Intralesional injection of triamcinolone hexacetonide as an alternative treatment for central giant cell lesions: a prospective study.

The aim of this prospective study was to report on the response to treatment of central giant cell lesions (CGCL) with intralesional corticosteroid injections. Consecutive cases of CGCL were treated with a biweekly intralesional injection of 20mg/ml triamcinolone hexacetonide diluted in an anaesthetic solution of 2% lidocaine/epinephrine 1:200 000 at the proportion 1:1. All patients were monitored using cone beam computed tomography. Eleven patients were treated; their ages ranged from 15-34 (mean 22 years); and eight lesions were in the mandible, and three in the maxilla. Three cases were diagnosed as non-aggressive, and eight as aggressive. Six cases presented good results (four aggressive and two non-aggressive); three cases presented a moderate response (two aggressive and one non-aggressive); and two had a poor response to treatment (both aggressive). In four cases with a good response, osteoplasty was done. In all cases with a moderate response, the remaining lesion was curetted. Cases with a poor response were submitted to either curettage or denosumab injections. Corticotherapy, as main or neoadjuvant therapy, may be an option for treatment of CGCL.

Pharyngeal airway space changes after maxillomandibular advancement: a five-year retrospective study.

The aim of this study was to compare the alterations in three regions of the airway-nasopharynx, oropharynx, and hypopharynx-in relation to the area of the midsagittal plane, volume, and minimal axial area after maxillomandibular advancement (MMA) surgery. Thirty patients who had undergone MMA surgery were evaluated at four time points: preoperative (T0), immediately postoperative (T1), 1year postoperative (T2), and ≥5 years postoperative (T3). All measurements were performed using computed tomography, analyzed in Dolphin Imaging 11.0 Premium 3D software. The area in the midsagittal plane presented a mean increase of 22.0% between T0 and T3 (P<0.001), with the highest increase in the oropharynx (24.1%, P<0.001). The total volumetric increase at T3 was 16.7% (P<0.001), with the highest increase in the nasopharynx (15.7%; P<0.001). The lowest minimal axial area was found for the oropharynx at all time points, and the highest increase in minimal axial area was found for the nasopharynx (114.9%; P<0.001). MMA surgery showed the highest increase in upper posterior airway between T0 and T1, and this was followed by a progressive reduction until T3, but with a statistically significant increase at T3 compared with T0 in all cases.

Dorsal periaqueductal gray stimulation facilitates anxiety-, but not panic-related, defensive responses in rats tested in the elevated T-maze

The escape response to electrical or chemical stimulation of the dorsal periaqueductal gray matter (DPAG) has been associated with panic attacks. In order to explore the validity of the DPAG stimulation model for the study of panic disorder, we determined if the aversive consequences of the electrical or chemical stimulation of this midbrain area can be detected subsequently in the elevated T-maze. This animal model, derived from the elevated plus-maze, permits the measurement in the same rat of a generalized anxiety- and a panic-related defensive response, i.e., inhibitory avoidance and escape, respectively. Facilitation of inhibitory avoidance, suggesting an anxiogenic effect, was detected in male Wistar rats (200-220 g) tested in the elevated T-maze 30 min after DPAG electrical stimulation (current generated by a sine-wave stimulator, frequency at 60 Hz) or after local microinjection of the GABA A receptor antagonist bicuculline (5 pmol). Previous electrical (5, 15, 30 min, or 24 h before testing) or chemical stimulation of this midbrain area did not affect escape performance in the elevated T-maze or locomotion in an open-field. No change in the two behavioral tasks measured by the elevated T-maze was observed after repetitive (3 trials) electrical stimulation of the DPAG. The results indicate that activation of the DPAG caused a short-lived, but selective, increase in defensive behaviors associated with generalized anxiety.

Dorsal periaqueductal gray stimulation facilitates anxiety-, but not panic-related, defensive responses in rats tested in the elevated T-maze.

The escape response to electrical or chemical stimulation of the dorsal periaqueductal gray matter (DPAG) has been associated with panic attacks. In order to explore the validity of the DPAG stimulation model for the study of panic disorder, we determined if the aversive consequences of the electrical or chemical stimulation of this midbrain area can be detected subsequently in the elevated T-maze. This animal model, derived from the elevated plus-maze, permits the measurement in the same rat of a generalized anxiety- and a panic-related defensive response, i.e., inhibitory avoidance and escape, respectively. Facilitation of inhibitory avoidance, suggesting an anxiogenic effect, was detected in male Wistar rats (200-220 g) tested in the elevated T-maze 30 min after DPAG electrical stimulation (current generated by a sine-wave stimulator, frequency at 60 Hz) or after local microinjection of the GABA A receptor antagonist bicuculline (5 pmol). Previous electrical (5, 15, 30 min, or 24 h before testing) or chemical stimulation of this midbrain area did not affect escape performance in the elevated T-maze or locomotion in an open-field. No change in the two behavioral tasks measured by the elevated T-maze was observed after repetitive (3 trials) electrical stimulation of the DPAG. The results indicate that activation of the DPAG caused a short-lived, but selective, increase in defensive behaviors associated with generalized anxiety.

Cephalometric and three-dimensional assessment of superior posterior airway space after maxillomandibular advancement.

The purpose of this study was to quantify cephalometric and three-dimensional alterations of the posterior airway space of patients who underwent maxillomandibular advancement surgery. 20 patients treated by maxillomandibular advancement were selected. The minimal postoperative period was 6 months. The treated patients underwent cone-beam computed tomography at 3 distinct time intervals, preoperative (T1), immediate postoperative period up to 15 days after surgery (T2), and late postoperative period at least 6 months after surgery. The results showed that the maxillomandibular advancement promoted an increase in the posterior airway space in each patient in all the analyses performed, with a statistically significant difference between T2 and T1, and between T3 and T1, p<0.05. There was a statistical difference between T2 and T3 in the analysis of area and volume, which means that the airway space became narrower after 6 months compared with the immediate postoperative period. The maxillomandibular advancement procedure allowed great linear area and volume increase in posterior airway space in the immediate and late postoperative periods, but there was partial loss of the increased space after 6 months. The linear analysis of airway space has limited results when compared with analysis of area and volume.

Glucocorticoid and calcitonin receptor expression in central giant cell lesions: implications for therapy.

Central giant cell lesion is an uncommon benign jaw lesion, with uncertain aetiology, and variable clinical behaviour. Studies of molecular markers may help to understand the nature and behaviour of this lesion, and eventually may represent a target for pharmacological approaches to treatment. The aim of this study was to analyse the expression of glucocorticoid and calcitonin receptors in central giant cell lesions before and after treatment with intralesional steroid. Paraffin-embedded blocks from patients who underwent treatment with intralesional triamcinolone hexacetonide injections were stained immunohistochemically. Biological material from patients who underwent a surgical procedure after treatment were tested immunohistochemically. 18 cases (9 aggressive and 9 non-aggressive) were included. The difference in calcitonin receptor expression was not statistically significant between the aggressive and non-aggressive lesions and between the patients with a good response and those with a moderate/negative response to treatment. Glucocorticoid receptor expression in the multinucleated giant cells was higher in patients with a good response. It can be postulated that immunohistochemical staining for glucocorticoid receptors may provide a tool for selecting the therapeutic strategy. An H-score greater than 48 for glucocorticoid receptors in multinucleated giant cells predicted a good response in this study.

SH3BP2-encoding exons involved in cherubism are not associated with central giant cell granuloma.

Central giant cell granuloma (CGCG) is a benign lesion with unpredictable biological behaviour ranging from a slow-growing asymptomatic swelling to an aggressive lesion associated with pain, bone and root resorption and also tooth displacement. The aetiology of the disease is unclear with controversies in the literature on whether it is mainly of reactional, inflammatory, infectious, neoplasic or genetic origin. To test the hypothesis that mutations in the SH3BP2 gene, as the principal cause of cherubism, are also responsible for, or at least associated with, giant cell lesions, 30 patients with CGCG were recruited for this study and subjected to analysis of germ line and/or somatic alterations. In the blood samples of nine patients, one codon alteration in exon 4 was found, but this alteration did not lead to changes at the amino acid level. In conclusion, if a primary genetic defect is the cause for CGCG it is either located in SH3BP2 gene exons not yet related to cherubism or in a different gene.

Intralesional injection of triamcinolone hexacetonide as an alternative treatment for central giant-cell granuloma in 21 cases.

Central giant-cell granulomas are benign, but occasionally aggressive, lesions that traditionally have been treated surgically. 21 cases of central giant-cell granuloma of the jaw were treated with intralesional injection of corticosteroids. The treatment protocol adopted was intralesional injection of 20mg/ml triamcinolone hexacetonide diluted in an anaesthetic solution of 2% lidocaine/epinephrine 1:200,000 in the proportion 1:1; 1.0ml of the solution was infiltrated for every 1cm(3) of radiolucid area of the lesion, totalling 6 biweekly applications. Ten patients had aggressive lesions and 11 nonaggressive. Two patients showed a negative response to the treatment and underwent surgical resection, 4 showed a moderate response and 15 a good response. 8 of the 19 who had a moderate-to-good response to the drug treatment underwent osteoplasty to reestablish facial aesthetics. In these cases, only mature or dysplastic bone was observed, with the presence or absence of rare giant multinucleated cells. The advantages of this therapy are its less-invasive nature, the probable lower cost to the patient, lower risk and the ability to treat the lesion surgically in the future, if necessary.

Apnoea-hypopnoea and mandibular retrusion as uncommon findings associated with Proteus syndrome.

The aetiology of Proteus syndrome (PS) is yet unclear. This disease includes partial gigantism of the hands and/or feet, nevi, hemihypertrophy due to overgrowth of long bones, subcutaneous tumours, macrocephaly, cranial hyperostosis, and pulmonary and renal abnormalities. This case report is about a 17-year-old boy with two uncommon findings associated with PS: apnoea-hypopnoea and mandibular retrusion. A multidisciplinary team was important to provide professional care for this patient. Dentists and physicians proposed an adjusted treatment plan. Maxillary disjunction was achieved with a combination of orthodontic treatment and surgical procedure. This represented the initial care for malocclusion treatment and also the preparation for orthognathic surgery. The oral maxillofacial surgeon and the otorhinolaryngologist proposed this approach in an attempt to improve pharynx airflow. The patient has been followed for almost 3 years.

Chronic imipramine treatment sensitizes 5-HT1A and 5-HT 2 A receptors in the dorsal periaqueductal gray matter: evidence from the elevated T-maze test of anxiety.

The dorsal periaqueductal gray matter (DPAG) has been implicated in the mediation of escape, a defensive behavior associated with panic disorder (PD). Chronic treatment with the anti-panic agent imipramine enhances the inhibitory effect on escape evoked by DPAG electrical stimulation of intra-DPAG administration of the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the preferential 5-HT 2 A receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). In the present study we further explore the hypothesis that sensitization of 5-HT1A and 5-HT 2 A receptors in the DPAG is involved in the anti-panic effect of imipramine. To this end, Wistar rats, subchronically or chronically treated with imipramine, were intra-DPAG injected with 8-OH-DPAT (0.4 or 3.2 nmoles) or DOI (16 nmoles), and tested in the elevated T-maze. In addition to its possible relevance to panic disorder, this test also measures inhibitory avoidance, a behavior that has been associated with generalized anxiety disorder (GAD). The effects of these 5-HT agonists in the DPAG were also investigated in animals chronically injected with buspirone, a drug clinically effective in treating GAD, but not PD. The results showed that intra-DPAG administration of the highest dose of 8-OH-DPAT and of DOI inhibited escape, and this panicolytic-like effect was significantly higher in animals previously treated chronically, but not subchronically, with imipramine. 8-OH-DPAT (0.4 nmole), although not affecting escape in animals systemically treated with saline, had a panicolytic-like effect in those receiving long-term treatment with imipramine. Microinjection of 8-OH-DPAT (3.2 nmoles), but not of DOI, impaired inhibitory avoidance, and this anxiolytic effect did not differ between animals treated with saline or imipramine. Chronic buspirone did not change the effect of 8-OH-DPAT and DOI on inhibitory avoidance and escape. Therefore, chronic imipramine seems to sensitize both 5-HT1A and 5-HT 2 A receptors in the DPAG, strengthening the view that these receptors are involved in the mode of action of anti-panic drugs.

Effect of acute treatment with a water-alcohol extract of Erythrina mulungu on anxiety-related responses in rats.

We investigated the effect of acute oral treatment with a water-alcohol extract of the inflorescence of Erythrina mulungu (EM, Leguminosae-Papilionaceae) (100, 200 and 400 mg/kg) on rats submitted to different anxiety models: the elevated T-maze (for inhibitory avoidance and escape measurements), the light/dark transition, and the cat odor test. These models were selected for their presumed capacity to demonstrate specific subtypes of anxiety disorders as recognized in clinical practice. Treatment with 200 mg/kg EM impaired avoidance latencies (avoidance 1 - 200 mg/kg EM: 18 +/- 7 s, control group: 40 +/- 9 s; avoidance 2 - 200 mg/kg EM: 15 +/- 4 s, control group: 110.33 +/- 38 s) in a way similar to the reference drug diazepam (avoidance 1: 3 +/- 0.79 s; avoidance 2: 3 +/- 0.76 s), without altering escape. Additionally, the same treatments increased the number of transitions (200 mg/kg EM: 6.33 +/- 0.90, diazepam: 10 +/- 1.54, control group: 2.78 +/- 0.60) between the two compartments and the time spent in the lighted compartment in the light/dark transition model (200 mg/kg EM: 39 +/- 7 s; diazepam: 61 +/- 9 s; control group: 14 +/- 4 s). The dose of 400 mg/kg EM also increased this last measurement (38 +/- 8 s). These results were not due to motor alterations since no significant effects were detected in the number of crossings or rearings in the arena. Furthermore, neither EM nor diazepam altered the behavioral responses of rats to a cloth impregnated with cat odor. These observations suggest that EM exerts anxiolytic-like effects on a specific subset of defensive behaviors, particularly those that have been shown to be sensitive to low doses of benzodiazepines.

Effect of acute treatment with a water-alcohol extract of Erythrina mulungu on anxiety-related responses in rats

We investigated the effect of acute oral treatment with a water-alcohol extract of the inflorescence of Erythrina mulungu (EM, Leguminosae-Papilionaceae) (100, 200 and 400 mg/kg) on rats submitted to different anxiety models: the elevated T-maze (for inhibitory avoidance and escape measurements), the light/dark transition, and the cat odor test. These models were selected for their presumed capacity to demonstrate specific subtypes of anxiety disorders as recognized in clinical practice. Treatment with 200 mg/kg EM impaired avoidance latencies (avoidance 1 - 200 mg/kg EM: 18 + or - 0 7 s, control group: 40 or - 9 s; avoidance 2 - 200 mg/kg EM: 15 + or - 4 s, control group: 110.33 + or - 38 s) in a way similar to the reference drug diazepam (avoidance 1: 3 + or - 0.79 s; avoidance 2: 3 + or - 0.76 s), without altering escape. Additionally, the same treatments increased the number of transitions (200 mg/kg EM: 6.33 + or - 0.90, diazepam: 10 + or - 1.54, control group: 2.78 + or - 0.60) between the two compartments and the time spent in the lighted compartment in the light/dark transition model (200 mg/kg EM: 39 + or - 7 s; diazepam: 61 + or - 9 s; control group: 14 + or - 4 s). The dose of 400 mg/kg EM also increased this last measurement (38 + or - 8 s). These results were not due to motor alterations since no significant effects were detected in the number of crossings or rearings in the arena. Furthermore, neither EM nor diazepam altered the behavioral responses of rats to a cloth impregnated with cat odor. These observations suggest that EM exerts anxiolytic-like effects on a specific subset of defensive behaviors, particularly those that have been shown to be sensitive to low doses of benzodiazepines

Serotonergic regulation of inhibitory avoidance and one-way escape in the rat elevated T-maze.

It has been proposed that distinct 5-HT pathways modulate different types of anxiety. Activation of the ascending dorsal raphe (DR)-5-HT pathway, innervating the amygdala and frontal cortex, would facilitate learned defensive behaviors. On the other hand, activation of the DR-periventricular 5-HT pathway, which innervates the dorsal periaqueductal gray matter (DPAG), would inhibit innate flight or fight reactions. Dysfunction of these pathways has been suggested to relate to generalized anxiety disorder (GAD) and panic disorder (PD) in humans, respectively. The elevated T-maze has been developed to separate conditioned (inhibitory avoidance) from unconditioned (escape) defensive responses in the same rat. Pharmacological validation of this model has shown that the GAD-effective serotonergic anxiolytic buspirone or the putative anxiolytic ritanserin selectively impaired inhibitory avoidance while leaving one-way escape unchanged. Chronic injection of the 5-HT/noradrenaline reuptake inhibitor imipramine impaired inhibitory avoidance and prolonged escape, an effect that may be related to the therapeutic action of this drug on both GAD and PD. Like imipramine, intra-DPAG injection of the 5-HT(1A) agonist 8-OH-DPAT impaired both inhibitory avoidance and one-way escape. Intra-DPAG administration of the 5-HT(2A/2C) agonist DOI prolonged escape, without affecting inhibitory avoidance. The reversible inactivation of the DRN by muscimol impaired inhibitory avoidance, while facilitating escape from the open arm. Taken together, these results suggest that 5-HT exerts differential control on inhibitory avoidance and escape response in the elevated T-maze, mobilizing different types of 5-HT receptors in key structures implicated in fear/anxiety.

Evaluation of the elevated T-maze as an animal model of anxiety in the mouse.

The elevated T-maze has been developed as an animal model of anxiety to generate both conditioned and unconditioned fears in the same rat. This study explores a version of the elevated T-maze fit for mice. Inhibitory (passive) avoidance- conditioned fear-is measured by recording the latency to leave the enclosed arm during three consecutive trials. One-way escape- unconditioned fear-is measured by recording the time to withdraw from open arms. The results showed that mice do not appear to acquire inhibitory avoidance in the standard T-maze, since their latencies to leave enclosed arm did not increase along trials. Nevertheless, the open arms seemed to be aversive for mice, because the latency to leave the enclosed arm after the first trial was lower in a T-maze with the three enclosed arms than in the standard elevated T-maze. In agreement, the exposure of mice to an elevated T-maze without shield, that reduces the perception of openness, increased significantly the latencies to leave the enclosed arm. However, the absence of the shield also increased the time taken to leave the open arms when compared to that recorded in standard T-maze. Systematic observation of behavioral items in the enclosed arm has shown that risk assessment behavior decreases along trials while freezing increases. In the open arms, freezing did not appear to influence the high latency to leave this compartment, since mice spend only about 8% of their time exhibiting this behavior. These results suggest that mice acquire inhibitory avoidance of the open arms by decreasing and increasing time in risk assessment and freezing, respectively, along three consecutive trials. However, one-way escape could not be characterized. Therefore, there are important differences between mice (present results) and rats (previously reported results) in the performance of behavioral tasks in the elevated T-maze.

Role of 5-HT receptor subtypes in the modulation of dorsal periaqueductal gray generated aversion.

To explore the role of 5-HT receptor subtypes in controlling aversion, we measured the effect of 5-HT1A and 5-HT2A/2C receptor agonists microinjected into the dorsal periaqueductal gray (DPAG) of rats on aversive behavior induced by electrical stimulation of the same brain area. The 5-HT1A agonists 8-OH-DPAT (4-16 nmol) and BAY-R-1531 (4-16 nmol) raised the threshold of aversive electrical stimulation in a dose-dependent way. Similarly, microinjection of the 5-HT2A/2C agonist DOI (4-16 nmol) increased the aversive mCPP (16 and 32 nmol) was ineffective. Previous intra-DPAG administration of the 5-HT1A receptor blocker NAN-190 (40 nmol) antagonized the antiaversive effect of 8-OH-DPAT (8 nmol), whereas pretreatment with the 5-HT2A receptor blocker spiperone (10 nmol) antagonized the effect of DOI (16 nmol). Spiperone also counteracted the effect of 8-OH-DPAT and NAN-190 counteracted the effect of DOI. These results indicate that activation of 5-HT1A and 5-HT2A receptors inhibits aversion in the DPAG and that both receptors have to be functional for the expression of each one's activation to occur.

Anxiolytic effect of glycine antagonists microinjected into the dorsal periaqueductal grey.

To investigate if blockade of the modulatory glycine site of NMDA receptors in the dorsal periaqueductal grey (DPAG) would produce anxiolytic effects, groups of 9-14 rats received microinjections into this structure of 7-chloro-kynurenic acid (7-Cl-KY, 4 and 8 nmol) or 3-amino-1-hydroxypyrrolid-2-one (HA-966, 30 or 100 nmol), two selective antagonists at the strychnine-insensitive glycine modulatory site, and were submitted to the elevated plus-maze, an ethologically based animal model of anxiety. Both drugs increased the percentage of entries and of time spent in open arms as compared to rats receiving isotonic saline. Injections of the active compounds outside the DPAG were not effective. In another experiment microinjections of 7-Cl-KY (8 nmol) and HA-966 (100 nmol) into the DPAG raised the threshold of aversive electrical stimulation of the rat DPAG. These results indicate that microinjections of 7-Cl-KY and HA-966 into the DPAG cause anxiolytic effects in two different models of anxiety and support the proposal that NMDA-mediated neurotransmission in the DPAG may be related to anxiety and panic.

Role of the amygdala and periaqueductal gray in anxiety and panic.

The amygdala (AM) and the periaqueductal gray (PAG) represent the rostral and the caudal pole, respectively, of a longitudinally organized neural system, that is responsible for the integration of behavioral and physiological manifestations of defensive reactions against innate and learned threats. Microinjection of benzodiazepine (BZD) anxiolytics, GABAA receptor agonists or 5-HT receptor antagonists into the AM has anxiolytic effects in conflict tests and other models of conditioned fear, while similar administration of 5-HT or of a 5-HT1A receptor agonist has anxiogenic effects. On the other hand, in the test of electrical stimulation of the PAG, microinjection of 5-HT, 5-HT mimetics, or of drugs that enhance the action of endogenous 5-HT into the same brain area has an antiaversive effect, like BZD and GABAA agonists. Furthermore, microinjection of midazolam, of the NMDA receptor antagonist AP-7, or of the 5-HT1A/1B receptor blocker propranolol increased the exploration of the open arms of the elevated plus-maze, having therefore an anxiolytic effect. These results point to an inhibitory role of the GABA-BZD system in both the AM and the PAG. In contrast, 5-HT seemingly enhances conditioned fear in the AM, while inhibiting unconditioned fear in the PAG. Thus, 5-HT2/1C antagonists reportedly release punished behavior when injected into the AM, whereas they antagonized the antiaversive effect of 5-HT, zimelidine and 5-HT1A/1B receptor blockers in the PAG. Since reported clinical studies revealed that one of such compounds, ritanserin, relieves generalized anxiety but tends to aggravate panic disorder, a relationship may be established between the AM and anxiety and the PAG and panic.

5-HT mediation of the antiaversive effect of isamoltane injected into the dorsal periaqueductal grey.

A previous study from this laboratory reported an antiaversive effect of the beta-adrenoceptor blocker propranolol microinjected into the dorsal periaqueductal grey (DPAG) of the rat, that was antagonized by the 5-HT(2) receptor blocker ritanserin. The present results show that microinjection into the DPAG of isamoltane (4-32nmol) a beta-blocking agent that binds to 5-HT(1B) receptors more selectively than propranolol, raised the threshold of aversive electrical stimulation of the rat DPAG in a dose-dependent manner. The antiaversive effect of 8nmol of isamoltane was antagonized by pretreatment with ritanserin (10nmol), as well as by the more selective 5-HT(2) receptor blocker ketanserin (10nmol). Therefore, the antiaversive effect of beta-adrenoceptor/5-HT(1B) receptor antagonists injected into the DPAG is likely to be mediated by endogenous 5-HT, through activation of 5-HT(2) receptors.