Western diet-induced obesity interferes with the HPA axis-blunting effects of palatable food in male rats.

Limited intermittent consumption of palatable food reduces HPA axis responses to stress in chow-fed rats, and this effect is dependent on the rewarding properties of the palatable food. However, obesity may be a state of reduced consummatory food reward, suggesting that palatable foods may be less effective at blunting HPA axis reactivity in the context of diet-induced obesity (DIO). To test this hypothesis, adult male Long-Evans rats were given unlimited access to Western (high-fat, high-sugar) diet (WD) vs. normal chow (controls). After 8 weeks of diet exposure, rats were given limited sucrose intake (LSI) consisting of additional twice-daily access to a small amount (4 ml) of either 3% or 30% sucrose drink, or water (controls) for 2 weeks. Rats then received an acute restraint stress challenge, with collection of tail blood samples for measurement of plasma corticosterone. WD-fed rats had increased caloric intake, body weight and adiposity, as expected. Rats offered LSI (3% or 30%) readily drank the maximal amount allowed (8 ml/day) and reduced their dietary intake to compensate for the sucrose calories, such that LSI did not alter body weight regardless of diet type. In chow-fed lean rats, LSI with either 3% or 30% sucrose reduced the plasma corticosterone response to restraint stress, but this effect was absent in WD-fed DIO rats. Together, these data support the hypothesis that obesity attenuates stress blunting by palatable foods and suggest the possibility that consequently, individuals with obesity may need to consume larger amounts of palatable food to obtain adequate stress relief.

Oral parafunction and bruxism in Rett syndrome and associated factors: An observational study.

OBJECTIVES: To explore patterns of parafunction, and bruxism, and its relationships with genotype and snoring in individuals with Rett syndrome (RTT). METHODS: Retrospective observational data of those with confirmed MECP2 mutations in the InterRett database (n = 216) were used to investigate experience of parafunctional habits, and bruxism and their relationships with genotype and snoring using multivariable linear regression. RESULTS: The prevalence of parafunction was 98.2%. Bruxism was reported (66.2%) with the patterns mostly both diurnal and nocturnal (44.1%) and exclusively diurnal (42.7%). Compared to individuals with C-terminal deletion, individuals with p.Arg106Trp mutations were less likely to have bruxism reported (aOR = 0.15; 95% CI 0.02-0.98, p = 0.05) and those with p.Arg168* mutation were more likely to have frequent bruxism than none or occasional bruxism reported (aROR 3.4; 95% CI 1.1-10.7 p = 0.04). The relative odds of having nocturnal bruxism constantly, compared to none/occasionally, were higher among those 'always' snoring (aROR 6.24; 95% CI 2.1-18.2, p = 0.001) than those with no snoring. CONCLUSIONS: There appeared to be genotypic association with bruxism in p.Arg168* and p.Arg106Trp mutations and association between nocturnal bruxism and frequent snoring in an international sample of individuals with RTT. Clinical significance of the high prevalence of bruxism should be highlighted in relation to difficulty communicating pain and increased dental treatment need in RTT.

Inhibition of PSD95-nNOS protein-protein interactions decreases morphine reward and relapse vulnerability in rats.

Glutamate signalling through the N-methyl-d-aspartate receptor (NMDAR) activates the enzyme neuronal nitric oxide synthase (nNOS) to produce the signalling molecule nitric oxide (NO). We hypothesized that disruption of the protein-protein interaction between nNOS and the scaffolding protein postsynaptic density 95 kDa (PSD95) would block NMDAR-dependent NO signalling and represent a viable therapeutic route to decrease opioid reward and relapse-like behaviour without the unwanted side effects of NMDAR antagonists. We used a conditioned place preference (CPP) paradigm to evaluate the impact of two small-molecule PSD95-nNOS inhibitors, IC87201 and ZL006, on the rewarding effects of morphine. Both IC87201 and ZL006 blocked morphine-induced CPP at doses that lacked intrinsic rewarding or aversive properties. Furthermore, in vivo fast-scan cyclic voltammetry (FSCV) was used to ascertain the impact of ZL006 on morphine-induced increases in dopamine (DA) efflux in the nucleus accumbens shell (NAc shell) evoked by electrical stimulation of the medial forebrain bundle (MFB). ZL006 attenuated morphine-induced increases in DA efflux at a dose that did not have intrinsic effects on DA transmission. We also employed multiple intravenous drug self-administration approaches to examine the impact of ZL006 on the reinforcing effects of morphine. Interestingly, ZL006 did not alter acquisition or maintenance of morphine self-administration, but reduced lever pressing in a morphine relapse test after forced abstinence. Our results provide behavioural and neurochemical support for the hypothesis that inhibition of PSD95-nNOS protein-protein interactions decreases morphine reward and relapse-like behaviour, highlighting a previously unreported application for these novel therapeutics in the treatment of opioid addiction.

Enablers and barriers in dental attendance in Rett syndrome: an international observational study.

AIMS: Intellectual and developmental disabilities are heterogeneous in aetiology and presentation, and one cannot make assumptions about the oral health barriers of those with Rett syndrome (RTT) based on findings from generic studies. This study investigated caregivers' perceptions regarding access to dental care for those with (RTT), and associations of dental treatments received by those with RTT with their caregivers' perceived value of oral health and perception of their own as well as their daughter's dental anxiety. METHODS AND RESULTS: Retrospective observational data of a subset of individuals with confirmed MECP2 mutations in the InterRett database (n = 216) were used to explore caregiver-related factors and their relationships with longitudinal data on dental service utilisation, using negative binomial regression. The main reported barriers to dental care access for individuals with RTT were primarily dentist-related in nature, regardless of dental service history. Those with reported dental nonattendance were of older age. Increasing levels of caregiver-reported dental fear were associated with less frequent dental check-ups or for any appointments for affected individuals. CONCLUSIONS: Dentist-related barriers and caregiver-reported anxiety may both adversely affect dental attendance for those with RTT. Future research should explore caregivers' beliefs and oral health literacy.

Inhaled Pulmonary Vasodilator Utilization and Cost Following Initiation of a Protocol in a Quaternary Academic Heart Center Intensive Care Unit.

OBJECTIVES: To examine the use of inhaled nitric oxide (iNO) and inhaled epoprostenol (iPGI2) before and after implementation of an iPGI2-preferential protocol and the associated cost differences after rollout. DESIGN: A single-center, retrospective analysis. SETTING: A quaternary university hospital. PARTICIPANTS: All patients admitted to the Heart Center Intensive Care Unit (HCICU) who required inhaled pulmonary vasodilator use between December 2017 and November 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The HCICU comprised 84% of hospital-wide iNO utilization and 59% of hospital-wide iPGI2 use across the entire study period. There was no significant difference in postsurgical HCICU admission rates across the study period. There was a significant decrease in iNO mean monthly use from 578 ± 230 to 69 ± 71 hours, and a significant concurrent increase in iPGI2 from 756 ± 443 to 1,210 ± 547 hours after the implementation of a protocol. There were no changes in the average length of ICU stay between the 2 time periods. The protocol implementation led to a projected annual savings of roughly $1,180,000. CONCLUSIONS: These findings showed that multidisciplinary protocol development and implementation can have a substantial impact on medication utilization and lead to significant reductions in cost.

Oral health education and promotion in special needs children: Systematic review and meta-analysis.

OBJECTIVE: To review the effectiveness of oral health education and oral health promotion interventions for children and adolescents with intellectual and developmental disabilities (IDD), in ensuring optimal gingival health, caries experience and oral health-related quality of life, compared to no interventions or alternative interventions. METHODS: A systematic review was conducted to identify published studies from four databases (Medline, PsycINFO, CINAHL and ERIC). Randomised or quasi-randomised controlled trials were included. Two independent reviewers performed risk of bias and qualitative analysis. Meta-analysis was performed as appropriate. RESULTS: Eight treatment comparisons were identified. There was low certainty evidence that fluoride interventions provided long-term reductions in caries in those with IDD; and there was some evidence that chlorhexidine albeit with low certainty provided short-term and long-term reductions in plaque and gingivitis. There was moderate certainty evidence for short-term reductions in dental plaque from the use of modified toothbrushes, but not compelling evidence for powered toothbrushes. CONCLUSIONS: Most studies provided a low quality of evidence, and so any adaptations made to oral health practices of individuals with IDD need to consider their individual needs. PROSPERO registration: CRD42019145784.

Human Spinal Organoid-on-a-Chip to Model Nociceptive Circuitry for Pain Therapeutics Discovery.

The discovery of new pain therapeutics targeting human nociceptive circuitry is an emerging, exciting, and rewarding field. However, current models for evaluating prospective new therapeutics [e.g., animals and two-dimensional (2D) in vitro cultures] fail to fully recapitulate the complexity of human nociceptive neuron and dorsal horn neuron biology, significantly limiting the development of novel pain therapeutics. Here, we report human spinal organoid-on-a-chip devices for modeling the biology and electrophysiology of human nociceptive neurons and dorsal horn interneurons in nociceptive circuitry. Our device can be simply made through the integration of a membrane with a three-dimensional (3D)-printed organoid holder. By combining air-liquid interface culture and spinal organoid protocols, our devices can differentiate human stem cells into human sensori-spinal-cord organoids with dorsal spinal cord interneurons and sensory neurons. By easily transferring from culture well plates to the multiple-electrode array (MEA) system, our device also allows the plug-and-play measurement of organoid activity for testing nociceptive modulators (e.g., mustard oil, capsaicin, velvet ant venom, etc.). Our organoid-on-a-chip devices are cost-efficient, scalable, easy to use, and compatible with conventional well plates, allowing the plug-and-play measurement of spinal organoid electrophysiology. By the integration of human sensory-spinal-cord organoids with our organoid-on-a-chip devices, our method may hold the promising potential to screen and validate novel therapeutics for human pain medicine discovery.

An adolescent rat model of vincristine-induced peripheral neuropathy.

Childhood acute lymphoblastic leukemia (ALL) is a significant clinical problem that can be effectively treated with vincristine, a vinca alkaloid-based chemotherapeutic agent. However, nearly all children receiving vincristine treatment develop vincristine-induced peripheral neuropathy (VIPN). The impact of adolescent vincristine treatment across the lifespan remains poorly understood. We, consequently, developed an adolescent rodent model of VIPN which can be utilized to study possible long term consequences of vincristine treatment in the developing rat. We also evaluated the therapeutic efficacy of voluntary exercise and potential impact of obesity as a genetic risk factor in this model on the development and maintenance of VIPN. Out of all the dosing regimens we evaluated, the most potent VIPN was produced by fifteen consecutive daily intraperitoneal (i.p.) vincristine injections at 100 µg/kg/day, throughout the critical period of adolescence from postnatal day 35 to 49. With this treatment, vincristine-treated animals developed hypersensitivity to mechanical and cold stimulation of the plantar hind paw surface, which outlasted the period of vincristine treatment and resolved within two weeks following the cessation of vincristine injection. By contrast, impairment in grip strength gain was delayed by vincristine treatment, emerging shortly following the termination of vincristine dosing, and persisted into early adulthood without diminishing. Interestingly, voluntary wheel running exercise prevented the development of vincristine-induced hypersensitivities to mechanical and cold stimulation. However, Zucker fa/fa obese animals did not exhibit higher risk of developing VIPN compared to lean rats. Our studies identify sensory and motor impairments produced by vincristine in adolescent animals and support the therapeutic efficacy of voluntary exercise for suppressing VIPN in developing rats.

Sexual dimorphism in intestinal absorption and lymphatic transport of dietary lipids.

Although the basic process of intestinal lipid absorption and transport is understood, many critical aspects remain unclear. One question in particular is whether intestinal lipid absorption and transport differ between the sexes. Using a well-established lymph fistula model, we found that intact female mice exhibited lower lymphatic output of triacylglycerol (TAG) than male mice. Further analysis revealed that the female mice segregated into two groups: the high group having similar lymphatic TAG transport to the males, and the low group having significantly less lymphatic output, implying the impact of cyclical variation of ovarian hormonal levels. These led us to examine whether oestradiol (E2) and progesterone (P) affect intestinal absorption and lymphatic transport of dietary lipids. In ovariectomized (OVX) rats, E2 treatment significantly reduced [3 H]-TAG lymphatic output through reducing TAG transport; and P treatment decreased [14 C]cholesterol (Chol) lymphatic output by inhibiting Chol absorption, compared to vehicle treatment. Gene expression data suggested that E2 enhances vascular endothelial growth factor-A (VEGF-A) signalling to reduce the permeability of lacteals, leading to reduced CM transport through the lymphatic system. Interestingly, E2 treatment also increased lymphatic output of apolipoprotein A-I (apoA-I), but not apoB-48 and apoA-IV, in the OVX rats. Collectively, these data suggested that ovarian hormone-induced reductions of intestinal lipid absorption and lymphatic transport, as well as increased lymphatic output of apoA-I, may contribute to a beneficial protection from atherosclerosis in females. KEY POINTS: Significant differences in intestinal lipid absorption and lymphatic transport were found between female and male animals. Oestrogen treatment significantly reduced [3 H]triacylglycerol (TAG) lymphatic output through suppressing TAG transport in ovariectomized (OVX) rats, and this effect is associated with enhanced vegfa gene expression in the intestine. Progesterone treatment significantly decreased the output of [14 C]cholesterol in lymph by inhibiting cholesterol absorption in the OVX rats. Oestrogen treatment also increased lymphatic output of apolipoprotein A-I (apoA-I) in the OVX rats, which may contribute to the reduced risk of atherosclerosis in females.

Limited cheese intake reduces HPA axis and behavioral stress responses in male rats.

Eating palatable foods reduces behavioral and hypothalamic-pituitary-adrenocortical (HPA) axis responses to stress - an idea referred to by the colloquial term "comfort" food. To study the underlying stress-relieving mechanisms of palatable foods, we previously developed a paradigm of limited sucrose feeding in which male rats are given twice-daily access to a small amount of sucrose drink and subsequently have reduced stress responses. Prior research in humans and rodents implicates high dietary sugars/carbohydrates with reduced stress responsivity. However, it is not clear whether the stress-relieving effects of the limited sucrose paradigm depend upon its macronutrient content. To test this idea, the current work measures stress responses in male rats following the limited intermittent intake of cheese - a highly palatable food that is low in sugar and other carbohydrates. The data show that a history of limited cheese intake (LCI) reduced HPA axis responses to acute psychological (restraint) and physiological (hypoxia) stressors. LCI also reduced behavioral struggling during restraint, increased sociability during a social interaction test, and increased open arm activity in the elevated plus-maze test. Z-score analyses evaluated the extent to which these behavioral effects extended within and across assays, and indicated that there was an overall reduction in stress-related behaviors following LCI. Finally, LCI increased immunolabeling for FosB/deltaFosB (a protein associated with repeated or chronic neuronal activation) in the nucleus accumbens. These results indicate that palatable foods can provide stress blunting regardless of their sugar/carbohydrate composition, and support the idea that food reward per se contributes to stress relief.

A multicenter study of dental curricula in Asia/Pacific nations: The views and experiences of final-year dental students.

OBJECTIVES: The objective of this qualitative study was to gain greater understanding of final-year dental students' views on and experience of their dental curricula in 4 universities from different Asia/Pacific countries, including New Zealand, Australia, and Hong Kong (China). METHODS: A qualitative study approach was used, with semistructured interviews conducted with final-year students from each of the 4 universities. RESULTS: Interviews were conducted with 60 final-year dental students, and 5 main themes were extracted from the interviews: (1) the definition of an "ideal" dental curriculum, (2) theoretical teaching, (3) transitional tools, (4) assessment, and (5) grading. CONCLUSION: The findings provide insight into final-year students' views of dental curricula and suggestions on possible areas of reform in the dental curriculum. Further investigations are necessary to provide a curriculum that enables students to become competent, future-ready dental practitioners.

Final year dental students' career plans, work patterns, work-life balance and domestic life in New Zealand and Australia.

INTRODUCTION: Having insight into final year dental students' career planning is vital in maintaining and enhancing the quality of dental education. The aim of this study was to investigate final year dental students' career plans, work patterns, work-life balance and domestic life, in New Zealand and Australia. METHODS: The design of the study was a two-centred cross-sectional study. RESULTS: A total of 148 students, including 95 females (64%) and 53 males (36%), completed the survey (response rate = 87%). The mean age of students across two Australasian universities was 23 ± 3 years. Findings from this study demonstrate that students prefer their first job is an urban, full-time and salary-based with a good mentor. However, when describing their long-term planning, work-life balance becomes more important. The growth in the number of female dentists will continue to shape the future patterns of our dental profession. CONCLUSION: The current study has highlighted several similarity and differences in career plans, work patterns, work-life balance and domestic life between two Australasian universities. The information might be useful for the policymakers involved in future workforce planning and infrastructure and for those involved in the delivery of dental education.

Virtual Reality as a novel educational tool in pre-clinical paediatric dentistry training: Students' perceptions.

BACKGROUND: Dental students are required to demonstrate competency by pre-clinical simulated practice before performing invasive clinical procedures on patients. The Moog Simodont® Dental Trainer provides a virtual reality-based dental simulation environment for training students. AIM: This cross-sectional questionnaire-based study compared students' perception of the pre-clinical paediatric dentistry training gained in Simodont® and conventional simulation environment. DESIGN: The dental students who completed pulpotomies and stainless steel crowns (SSCs) training in Simodont® and conventional pre-clinical simulation laboratory were invited to complete a questionnaire on their experience in both environments. The percentages for the distribution of responses to statements about training modality were tabulated, and intra-participant comparisons were used to measure student preference for either Simodont® or conventional simulation training. RESULTS: One hundred students completed the survey. Fifty-one per cent of students agreed that using Simodont® assisted their learning, and 56% felt Simodont® training facilitated their understanding of paediatric dentistry tasks. Generally, participants felt more comfortable with simulation training than Simodont® for both practical exercises. Eighty-eight per cent of the participants disagreed that Simodont® should replace conventional simulation. CONCLUSIONS: The study suggests that Simodont® could be used as an adjunct in training dental students for pre-clinical paediatric dentistry restorative exercises.

Disrupting nNOS-PSD95 Interaction Improves Neurological and Cognitive Recoveries after Traumatic Brain Injury.

Excessive activation of N-methyl-D-aspartate receptors (NMDARs) and the resulting neuronal nitric oxide synthase (nNOS) activation plays a crucial role in the pathogenesis of traumatic brain injury (TBI). However, directly inhibiting NMDARs or nNOS produces adverse side effects because they play key physiological roles in the normal brain. Since interaction of nNOS-PSD95 is a key step in NMDAR-mediated excitotoxicity, we investigated whether disrupting nNOS-PSD95 interaction with ZL006, an inhibitor of nNOS-PSD95 interaction, attenuates NMDAR-mediated excitotoxicity. In cortical neuronal cultures, ZL006 treatment significantly reduced glutamate-induced neuronal death. In a mouse model of controlled cortical impact (CCI), administration of ZL006 (10 mg/kg, i.p.) at 30 min postinjury significantly inhibited nNOS-PSD95 interaction, reduced TUNEL- and phospho-p38-positive neurons in the motor cortex. ZL006 treatment also significantly reduced CCI-induced cortical expression of apoptotic markers active caspase-3, PARP-1, ratio of Bcl-2/Bax, and phosphorylated p38 MAPK (p-p38). Functionally, ZL006 treatment significantly improved neuroscores and sensorimotor performance, reduced somatosensory and motor deficits, reversed CCI-induced memory deficits, and attenuated cognitive impairment. Histologically, ZL006 treatment significantly reduced the brain lesion volume. These findings collectively suggest that blocking nNOS-PSD95 interaction represents an attractive strategy for ameliorating consequences of TBI and that its action is mediated via inhibiting neuronal apoptosis and p38 MAPK signaling.

Differential Regulation of the Glucocorticoid Receptor in a Rat Model of Inflammatory Pain.

BACKGROUND: Anti-inflammatory corticosteroids are a common treatment for different conditions involving chronic pain and inflammation. Clinically used steroids target the glucocorticoid receptor (GR) for its anti-inflammatory effects. We previously reported that GR in sensory neurons may play central roles in some pain models and that GR immunoreactivity signal in dorsal root ganglia (DRG) decreased after local inflammation of the DRG (a model of low back pain). In the current study, we aimed to determine if similar changes in GR signal also exist in a skin inflammation model, the complete Freund's adjuvant (CFA) model (a model of peripheral inflammatory pain), in which the terminals of the sensory neurons rather than the somata are inflamed. METHODS: A low dose of CFA was injected into the hind paw to establish the peripheral inflammation model in Sprague-Dawley rats of both sexes, as confirmed by measurements of behavior and paw swelling. Immunohistochemical and western blotting techniques were used to determine the expression pattern of the GR in the inflamed hind paw and the DRGs. Plasma corticosterone levels were measured with radioimmunoassay. RESULTS: The immunohistochemical staining revealed that GR is widely expressed in the normal DRG and skin tissues. Paw injection with CFA caused upregulation of the GR in the skin tissue on postinjection day 1, mostly detected in the dermis area. However, paw inflammation significantly reduced the GR signal in the L5 DRG 1 day after the injection. The GR downregulation was still evident 14 days after CFA inflammation. On day 1, western blotting confirmed this downregulation and showed that it could also be observed in the contralateral L5 DRG, as well as in the L2 DRG (a level which does not innervate the paw). Plasma corticosterone levels were elevated in both sexes on day 14 after CFA compared to day 1, suggesting autologous downregulation of the GR by corticosterone may have contributed to the downregulation observed on day 14 but not day 1. CONCLUSIONS: There are distinctive patterns of GR activation under different pain conditions, depending on the anatomical location. The observed downregulation of the GR in sensory neurons may have a significant impact on the use of steroids as treatment in these conditions and on the regulatory effects of endogenous glucocorticoids.

Implementing a Cardiac Enhanced Recovery After Surgery Protocol: Nuts and Bolts.

The use of Enhanced Recovery After Surgery (ERAS) protocols among various surgical subspecialties is increasing, including in cardiac surgery. The goal of these protocols is to optimize patient outcomes and satisfaction and improve the value of healthcare delivered. Cardiac ERAS protocols are divided into the following 3 stages of perioperative care: preoperative, intraoperative, and postoperative. ERAS strategies have been shown to work synergistically to reduce the length of hospital stay, postoperative complications, hospital cost, and opioid consumption; increase patient satisfaction; and result in less and early extubation. The ERAS team should consist of clinicians involved in the patient's care throughout the entire ERAS process. A cardiac ERAS program is an example of value-based care applied to a specific surgical specialty with goals to improve patient satisfaction, provide earlier recovery, and reduce hospital cost. This narrative review details the updates and gaps in the literature regarding the efficacy and utility of an ERAS protocol in cardiac surgery, outlines the individual components of a cardiac surgery ERAS protocol, and describes the implementation science that can be used to execute a cardiac ERAS protocol successfully.

A lung rescue team improves survival in obesity with acute respiratory distress syndrome.

BACKGROUND: Limited data exist regarding ventilation in patients with class III obesity [body mass index (BMI) > 40 kg/m2] and acute respiratory distress syndrome (ARDS). The aim of the present study was to determine whether an individualized titration of mechanical ventilation according to cardiopulmonary physiology reduces the mortality in patients with class III obesity and ARDS. METHODS: In this retrospective study, we enrolled adults admitted to the ICU from 2012 to 2017 who had class III obesity and ARDS and received mechanical ventilation for > 48 h. Enrolled patients were divided in two cohorts: one cohort (2012-2014) had ventilator settings determined by the ARDSnet table for lower positive end-expiratory pressure/higher inspiratory fraction of oxygen (standard protocol-based cohort); the other cohort (2015-2017) had ventilator settings determined by an individualized protocol established by a lung rescue team (lung rescue team cohort). The lung rescue team used lung recruitment maneuvers, esophageal manometry, and hemodynamic monitoring. RESULTS: The standard protocol-based cohort included 70 patients (BMI = 49 ± 9 kg/m2), and the lung rescue team cohort included 50 patients (BMI = 54 ± 13 kg/m2). Patients in the standard protocol-based cohort compared to lung rescue team cohort had almost double the risk of dying at 28 days [31% versus 16%, P = 0.012; hazard ratio (HR) 0.32; 95% confidence interval (CI95%) 0.13-0.78] and 3 months (41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16-0.74), and this effect persisted at 6 months and 1 year (incidence of death unchanged 41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16-0.74). CONCLUSION: Individualized titration of mechanical ventilation by a lung rescue team was associated with decreased mortality compared to use of an ARDSnet table.