Brain Stimulation Differentially Modulates Nociception and Inflammation in Aversive and Non-aversive Behavioral Conditions.

Inflammation and pain are major clinical burdens contributing to multiple disorders and limiting the quality of life of patients. We previously reported that brain electrical stimulation can attenuate joint inflammation in experimental arthritis. Here, we report that non-aversive electrical stimulation of the locus coeruleus (LC), the paraventricular hypothalamic nucleus (PVN) or the ventrolateral column of the periaqueductal gray matter (vlPAG) decreases thermal pain sensitivity, knee inflammation and synovial neutrophilic infiltration in rats with intra-articular zymosan. We also analyzed the modulation of pain and inflammation during aversive neuronal stimulation, which produces defensive behavioral responses such as freezing immobility to avoid predator detection. Electrical stimulation with higher intensity to induce freezing immobility in rats further reduces pain but not inflammation. However, tonic immobility further reduces pain, knee inflammation and synovial neutrophilic infiltration in guinea pigs. The duration of the tonic immobility increases the control of pain and inflammation. These results reveal survival behavioral and neuromodulatory mechanisms conserved in different species to control pain and inflammation in aversive life-threatening conditions. Our results also suggest that activation of the LC, PVN, or vlPAG by non-invasive methods, such as physical exercise, meditation, psychological interventions or placebo treatments may reduce pain and joint inflammation in arthritis without inducing motor or behavioral alterations.

Inhibition of substance P-induced defensive behavior via neurokinin-1 receptor antagonism in the central and medial but not basolateral nuclei of the amygdala in male Wistar rats.

RATIONALE: The production of unconditioned defensive behaviors has been related to the amygdala, a key component of the encephalic aversion system. Microinjection of the neuropeptide substance P (SP) in the amygdala elicits defensive behaviors via the activation of type 1 neurokinin (NK-1) receptors. However, no studies have investigated whether intra-amygdala SP/NK-1 mechanisms can elicit other types of defensive responses, such as antinociception and ultrasonic vocalizations (USVs). METHODS: The present study investigated the effects of SP-induced activation of the neurokininergic system in three main nuclei of the amygdala-basolateral (BLA), central (CeA), and medial (MeA) nuclei-in rats that were subjected to the elevated plus maze (EPM), tail-flick test, and USV recording. The effects of SP in these amygdaloid nuclei were challenged with combined injections of the NK-1 receptor antagonist spantide. RESULTS: The present study showed that SP injections in the CeA and MeA but not BLA exerted anxiogenic-like effects. In contrast to the CeA, the anxiogenic-like effects of SP in the MeA were not dependent on NK-1 mechanisms. In the tail-flick test, SP microinjections produced antinociceptive effects only in the MeA through NK-1 receptor activation. No USV emissions were detected after the SP microinjections. CONCLUSIONS: The present study showed that NK-1 receptors in the CeA and MeA but not BLA are involved in defensive reactions to conditions of fear. The present results may provide a better understanding of the neurochemical mediation of fear states.

The interdisciplinary management of hypodontia patients in the UK: a national service evaluation.

Objective To examine the distribution of interdisciplinary clinics for hypodontia patients in the UK and to assess the provision of orthodontic-restorative care for hypodontia patients in units where this service is and is not available.Design Prospective, online-questionnaire.Setting Hospital orthodontic departments in the UK.Participants In total, consultants from 92 orthodontic departments completed the questionnaire.Methods Orthodontic consultants were asked to complete a questionnaire regarding the provision of orthodontic-restorative care for hypodontia patients in their units.Results Overall, 100% of teaching hospitals and 51% of district general hospitals (DGHs) that responded have an interdisciplinary clinic for hypodontia patients. In 51% of units, the majority of patients assessed on the interdisciplinary clinic undergo their restorative care at the same secondary care unit. In 59% of units where an interdisciplinary clinic is not available most of the restorative care for hypodontia patients is provided by the GDP, whilst in 38% of units a specialist restorative dentist in another secondary care unit provides most of the restorative care.Conclusions The provision of an interdisciplinary clinic for hypodontia patients varies amongst hospital units throughout the UK. The provision of orthodontic-restorative care for hypodontia patients also varies between these units.

Pre- and post-operative management of dental implant placement. Part 2: management of early-presenting complications.

Despite morbidity factors that include pain and complications with healing, there is currently little available guidance regarding optimal pre-and post-operative protocols for dental implant placement. While the first paper of this two-part series discussed the management of post-operative pain, the second instalment reviews pre- and post-operative means of managing early complications associated with dental implant placement.

Pre- and post-operative management of dental implant placement. Part 1: management of post-operative pain.

Although dental implant placements have high success rates and a low incidence of morbidity, post-operative pain and complications with the healing process have been reported. There is little guidance available regarding optimal pre- and post-operative management of dental implant placement. This first paper discusses the mechanisms of pain associated with dental implant placement and offers guidance to clinicians on optimal pre- and post-operative pain management regimes. The second paper aims to discuss pre- and post-operative means of reducing the risk of early healing complications.

Participation of NK1 receptors of the amygdala on the processing of different types of fear.

The amygdala, medial hypothalamus, dorsal periaqueductal gray (dPAG), superior and inferior colliculus together constitutes the encephalic aversion system which has been considered the main neural substrate for the integration of unconditioned aversive behavioral states. Within the amygdala the basolateral nucleus (BLA) is thought to act as a filter for innate and learned aversive information to higher structures, whereas the central nucleus (CeA) is considered the main output for the expression of fear reactions through projections to limbic and brainstem regions. Although neurokinin (NK) receptors are abundant in the amygdala, their role in the processing and expression of fear is yet unclear. In this study, we examined the role of SP/NK1 receptor system of the CeA and BLA on the expression of defensive responses elaborated by Wistar rats submitted to elevated plus maze (EPM) and to electrical stimulation (ES) of the dPAG. For EPM test, cannulae were implanted in the CeA and BLA for injections of substance P (SP - 10 and 100pmol/0.2µL) and spantide (SPA - 10, 100 and 500pmol/0.2µL). For ES of dPAG, aversive thresholds for freezing and escape responses as well as post-stimulation freezing (PSF) were measured in rats treated with PBS and SPA (100pmol/0.2µL) in CeA. Injections of SP into the CeA, but not the BLA, produced anxiogenic-like effects in the EPM test. SPA injected into the CeA had no effect on the exploratory behavior of rats submitted to the EPM but blocked the effects of SP. The duration of dPAG-PSF was also reduced significantly following injection of SPA in CeA but had no effect on thresholds for freezing and escape responses. The EPM gives the animal a control over its environment i.e. the option to choose or not to enter into the open arm and dPAG-PSF is thought to reflect a period when the animal evaluates the significance of dPAG-evoked aversion once the unconditioned responses of freezing and escape were elicited. The data indicate that SP may be involved in mediating responses of the animal in only certain types of aversive behavior and suggests a differential participation of the NK1 receptors in the processing of distinct types of fear in the amygdala.

Use of the multi-cup denture for a severely resorbed maxilla: a clinical report.

Obtaining a satisfactory outcome for a patient with a severely resorbed maxilla can be extremely challenging. This clinical report describes the treatment of a patient with a history of multiple implant failures in the maxilla. A conventional upper complete denture had poor retention and so did not fulfil the patient's needs. Further surgery was not considered appropriate. A new upper complete denture was made with a fitting surface covered in multiple suction cups to attempt to improve the retention without surgery and resulted in a pleasing outcome for both the patient and authors.

Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety

Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by γ-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 μL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG.

Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety.

Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by γ-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 µL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG.

Effects of neurokinin-1 and 3-receptor antagonists on the defensive behavior induced by electrical stimulation of the dorsal periaqueductal gray.

The dorsal periaqueductal gray (dPAG) is the main output structure for the defensive response to proximal aversive stimulation. Panic-like responses, such as freezing and escape behaviors, often result when this structure is electrically stimulated. Freezing also ensues after termination of the dPAG stimulation (post-stimulation freezing (PSF)). GABA and 5-HT have been proposed as the main neuromediators of these defense reactions. Neurokinins (NKs) also play a role in the defense reaction; however, it is unclear how the distinct types of NK receptors are involved in the expression of these fear responses. This study investigated the role of NK-1 and NK-3 receptors in the unconditioned defensive behaviors induced by electrical stimulation of the dPAG of rats, with and without previous experience with contextual fear conditioning (CFC). Spantide (100 ρmol/0.2 µl) and SB 222200 (50 and 100 ρmol/0.2 µl), selective antagonists of NK-1 and NK-3 receptors, respectively, were injected into the dPAG. Injection of spantide had antiaversive effects as determined by stimulation of the dPAG in naive animals and in animals subjected previously to CFC. SB 222200 also increased these aversive thresholds but only at doses that caused a motor deficit. Moreover, neither spantide nor SB 222200 influenced the PSF. The results suggest that NK-1 receptors are mainly involved in the mediation of the defensive behaviors organized in the dPAG. Because dPAG-evoked PSF was not affected by intra-dPAG injections of either spantide or SB 222200, it is suggested that neurokinin-mediated mechanisms are not involved in the processing of ascending aversive information from the dPAG.

Withdrawal from methylphenidate increases neural reactivity of dorsal midbrain.

Ritalin (methylphenidate hydrochloride, MP) is a non-amphetamine psychostimulant and is the drug of choice to treat children and adults diagnosed with the attention deficit hyperactivity disorder (ADHD). Several studies have demonstrated that rats treated with MP during early developmental stage exhibit alterations in anxiety-related processes such as an increased response to stressful stimuli and elevated plasma levels of corticosterone. Accordingly, the present study was designed to further characterize the neural and behavioral consequences of withdrawal from MP in adult rats and its influence on the neural reactivity of the dorsal midbrain. After initial exposure to an elevated plus-maze (EPM), brainstem neural activation, elicited by exposure to EPM aversive cues, was analyzed using a Fos-protein immunolabeling technique. Additional independent groups of animals were submitted to electrical stimulation of the dorsal column (DPAG) or the startle response procedure, in order to verify the influence of withdrawal from MP on the expression of unconditioned fear induced by DPAG activation and the effects of or withdrawal from MP on motor response, respectively. Our results provide new findings about the influence of MP treatment in adult rats, showing that, after a sudden MP treatment-break, increased anxiety, associated with the neural sensitization of anxiety-related regions, ensues.

The etiology and management of gagging: a review of the literature.

Gagging in dental patients can be disruptive to dental treatment and may be a barrier to patient care, preventing the provision of treatment and the wearing of prostheses. This article reviews the literature on the gagging problem from English-language peer-reviewed articles from the years 1940 to 2002 found by conducting an electronic search of PubMed, coupled with additional references from citations within the articles. Dentally relevant articles have been cited wherever evidence exists, and a balanced view given in situations where there is controversy. The first section considers the normal gag reflex and factors that may be associated with the etiology of gagging, including anatomical and iatrogenic factors, systemic disorders, and psychological conditions. A review of the management of patients with an exaggerated gag reflex follows and includes strategies to assist clinicians.

Improved resuscitation training of senior house officers in oral and maxillofacial surgery.

All healthcare professionals are expected to be competent at cardiopulmonary resuscitation. In a previous study [Br J Oral Maxillofac Surg 1999; 37: 1], senior house officers in oral and maxillofacial surgery (OMFS) expressed dissatisfaction about their training in resuscitation, and we now report the results of a follow-up survey. The amount of training in resuscitation has increased in the 5 years since the initial questionnaire, and 77% of the 73 respondents (n=56) been given such training in the 12 months before the present survey, compared to 48% in the previous study. Fifty-one (70%) now think that they would feel confident if required to resuscitate a patient who had a cardiorespiratory arrest, and this has increased from 47%. Despite this, 70 (96%) of senior house officers in OMFS stated that they wanted further training in cardiopulmonary resuscitation.

An unusual presentation of non-Hodgkin's lymphoma in the head and neck.

The lymphomas are a group of lymphoproliferative disorders that can be divided histologically in the two main groups of Hodgkin's and non-Hodgkin's lymphoma. They sometimes present in the head and neck, and the diagnosis and management require a multidisciplinary approach. An unusual case is described presenting at an advanced stage because of patient delay in seeking medical help.

An alternative putty/wash impression technique.

Conventionally, custom trays have been made in the laboratory on casts constructed from preliminary impressions. A spaced tray made in this way allows a uniform thickness of impression material of approximately 2 mm which is said to enhance the accuracy of the impression-taking procedure. A technique is described to fulfill this criterion without the need for a primary impression, by constructing a spaced putty custom tray inside the mouth.

RNA folding and misfolding of the hammerhead ribozyme.

The hammerhead ribozyme undergoes a well-defined two-stage folding process induced by the sequential binding of two magnesium ions. These probably correspond to the formation of domain 2 (0-500 microM magnesium ions) and domain 1 (1-20 mM magnesium ions), respectively. In this study we have used fluorescence resonance energy transfer (FRET) to analyze the ion-induced folding of a number of variants of the hammerhead ribozyme. We find that both A14G and G8U mutations are highly destabilizing, such that these species are essentially unfolded under all conditions. Thus they appear to be blocked in the first stage of the folding process, and using uranyl-induced photocleavage we show that the core is completely accessible to this probe under these conditions. Changes at G5 do not affect the first transition but appear to provide a blockage at the second stage of folding; this is true of changes in the sugar (removal of the 2'-hydroxyl group) and base (G5C mutation, previously studied by comparative gel electrophoresis). Arrest of folding at this intermediate stage leads to a pattern of uranyl-induced photocleavage that is changed from the wild-type, but suggests a structure less open than the A14G mutant. Specific photocleavage at G5 is found only in the wild-type sequence, suggesting that this ion-binding site is formed late in the folding process. In addition to folding that is blocked at selected stages, we have also observed misfolding. Thus the A13G mutation appears to result in the ion-induced formation of a novel tertiary structure.

Ion-induced folding of the hammerhead ribozyme: a fluorescence resonance energy transfer study.

The ion-induced folding transitions of the hammerhead ribozyme have been analysed by fluorescence resonance energy transfer. The hammerhead ribozyme may be regarded as a special example of a three-way RNA junction, the global structure of which has been studied by comparing the distances (as energy transfer efficiencies) between the ends of pairs of labelled arms for the three possible end-to-end vectors as a function of magnesium ion concentration. The data support two sequential ion-dependent transitions, which can be interpreted in the light of the crystal structures of the hammerhead ribozyme. The first transition corresponds to the formation of a coaxial stacking between helices II and III; the data can be fully explained by a model in which the transition is induced by a single magnesium ion which binds with an apparent association constant of 8000-10 000 M-1. The second structural transition corresponds to the formation of the catalytic domain of the ribozyme, induced by a single magnesium ion with an apparent association constant of approximately 1100 M-1. The hammerhead ribozyme provides a well-defined example of ion-dependent folding in RNA.

Nucleic acid structure and recognition.

We review the global structures adopted by branched nucleic acids, including three- and four-way helical junctions in DNA and RNA. We find that some general folding principles emerge. First, all the structures exhibit a tendency to undergo pairwise coaxial helical stacking when permitted by the local stereochemistry of strand exchange. Second, metal ions generally play an important role in facilitating folding of branched nucleic acids. These principles can be applied to functionally important branched nucleic acids, such as the Holliday DNA junction of genetic recombination, and the hammerhead ribozyme in RNA.