No disease-modifying therapy is currently available for Parkinson's disease (PD), the second most common neurodegenerative disease. The long nonmotor prodromal phase of PD is a window of opportunity for early detection and intervention. However, we lack the pathophysiological understanding to develop selective biomarkers and interventions. By using a mutant α-synuclein selective-overexpression mouse model of prodromal PD, we identified a cell-autonomous selective Kv4 channelopathy in dorsal motor nucleus of the vagus (DMV) neurons. This functional remodeling of intact DMV neurons leads to impaired pacemaker function in vitro and in vivo, which, in turn, reduces gastrointestinal motility, a common early symptom of prodromal PD. We identify a chain of events from α-synuclein via a biophysical dysfunction of a specific neuronal population to a clinically relevant prodromal symptom. These findings will facilitate the rational design of clinical biomarkers to identify people at risk for developing PD.

OBJECTIVES: To investigate the association of psychiatric disorders with (1) caries experience, (2) periodontal status, and (3) metabolic syndrome (MetS) components.

METHOD AND MATERIALS: This 7-year cross-sectional study retrospectively analyzed the medical records of 504 individuals aged 18 to 90 years who attended the student dental clinic. Collected data included: demographics, smoking habits, systolic and diastolic blood pressures, pulse, waist circumference, full-mouth plaque score (FMPS), full-mouth bleeding score (FMBS), maximal pocket probing depth (PPD), average and maximal radiographic bone loss (RBL), the sum of the number of decayed (D), missing (M), and filled (F) teeth (DMFT score), and presence of MetS components, consequences and related conditions including diabetes, hypertension, hyperlipidemia, ischemic heart disease, heart failure, s/p stroke, and cancer.

RESULTS: 68 (13.5%) had psychiatric disorders with an average age of 53.42 ± 15.71 years. Psychiatric disorders were positively associated with smoking (P = .008), smoking pack-years (P = .004), DMFT score (P = .005), and negatively associated with hypertension (P = .046). Psychiatric disorders had no statistically significant associations with all periodontal indices studied and with other components of MetS. Following multivariate analysis, psychiatric disorders retained a statistically significant positive association with smoking (odds ratio [OR] and 95% confidence interval [CI] = 2.24 [1.28 to 3.92]) and with DMFT (OR and 95% CI = 1.08 [1.02 to 1.14]), and a statistically significant negative association with hypertension (OR and 95% CI = 0.46 [0.25 to 0.84]).

CONCLUSIONS: Psychiatric disorders were positively associated with smoking and caries experience but not with periodontal status and metabolic morbidity. Communication between dental and medical professionals is needed to address the higher smoking consumption and caries morbidity in psychiatric patients. (Quintessence Int 2021;52:516-526; doi: 10.3290/j.qi.b1044091).

Conflicting results have been published regarding the associations between dental status and hypertension. This study aims to explore whether or not hypertension is associated with dental status among young to middle-aged adults. To that end, data from the Dental, Oral, Medical Epidemiological (DOME) study were analyzed. The DOME is a cross-sectional records-based study that combines comprehensive socio-demographic, medical, and dental databases of a nationally representative sample of military personnel. Included were 132,529 subjects aged 18-50 years who attended the military dental clinics for one year. The prevalence of hypertension in the study population was 2.5% (3363/132,529). Following multivariate analysis, the associations between hypertension and dental parameters were lost and hypertension retained a positive association with obesity (Odds ratio (OR) = 4.2 (3.7-4.9)), diabetes mellitus (OR = 4.0 (2.9-5.7)), birth country of Western Europe vs. Israeli birth country (OR = 1.9 (1.6-2.2)), male sex (OR = 1.9 (1.6-2.2)), cardiovascular disease (OR = 1.9 (1.6-2.3)), presence of fatty liver (OR = 1.8 (1.5-2.3)), the birth country Asia vs. Israeli birth country (OR = 1.6 (1.1-2.3)), smoking (OR = 1.2 (1.05-1.4)), and older age (OR = 1.05 (1.04-1.06)). Further analysis among an age-, smoking- and sex matched sub-population ( = 13,452) also revealed that the dental parameters lost their statistically significant association with hypertension following multivariate analysis, and hypertension retained a positive association with diabetes (OR = 4.08 (2.6-6.1)), obesity (OR = 2.7 (2.4-3.2)), birth country of Western Europe vs. Israel (OR = 1.9 (1.6-2.3)), cardiovascular disease (OR = 1.8 (1.5-2.2)), fatty liver (OR = 1.7 (1.3-2.3)), high school education vs. academic (OR = 1.5 (1.3-1.8)), and low socio-economic status (SES) vs. high (OR = 1.4 (1.03-1.8)). We analyzed the associations between C-reactive protein (CRP) and dental parameters and combined the statistically significant variables to create a dental inflammation score (DIS). This crated a final model with the appropriate weights written as follows: DIS = (periodontal disease × 14) + (the number of teeth that required crowns × 11) + (missing teeth × 75). The mean DIS was 10.106 ± 25.184, and it exhibited a weak positive association with hypertension in the univariate analysis (OR = 1.011 (1.010-1.012)). Receiver operating characteristic (ROC) analysis of the DIS against hypertension produced a failed area under the curve (AUC) result (0.57 (0.56-0.58)). Moreover, the DIS also lost its statistical significance association with hypertension following multivariate analysis. We conclude that hypertension had no statistically significant nor clinically significant association with dental status. The study established a profile of the "patient vulnerable to hypertension", which retained well-known risk factors for hypertension such as older age, male sex, smoking, diabetes, obesity, and fatty liver but not dental parameters.

Both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are classified as autoimmune diseases, where the body's own immune response causes it to attack the host tissues, as if the latter were antigens. RA is the most common autoimmune disease that affects joints. The clinical diagnosis of RA is based on the history and examination, integrated with laboratory tests including blood tests on inflammatory markers, serology, and imaging. There are no diagnostic criteria, but there are classification criteria. SLE affects most major organ systems in the body. The diagnosis of SLE relies on the constellation of characteristic symptoms, signs, and laboratory findings in the appropriate clinical context and after excluding other reasonable diagnoses. Epidemiologically, both conditions show a definitive female predilection. The focus of this review article is epidemiology, and the major clinical features with an emphasis on the orofacial manifestations. The relevant clinical points for the dental practitioner area summarized.

OBJECTIVE: Occlusal stabilization splints (OSSs) are first-line therapy for temporomandibular disorder (TMD) and sleep-related-bruxism (SRB). The main goal of this study was to quantify adherence rates to OSS therapy in TMD patients and among non-painful conditions such as clenching and bruxism. It was hypothesized that adherence rates would be similar to those for other chronic conditions.

METHOD AND MATERIALS: Medical records of 99 patients seen in the Orofacial Pain Clinic between 2006 and 2014 were reviewed. Patients meeting the inclusion criteria were interviewed over the telephone regarding OSS adherence.

RESULTS: Of the 99 patients interviewed, 80 had chronic orofacial pain related to TMD and 19 received OSS due to (non-painful) SRB. Patients were divided according to usage; the USER group (58 patients, 58.6%) used their OSS for more than 1 year; the NUSE group was the remaining 41 (41.4%) patients who used their device for less than 1 year. Of the patients with pain as the reason for OSS use, 50 (62.5%) were in the USER group and 30 (37.5%) were in the NUSE group. The most common diagnosis was masticatory muscle disorders (MMD) with a 71.4% adherence rate, representing 60.3% of the USER group, which was significantly higher than those with SRB and other facial pain (P = .039). The most common reasons for non-adherence were sleep difficulties with OSS (31.6%) and resolution of the problem (25%).

CONCLUSIONS: Patients reporting mild to major pain reduction had higher adherence rates than those with complete pain relief or none at all. Patients with MMD exhibited higher adherence rates than those with other facial pain types and SRB.

PURPOSE: To characterise pain from medication-related osteonecrosis of the jaws (MRONJ) and the effects of antimicrobial treatment on it.

METHODS: Data from files of patients diagnosed with MRONJ according to the position paper of the American Association of Oral and Maxillofacial Surgeons (2014) and Multinational Association of Supportive Care in Cancer and American Society of Clinical Oncology (2019) were collected retrospectively, including gender, age, primary disease, bone-modifying agents (BMAs)/anti-angiogenics, administration route, involved jaw, location, and exposure size. The patients were treated according to the abovementioned position papers' recommendations, i.e. all patients who suffered from pain were staged as 2 or 3 and treated with systemic amoxicillin, or doxycycline or clindamycin in case of sensitivity, and local antiseptic and hygiene instructions.

RESULTS: Data from 77 MRONJ patients (aged 65.09 ± 11.9 years old) were analysed. Most (90.1%) received bisphosphonates for cancer (79%) and osteoporosis (17%). A total of 67.5% experienced pain; 36.5% had moderate-to-severe pain. Female gender was significantly associated with the presence of pain (p = 0.002). Osteonecrosis lesions after dento-alveolar surgery had a higher risk of pain development than spontaneous lesions (p = 0.045). Medical and oncologic background, type of pharmacotherapy, lesion size, and location were not associated with pain levels. Worse initial pain was significantly associated with better relief following MRONJ treatment (p = 0.045). Meaningful pain reduction (≥ 50%) was significantly correlated with initial pain severity (p = 0.0128, OR = 4.75).

CONCLUSIONS: Pain from infection and inflammation often accompanies MRONJ. The presence of pain is correlated with longer BMAs pre-therapy and if surgery preceded the MRONJ. Persistency of the mild pain together with a resistance to common antimicrobial treatment, although not complete, is a feature that MRONJ pain shares with neuropathic-"like" pain, and requires further study and consideration during treatment.

The brain undergoes rapid, dramatic, and reversible transitioning between states of wakefulness and unconsciousness during natural sleep and in pathological conditions such as hypoxia, hypotension, and concussion. Transitioning can also be induced pharmacologically using general anesthetic agents. The effect is selective. Mobility, sensory perception, memory formation, and awareness are lost while numerous housekeeping functions persist. How is selective transitioning accomplished? Classically a handful of brainstem and diencephalic "arousal nuclei" have been implicated in driving brain-state transitions on the grounds that their net activity systematically varies with brain state. Here we used transgenic targeted recombination in active populations mice to label neurons active during wakefulness with one reporter and neurons active during pentobarbital-induced general anesthesia with a second, contrasting reporter. We found 'wake-on' and 'anesthesia-on' neurons in widely distributed regions-of-interest, but rarely encountered neurons labeled with both reporters. Nearly all labeled neurons were either wake-on or anesthesia-on. Thus, anesthesia-on neurons are not unique to the few nuclei discovered to date whose activity appears to increase during anesthesia. Rather neuronal populations selectively active during anesthesia are located throughout the brain where they likely play a causative role in transitioning between wakefulness and anesthesia. The widespread neuronal suppression reported in prior comparisons of the awake and anesthetized brain in animal models and noninvasive imaging in humans reflects only net differences. It misses the ubiquitous presence of neurons whose activity increases during anesthesia. The balance in recruitment of anesthesia-on versus wake-on neuronal populations throughout the brain may be a key driver of regional and global vigilance states. [Correction added on September 22, 2021, after first online publication: Due to a typesetting error, the abstract text was cut off. This has been corrected now.].

The mesopontine tegmental anesthesia area (MPTA) was identified in rats as a singular brainstem locus at which microinjection of minute quantities of GABAergic agents rapidly and reversibly induces loss-of-consciousness and a state of general anesthesia, while lesioning renders animals insensitive to anesthetics at normal systemic doses. Obtaining similar results in mice has been challenging, however, slowing research progress on how anesthetics trigger brain-state transitions. We have identified roadblocks that impeded translation from rat to mouse and tentatively located the MPTA equivalent in this second species. We describe here a series of modifications to the rat protocol that allowed us to document pro-anesthetic changes in mice following localized stereotactic delivery of minute quantities (20 nL) of the GABA-receptor agonist muscimol into the brainstem mesopontine tegmentum. The optimal locus identified proved to be homologous to the MPTA in rats, and local neuronal populations in rats and mice were similar in size and shape. This outcome should facilitate application of the many innovative gene-based methodologies available primarily in mice to the study of how activity in brainstem MPTA neurons brings about anesthetic loss-of-consciousness and permits pain-free surgery.

General anesthetic agents are thought to induce loss-of-consciousness (LOC) and enable pain-free surgery by acting on the endogenous brain circuitry responsible for sleep-wake cycling. In clinical use, the entire CNS is exposed to anesthetic molecules with LOC and amnesia usually attributed to synaptic suppression in the cerebral cortex and immobility and analgesia to agent action in the spinal cord and brainstem. This model of patch-wise suppression has been challenged, however, by the observation that all functional components of anesthesia can be induced by focal delivery of minute quantities of GABAergic agonists to the brainstem mesopontine tegmental anesthesia area (MPTA). We compared spectral features of the cortical electroencephalogram (EEG) in rats during systemic anesthesia and anesthesia induced by MPTA microinjection. Systemic administration of (GABAergic) pentobarbital yielded the sustained, δ-band dominant EEG signature familiar in clinical anesthesia. In contrast, anesthesia induced by MPTA microinjection (pentobarbital or muscimol) featured epochs of δ-band EEG alternating with the wake-like EEG, the pattern typical of natural non-rapid-eye-movement (NREM) and REM sleep. The rats were not sleeping, however, as they remained immobile, atonic and unresponsive to noxious pinch. Recalling the paradoxical wake-like quality the EEG during REM sleep, we refer to this state as "paradoxical anesthesia". GABAergic anesthetics appear to co-opt both cortical and spinal components of the sleep network via dedicated axonal pathways driven by MPTA neurons. Direct drug exposure of cortical and spinal neurons is not necessary, and is probably responsible for off-target side-effects of systemic administration including monotonous δ-band EEG, hypothermia and respiratory depression. SIGNIFICANCE STATEMENT: The concept that GABAergic general anesthetic agents induce loss-of-consciousness by substituting for an endogenous neurotransmitter, thereby co-opting neural circuitry responsible for sleep-wake transitions, has gained considerable traction. However, the electroencephalographic (EEG) signatures of sleep and anesthesia differ fundamentally. We show that when the anesthetic state is generated by focal delivery of GABAergics into the mesopontine tegmental anesthesia area (MPTA) the resulting EEG repeatedly transitions between delta-wave-dominant and wake-like patterns much as in REM-NREM sleep. This suggests that systemic (clinical) anesthetic delivery, which indiscriminately floods the entire cerebrum with powerful inhibitory agents, obscures the sleep-like EEG signature associated with the less adulterated form of anesthesia obtained when the drugs are applied selectively to loci where the effective neurotransmitter substitution actually occurs.

Free nerve endings are key structures in sensory transduction of noxious stimuli. In spite of this, little is known about their functional organization. Transient receptor potential (TRP) channels have emerged as key molecular identities in the sensory transduction of pain-producing stimuli, yet the vast majority of our knowledge about sensory TRP channel function is limited to data obtained from in vitro models which do not necessarily reflect physiological conditions. In recent years, the development of novel optical methods such as genetically encoded calcium indicators and photo-modulation of ion channel activity by pharmacological tools has provided an invaluable opportunity to directly assess nociceptive TRP channel function at the nerve terminal.