanking region of the mouse gene. Analysis of the promoter region indicated the presence of putative consensus sequences for known hypoxia-responsive regulatory sites, including metal response elements and Sp1-like sites. In the present study, we show that the induction of PlGF expression by hypoxia is dependent on the presence of the metal response element-binding transcription factor 1 (MTF-1). Thus, in mEFs with targeted deletions of both MTF-1 alleles, hypoxia-induced increases of PIGF mRNA and protein levels were greatly attenuated compared with those in wild-type mEFs. Moreover, transient transfection of a PlGF promoter reporter gene into NIH 3T3 cells resulted in hypoxia-responsive transcriptional activation of the reporter. Finally, ectopic expression of MTF-1 resulted in increased basal transcriptional activity of a PlGF promoter reporter. Together, these findings demonstrate that the PlGF gene is responsive to hypoxia and that this response is mediated by MTF-1. It remains to be determined whether this activation is the result of direct and/or indirect transcriptional activation by MTF-1. The stimulatory effect of oncogenic Ras on the induction of PlGF expression in hypoxic cells suggests that PlGF could be an important proangiogenic factor in the tumor microenvironment.

Sleep bruxism in children: sleep studies correlate poorly with parental reports.

UNLABELLED: The prevalence of sleep bruxism (SB) is usually reported as highest during childhood and decreases with age. However, this is based on parental reports and self-reports in the absence of quantitative data. Moreover, although SB signs, symptoms, and cutoff criteria have been established in the adult population, they remain unassessed in the pediatric population. OBJECTIVES: This study aims to classify SB in children according to sleep variables and rhythmic masticatory muscle activity (RMMA) frequency indexes and to determine associations with objective signs and symptoms of SB in comparison with parental reports. MATERIALS AND METHODS: Thirty-two children (11.5 ± 0.3 years) recruited at the orthodontic clinic underwent a dental assessment and ambulatory sleep recording (type II). Parents responded to a validated screening questionnaire on tooth clenching and grinding. A two-step cluster analysis was performed to classify participants into RMMA frequency groups, as described subsequently, followed by one-way analysis of variance (ANOVA) to compare groups. Fisher's exact test was performed for analyzing the associations between the signs and symptoms according to RMMA. RESULTS: Three RMMA frequency groups were identified: low (n = 12), moderate-high (n = 13), and control (n = 7). Between-group comparisons for episodes per hour and bursts/hour were significant (p <0.001). No relationships were found between RMMA (presence/absence) and clinically assessed tooth wear or reports of tooth clenching or grinding or craniofacial complaints. CONCLUSIONS: RMMA frequency classification differs slightly between children and adults. No association was observed between parental reports and RMMA, suggesting the need to improve parental knowledge of children's SB.

Three- and four-class classification models for P-glycoprotein inhibitors using counter-propagation neural networks.

P-glycoprotein (P-gp) is an ATP binding cassette (ABC) transporter that helps to protect several certain human organs from xenobiotic exposure. This efflux pump is also responsible for multi-drug resistance (MDR), an issue of the chemotherapy approach in the fight against cancer. Therefore, the discovery of P-gp inhibitors is considered one of the most popular strategies to reverse MDR in tumour cells and to improve therapeutic efficacy of commonly used cytotoxic drugs. Until now, several generations of P-gp inhibitors have been developed but they have largely failed in preclinical and clinical studies due to lack of selectivity, poor solubility and severe pharmacokinetic interactions. In this study, three models (SION, SIO, SIN) to classify specific 'true' P-gp inhibitors as well as three other models (CPBN, CPB1, CPN) to distinguish between P-gp inhibitors, CYP 3A inhibitors and co-inhibitors of these proteins with rather high accuracy values for the test set and the external set were generated based on counter-propagation neural networks (CPG-NN). Such three and four-class classification models helped provide more information about the bioactivities of compounds not only on one target (P-gp), but also on a combination of multiple targets (P-gp, CYP 3A).

Lipid nanocapsules: a new platform for nanomedicine.

Nanomedicine, an emerging new field created by the fusion of nanotechnology and medicine, is one of the most promising pathways for the development of effective targeted therapies with oncology being the earlier and the most notable beneficiary to date. Indeed, drug-loaded nanoparticles provide an ideal solution to overcome the low selectivity of the anticancer drugs towards the cancer cells in regards to normal cells and the induced severe side-effects, thanks to their passive and/or active targeting to cancer tissues. Liposome-based systems encapsulating drugs are already used in some cancer therapies (e.g. Myocet, Daunoxome, Doxil). But liposomes have some important drawbacks: they have a low capacity to encapsulate lipophilic drugs (even though it exists), they are manufactured through processes involving organic solvents, and they are leaky, unstable in biological fluids and more generally in aqueous solutions for being commercialized as such. We have developed new nano-cargos, the lipid nanocapsules, with sizes below the endothelium fenestration (phi<100 nm), that solve these disadvantages. They are prepared according to a solvent-free process and they are stable for at least one year in suspension ready for injection, which should reduce considerably the cost and convenience for treatment. Moreover, these new nano-cargos have the ability to encapsulate efficiently lipophilic drugs, offering a pharmaceutical solution for their intravenous administration. The lipid nanocapsules (LNCs) have been prepared according to an original method based on a phase-inversion temperature process recently developed and patented. Their structure is a hybrid between polymeric nanocapsules and liposomes because of their oily core which is surrounded by a tensioactive rigid membrane. They have a lipoprotein-like structure. Their size can be adjusted below 100 nm with a narrow distribution. Importantly, these properties confer great stability to the structure (physical stability>18 months). Blank or drug-loaded LNCs can be prepared, with or without PEG (polyethyleneglycol)ylation that is a key parameter that affects the vascular residence time of the nano-cargos. Other hydrophilic tails can also be grafted. Different anticancer drugs (paclitaxel, docetaxel, etoposide, hydroxytamoxifen, doxorubicin, etc.) have been encapsulated. They all are released according to a sustained pattern. Preclinical studies on cell cultures and animal models of tumors have been performed, showing promising results.

Dose effect activity of ferrocifen-loaded lipid nanocapsules on a 9L-glioma model.

Ferrociphenol (Fc-diOH) is a new molecule belonging to the fast-growing family of organometallic anti-cancer drugs. In a previous study, we showed promising in vivo results obtained after the intratumoural subcutaneous administration of the new drug-carrier system Fc-diOH-LNCs on a 9L-glioma model. To further increase the dose of this lipophilic entity, we have created a series of prodrugs of Fc-diOH. The phenol groups were protected by either an acetyl (Fc-diAc) or by the long fatty-acid chain of a palmitate (Fc-diPal). LNCs loaded with Fc-diOH prodrugs have to be activated in situ by enzymatic hydrolysis. We show here that the protection of diphenol groups with palmitoyl results in the loss of Fc-diOH in vitro activity, probably due to a lack of in situ hydrolysis. On the contrary, protection with an acetate group does not affect the strong, in vitro, antiproliferative effect of ferrocifen-loaded-LNCs neither the reduction of tumour volume observed on an ectopic model, confirming that acetate is easily cleaved by cell hydrolases. Moreover, the cytostatic activity of Fc-diOH-LNCs is confirmed on an orthotopic glioma model since the difference in survival time between the infusion of 0.36 mg/rat Fc-diOH-LNCs and blank LNCs is statistically significant. By using LNCs or Labrafac to carry the drug, a dose-effect ranging from 0.005 to 2.5mg of Fc-diOH per animal can be evidenced.