Ultrasound-Guided Botulinum Neurotoxin Injection for Alleviating Cricopharyngeus Muscle Spasticity: A Cadaveric Feasibility Study with Nerve Ending Analysis.

Botulinum neurotoxin (BNT) injection into the cricopharyngeus muscle (CPM) under ultrasound (US) guidance is a minimally invasive technique performed to relieve cricopharyngeal dysphagia by reducing CPM spasticity. This technique is basically accessible only to both lateral sides of the CPM. This cadaveric study aimed to evaluate whether US-guided injection could effectively deliver BNT to abundant areas of gross nerve endings within the CPM. We utilized a newly modified Sihler's staining method to identify regions with abundant neural endings within the CPM while preserving the three-dimensional morphology of the muscle in 10 sides of 5 fresh cadavers. A mixture of 0.2 mL dye was injected into the 16 sides of CPM under US guidance in 8 cadavers. Nerve endings were abundant in posterolateral areas of the CPM; the injected dye was identified at the posterolateral area on 12 sides (12/16 side, 75%) without diffusion into the posterior cricoarytenoid muscle. The injection failed on four sides (two sides of the prevertebral fascia and two sides of the esophagus below the CPM). These results suggest that US-guided injection could be a feasible technique as it can deliver BNT to the most abundant nerve distribution areas within the CPM in most cases.

Designer Receptors Exclusively Activated by Designer Drugs Approach to Treatment of Sleep-disordered Breathing.

Rationale: Obstructive sleep apnea is recurrent upper airway obstruction caused by a loss of upper airway muscle tone during sleep. The main goal of our study was to determine if designer receptors exclusively activated by designer drugs (DREADD) could be used to activate the genioglossus muscle as a potential novel treatment strategy for sleep apnea. We have previously shown that the prototypical DREADD ligand clozapine-N-oxide increased pharyngeal diameter in mice expressing DREADD in the hypoglossal nucleus. However, the need for direct brainstem viral injections and clozapine-N-oxide toxicity diminished translational potential of this approach, and breathing during sleep was not examined.Objectives: Here, we took advantage of our model of sleep-disordered breathing in diet-induced obese mice, retrograde properties of the adeno-associated virus serotype 9 (AAV9) viral vector, and the novel DREADD ligand J60.Methods: We administered AAV9-hSyn-hM3(Gq)-mCherry or control AAV9 into the genioglossus muscle of diet-induced obese mice and examined the effect of J60 on genioglossus activity, pharyngeal patency, and breathing during sleep.Measurements and Main Results: Compared with control, J60 increased genioglossus tonic activity by greater than sixfold and tongue uptake of 2-deoxy-2-[18F]fluoro-d-glucose by 1.5-fold. J60 increased pharyngeal patency and relieved upper airway obstruction during non-REM sleep.Conclusions: We conclude that following intralingual administration of AAV9-DREADD, J60 can activate the genioglossus muscle and improve pharyngeal patency and breathing during sleep.

Effect of Venlafaxine on Apnea-Hypopnea Index in Patients With Sleep Apnea: A Randomized, Double-Blind Crossover Study.

BACKGROUND: One of the key mechanisms underlying OSA is reduced pharyngeal muscle tone during sleep. Data suggest that pharmacologic augmentation of central serotonergic/adrenergic tone increases pharyngeal muscle tone. RESEARCH QUESTION: We hypothesized that venlafaxine, a serotonin-norepinephrine reuptake inhibitor, would improve OSA severity. STUDY DESIGN AND METHODS: In this mechanistic, randomized, double-blind, placebo-controlled crossover trial, 20 patients with OSA underwent two overnight polysomnograms ≥ 4 days apart, receiving either 50 mg of immediate-release venlafaxine or placebo before bedtime. Primary outcomes were the apnea-hypopnea index (AHI) and peripheral oxygen saturation (Spo2) nadir, and secondary outcomes included sleep parameters and pathophysiologic traits with a view toward understanding the impact of venlafaxine on mechanisms underlying OSA. RESULTS: Overall, there was no significant difference between venlafaxine and placebo regarding AHI (mean reduction, -5.6 events/h [95% CI, -12.0 to 0.9]; P = .09) or Spo2 nadir (median increase, +1.0% [-0.5 to 5]; P = .11). Venlafaxine reduced total sleep time, sleep efficiency, and rapid eye movement (REM) sleep, while increasing non-REM stage 1 sleep (Pall < .05). On the basis of exploratory post hoc analyses venlafaxine decreased ("improved") the ventilatory response to arousal (-30%; P = .049) and lowered ("worsened") the predicted arousal threshold (-13%; [P = .02]; ie, more arousable), with no effects on other pathophysiologic traits (Pall ≥ .3). Post hoc analyses further suggested effect modification by arousal threshold (P = .002): AHI improved by 19% in patients with a high arousal threshold (-10.9 events/h [-3.9 to -17.9]) but tended to increase in patients with a low arousal threshold (+7 events/h [-2.0 to 16]). Other predictors of response were elevated AHI and less collapsible upper airway anatomy at baseline (|r| > 0.5, P ≤ .02). INTERPRETATION: In unselected patients, venlafaxine simultaneously worsened and improved various pathophysiologic traits, resulting in a zero net effect. Careful patient selection based on pathophysiologic traits, or combination therapy with drugs countering its alerting effects, may produce a more robust response. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02714400; URL: www.clinicaltrials.gov.

Cricopharyngeal achalasia associated with laryngomalacia as a cause of failure to thrive.

OBJECTIVE: To describe a case of concurrent cricopharyngeal achalasia with laryngomalacia as a cause of failure to thrive, and to review the literature and management options of cricopharyngeal achalasia in the paediatric population. METHODS: A chart review was performed on a four-month-old male, referred for failure to thrive, and diagnosed with cricopharyngeal achalasia and laryngomalacia. A PubMed and Embase search for 'cricopharyngeal achalasia' and 'laryngomalacia' was conducted. A review of reported paediatric cricopharyngeal achalasia patients, with emphasis on management options, was undertaken. RESULTS: A flexible laryngoscopic examination confirmed the laryngomalacia diagnosis, and videofluoroscopic evaluation of swallowing demonstrated cricopharyngeal achalasia via a cricopharyngeal bar. Supraglottoplasty was performed, with botulinum toxin injection into the cricopharyngeus muscle, with resultant improvement in oral intake and resolution of failure to thrive. The literature review revealed no reported case of the combined pathologies as a cause of failure to thrive. CONCLUSION: Functional endoscopic evaluation of swallowing and videofluoroscopic evaluation of swallowing are complimentary in the evaluation of paediatric patients with failure to thrive and suspected oropharyngeal dysphagia. Both supraglottoplasty and botulinum toxin injection are effective for definitive management in cases of combined pathology, and can be safely performed in a single surgical setting.

Pharyngeal Dystonia Mimicking Spasmodic Dysphonia.

OBJECTIVE: The aim of this study was to describe the presentation of pharyngeal dystonia (PD), which can occur as a focal or segmental dystonia with a primarily pharyngeal involvement for the discussion of treatment methods for controlling consequent symptoms. PD is specific to speech-related tasks. METHODS: A retrospective medical record review of four patients with PD was performed. RESULTS: All patients were initially misdiagnosed with adductor spasmodic dysphonia and failed standard treatment with botulinum toxin type A (BTX). On laryngoscopy, the patients were discovered to have segmental or focal dystonia primarily affecting the pharyngeal musculature contributing to their vocal manifestations. A novel treatment regimen was designed, which involved directing BTX injections into the muscles involved in spasmodic valving at the oropharyngeal level. After titrating to an optimal dose, all patients showed improvement in their voice and speech with only mild dysphagia. These patients have maintained favorable results with repeat injections at 6- to 12-week intervals. CONCLUSIONS: PD, or dystonia with predominant pharyngeal involvement, is a rare entity with vocal manifestations that are not well described. It can be easily mistaken for spasmodic dysphonia. PD is specific to speech-related tasks. A novel method of BTX injections into the involved muscles results in a significant improvement in voice without significant dysphagia.

Botulinum toxin alleviates dysphagia of patients with inclusion body myositis.

OBJECTIVES: Oropharyngeal dysphagia is a disabling and undertreated symptom that often occurs in patients with sporadic inclusion body myositis (s-IBM). In this study, we examined the effect of botulinum neurotoxin A (BoNT-A) injections to the cricopharyngeus muscle (CPM) of patients with s-IBM and dysphagia. PATIENTS, MATERIALS AND METHODS: A single-center retrospective study involving 40 biopsy-proven s-IBM-patients treated in the District of Southwest Finland from 2000 to 2013. The incidence of dysphagia, rate of aspirations, rate of aspiration pneumonias and treatment results of dysphagia were analyzed. Patients treated for dysphagia were evaluated before and after surgery by video-fluoroscopy and/or using a questionnaire. RESULTS: Twenty-five of the 40 s-IBM patients (62.5%) experienced dysphagia. BoNT-A was injected a median of 2 times (range 1-7) in 12 patients with dysphagia. Before the injections 7 patients reported aspiration, none afterwards. The corresponding figures for aspiration pneumonia were 3 and 0. All of these patients had normal swallowing function 12months (median, range 2-60) after the last injection. CONCLUSION: BoNT-A injections to the CPM alleviate the dysphagia of s-IBM patients reversibly and appear to reduce the rate of aspiration effectively.

Restoration of pharyngeal dilator muscle force in dystrophin-deficient (mdx) mice following co-treatment with neutralizing interleukin-6 receptor antibodies and urocortin 2.

NEW FINDINGS: What is the central question of this study? We previously reported impaired upper airway dilator muscle function in the mdx mouse model of Duchenne muscular dystrophy (DMD). Our aim was to assess the effect of blocking interleukin-6 receptor signalling and stimulating corticotrophin-releasing factor receptor 2 signalling on mdx sternohyoid muscle structure and function. What is the main finding and its importance? The interventional treatment had a positive inotropic effect on sternohyoid muscle force, restoring mechanical work and power to wild-type values, reduced myofibre central nucleation and preserved the myosin heavy chain type IIb fibre complement of mdx sternohyoid muscle. These data might have implications for development of pharmacotherapies for DMD with relevance to respiratory muscle performance. The mdx mouse model of Duchenne muscular dystrophy shows evidence of impaired pharyngeal dilator muscle function. We hypothesized that inflammatory and stress-related factors are implicated in airway dilator muscle dysfunction. Six-week-old mdx (n = 26) and wild-type (WT; n = 26) mice received either saline (0.9% w/v) or a co-administration of neutralizing interleukin-6 receptor antibodies (0.2 mg kg-1 ) and corticotrophin-releasing factor receptor 2 agonist (urocortin 2; 30 µg kg-1 ) over 2 weeks. Sternohyoid muscle isometric and isotonic contractile function was examined ex vivo. Muscle fibre centronucleation and muscle cellular infiltration, collagen content, fibre-type distribution and fibre cross-sectional area were determined by histology and immunofluorescence. Muscle chemokine content was examined by use of a multiplex assay. Sternohyoid peak specific force at 100 Hz was significantly reduced in mdx compared with WT. Drug treatment completely restored force in mdx sternohyoid to WT levels. The percentage of centrally nucleated muscle fibres was significantly increased in mdx, and this was partly ameliorated after drug treatment. The areal density of infiltrates and collagen content were significantly increased in mdx sternohyoid; both indices were unaffected by drug treatment. The abundance of myosin heavy chain type IIb fibres was significantly decreased in mdx sternohyoid; drug treatment preserved myosin heavy chain type IIb complement in mdx muscle. The chemokines macrophage inflammatory protein 2, interferon-γ-induced protein 10 and macrophage inflammatory protein 3α were significantly increased in mdx sternohyoid compared with WT. Drug treatment significantly increased chemokine expression in mdx but not WT sternohyoid. Recovery of contractile function was impressive in our study, with implications for Duchenne muscular dystrophy. The precise molecular mechanisms by which the drug treatment exerts an inotropic effect on mdx sternohyoid muscle remain to be elucidated.

Hox-mediated endodermal identity patterns pharyngeal muscle formation in the chordate pharynx.

The chordate pharynx, possessing gill slits and the endostyle, is a complex of multiple tissues that are highly organized along the anterior-posterior (AP) axis. Although Hox genes show AP coordinated expression in the pharyngeal endoderm, tissue-specific roles of these factors for establishing the regional identities within this tissue have not been demonstrated. Here, we show that Hox1 is essential for the establishment of AP axial identity of the endostyle, a major structure of the pharyngeal endoderm, in the ascidian Ciona intestinalis We found that knockout of Hox1 causes posterior-to-anterior transformation of the endostyle identity, and that Hox1 represses Otx expression and anterior identity, and vice versa. Furthermore, alteration of the regional identity of the endostyle disrupts the formation of body wall muscles, suggesting that the endodermal axial identity is essential for coordinated pharyngeal development. Our results demonstrate an essential role of Hox genes in establishment of the AP regional identity in the pharyngeal endoderm and reveal crosstalk between endoderm and mesoderm during development of chordate pharynx.

Desipramine Increases Genioglossus Activity and Reduces Upper Airway Collapsibility during Non-REM Sleep in Healthy Subjects.

RATIONALE: Obstructive sleep apnea is a state-dependent disease. One of the key factors that triggers upper airway collapse is decreased pharyngeal dilator muscle activity during sleep. To date, there have not been effective methods to reverse pharyngeal hypotonia pharmacologically in sleeping humans. OBJECTIVES: We tested the hypothesis that administration of desipramine 200 mg prevents the state-related reduction in genioglossus activity that occurs during sleep and thereby decreases pharyngeal collapsibility. METHODS: We conducted a placebo-controlled, double-blind, crossover trial with 10 healthy participants. Participants received active treatment or placebo in randomized order 2 hours before sleep in the physiology laboratory. MEASUREMENTS AND MAIN RESULTS: Genioglossus activity during wakefulness and sleep, genioglossus muscle responsiveness to negative epiglottic pressure, and upper airway collapsibility during passive and active conditions were compared between on- and off-drug states. Desipramine abolished the normal reduction of genioglossus activity from wakefulness to non-REM sleep that occurred on the placebo night. Specifically, tonic (median, 96% [86-120] vs. 75% [50-92] wakefulness; P = 0.01) but not phasic genioglossus activity was higher with desipramine compared with placebo. Upper airway collapsibility was also reduced with desipramine compared with placebo (-10.0 cm H2O [-15.2 to -5.8] vs. -8.1 cm H2O [-10.4 to -6.3]; P = 0.037). CONCLUSIONS: Desipramine reduces the state-related drop in tonic genioglossus muscle activity that occurs from wakefulness to non-REM sleep and reduces airway collapsibility. These data provide a rationale for a new pharmacologic therapy for obstructive sleep apnea. Clinical trial registered with www.clinicaltrials.gov (NCT02428478).

The ß2 -adrenoceptor agonist terbutaline recovers rat pharyngeal dilator muscle force decline during severe hypoxia.

RATIONALE: Obstructive sleep apnoea syndrome (OSAS) is a debilitating condition characterized by recurrent occlusions of the pharyngeal airway during sleep accompanied by arterial hypoxaemia. Upper airway muscle dysfunction is implicated in the pathophysiology of OSAS. Pharmacological agents that improve muscle contractile and endurance properties may have therapeutic value. AIM: We tested the hypothesis that the ß(2) -adrenoceptor agonist terbutaline improves rat sternohyoid muscle performance especially during hypoxic stress. METHODS: Isometric contractile and endurance properties were examined ex vivo in Krebs solution at 35°C. Muscles were incubated in tissue baths under hyperoxic (95% O(2) /5% CO(2)) conditions in the absence (control) or presence of the ß(2) -adrenoceptor agonist terbutaline (1 µM). In additional experiments under hypoxic (95% N(2) /5% CO(2)) conditions, the effects of terbutaline were examined in the presence of the ß-adrenoceptor antagonist propranolol (1 µM). RESULTS: Hypoxia significantly impaired sternohyoid force production. Terbutaline completely recovered hypoxic depression of force, an effect that was blocked by co-application with propranolol. CONCLUSION: The ß(2) -adrenoceptor agonist terbutaline completely recovers hypoxic depression of upper airway muscle force. ß(2) -adrenoceptor agonists warrant investigation in animal models of OSAS reporting upper airway and diaphragm muscle dysfunction.

The response to high CO2 levels requires the neuropeptide secretion component HID-1 to promote pumping inhibition.

Carbon dioxide (CO2) is a key molecule in many biological processes; however, mechanisms by which organisms sense and respond to high CO2 levels remain largely unknown. Here we report that acute CO2 exposure leads to a rapid cessation in the contraction of the pharynx muscles in Caenorhabditis elegans. To uncover the molecular mechanisms underlying this response, we performed a forward genetic screen and found that hid-1, a key component in neuropeptide signaling, regulates this inhibition in muscle contraction. Surprisingly, we found that this hid-1-mediated pathway is independent of any previously known pathways controlling CO2 avoidance and oxygen sensing. In addition, animals with mutations in unc-31 and egl-21 (neuropeptide secretion and maturation components) show impaired inhibition of muscle contraction following acute exposure to high CO2 levels, in further support of our findings. Interestingly, the observed response in the pharynx muscle requires the BAG neurons, which also mediate CO2 avoidance. This novel hid-1-mediated pathway sheds new light on the physiological effects of high CO2 levels on animals at the organism-wide level.

Influence of pharyngeal muscle activity on inspiratory negative effort dependence in the human upper airway.

The upper airway is often modeled as a Starling resistor, which predicts that flow is independent of inspiratory effort during flow limitation. However, while some obstructive sleep apnea (OSA) patients exhibit flat, Starling resistor-like flow limitation, others demonstrate considerable negative effort dependence (NED), defined as the percent reduction in flow from peak to mid-inspiration. We hypothesized that the variability in NED could be due to differences in phasic pharyngeal muscle activation between individuals. Therefore, we induced topical pharyngeal anesthesia to reduce phasic pharyngeal muscle activation to see if it increased NED. Twelve subjects aged 50±10 years with a BMI of 35±6 kg/m(2) and severe OSA (apnea-hypopnea index=52±28 events/h) were studied. NED and phasic genioglossus muscle activity (EMG(GG)) of flow limited breaths were determined before and after pharyngeal anesthesia with lidocaine. Pharyngeal anesthesia led to a 33% reduction in EMG(GG) activity (p<0.001), but NED worsened only by 3.6±5.8% (p=0.056). In conclusion, phasic EMG(GG) had little effect on NED. This finding suggests that individual differences in phasic EMG(GG) activation do not likely explain the variability in NED found among OSA patients.

Transient receptor potential melastatin (TRPM) channels mediate clozapine-induced phenotypes in Caenorhabditis elegans.

The molecular mechanisms of action of antipsychotic drugs (APDs) are not fully understood. Here, we characterize phenotypes of missense and knockout mutations in the Caenorhabditis elegans transient receptor potential melastatin (TRPM) channel ortholog gtl-2, a candidate APD target identified in a genome-wide RNAi (RNA interference) screen for Suppressors of Clozapine-induced Larval Arrest (scla genes). We then employ the developmental phenotypes of gtl-2(lf) mutants to validate our previous gtl-2(RNAi) result. GTL-2 acts in the excretory canal cell to regulate Mg(2+) homeostasis. Using exc (excretory canal abnormal) gene mutants, we demonstrate that excretory canal cell function is necessary for clozapine-induced developmental delay and lethality. Moreover, cell-specific promoter-driven expression studies reveal that GTL-2 function in the excretory canal cell is important for its role in the SCLA phenotype. We then investigate the mechanism by which GTL-2 function in the excretory canal cell impacts clozapine-induced phenotypes. gtl-2(lf) mutations cause hypermagnesemia, and we show that exposure of the wild-type strain to high Mg(2+) phenocopies gtl-2(lf) with respect to suppression of clozapine-induced developmental delay and lethality. Our results suggest that GTL-2 TRPM channel function in the excretory canal cell is important for clozapine's developmental effects. TRP channels are expressed in mammalian brain and are implicated in the pathogenesis of mental illnesses but have not been previously implicated in APD action.

Methods for studying the mechanisms of action of antipsychotic drugs in Caenorhabditis elegans.

Caenorhabditis elegans is a simple genetic organism amenable to large-scale forward and reverse genetic screens and chemical genetic screens. The C. elegans genome includes potential antipsychotic drug (APD) targets conserved in humans, including genes encoding proteins required for neurotransmitter synthesis and for synaptic structure and function. APD exposure produces developmental delay and/or lethality in nematodes in a concentration-dependent manner. These phenotypes are caused, in part, by APD-induced inhibition of pharyngeal pumping(1,2). Thus, the developmental phenotype has a neuromuscular basis, making it useful for pharmacogenetic studies of neuroleptics. Here we demonstrate detailed procedures for testing APD effects on nematode development and pharyngeal pumping. For the developmental assay, synchronized embryos are placed on nematode growth medium (NGM) plates containing APDs, and the stages of developing animals are then scored daily. For the pharyngeal pumping rate assay, staged young adult animals are tested on NGM plates containing APDs. The number of pharyngeal pumps per unit time is recorded, and the pumping rate is calculated. These assays can be used for studying many other types of small molecules or even large molecules.

Identification of a pharmacological target for genioglossus reactivation throughout sleep.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a significant public health problem caused by repeated episodes of upper airway closure that occur only during sleep. Attempts to treat OSA pharmacologically have been unsuccessful because there has not been identification of a target operating at cranial motor nuclei, blockade of which can reactivate pharyngeal muscle activity throughout sleep. Increasing potassium conductance is a common mechanism by which state-dependent neuromodulators reduce motoneuron excitability. Therefore, we aimed to determine if potassium channel blockade is an effective strategy to reactivate the pharyngeal musculature throughout sleep. DESIGN PARTICIPANTS AND INTERVENTIONS: In rats chronically instrumented for recording sleep-wake states and respiratory motor activities, we locally microperfused pharmacological agents into the hypoglossal motor pool to modulate potassium channels of three major classes: inwardly rectifying, two-pore domain, and voltage-gated. MEASUREMENTS AND RESULTS: Microperfusion of the inwardly rectifying potassium channel blocker, barium, as well as the voltage-gated potassium channel blockers, tetraethylammonium and 4-aminopyridine, increased tonic and respiratory-related genioglossus activities throughout nonrapid eye movement (non-REM) and rapid eye movement (REM) sleep to 133-300% of levels present during baseline wakefulness. In contrast, microperfusion of methanandamide (TWIK-related acid-sensitive potassium [TASK] channel blocker/cannabinoid receptor agonist) activated genioglossus in wakefulness but not in sleep. CONCLUSIONS: These findings establish proof-of-principle that targeted blockade of certain potassium channels at the hypoglossal motor pool is an effective strategy for reversing upper airway hypotonia and causing sustained reactivation of genioglossus throughout nonrapid eye movement and rapid eye movement sleep. These findings identify an important new direction for translational approaches to the pharmacological treatment of obstructive sleep apnea.

Effects of pharyngeal water stimulation on swallowing behaviors in healthy humans.

The aims of the present study were to determine whether the interval between swallows and the electromyographic (EMG) burst patterns of the suprahyoid muscles is affected by peripheral inputs during swallowing. Eighteen normal adults were asked to perform repetitive voluntary swallowing as quickly as possible, and three variables of swallowing were measured and evaluated, i.e., the swallowing intervals and the time interval between the onset and peak (rising time) and between the peak and offset (falling time) of the suprahyoid EMG burst. During recording, pharyngeal fluid infusion was applied with distilled water or 0.3 M NaCl solution at a very slow infusion rate (0.2 mL/min). The former and latter were used to activate and inhibit the excitation of water-sensitive receptors in the pharynx, respectively. The swallowing interval was significantly shorter during infusion of water than during infusion of NaCl solution. The rising time was also significantly shorter during infusion of water than during infusion of NaCl solution. There was a linear positive correlation between these values and facilitatory effects: the longer either the swallowing interval or rising time with infusion of 0.3 M NaCl solution, the stronger the facilitation of swallowing by the activation of water receptors. Facilitatory effects on the swallowing interval and rising time showed a linear correlation. It is suggested that weak liquid stimulation changed sensory inputs into the swallowing center and synchronously modulated the swallowing interval and time interval between the onset and peak of the EMG burst.

Phasic genioglossus and palatoglossus muscle activity during recovery from sevoflurane anesthesia: a prospective observational study in children.

BACKGROUND: Inhalational anesthetic effects on upper airway muscle activity in children are largely unknown. The authors tested the hypothesis that phasic inspiratory genioglossus and palatoglossus activity increases during recovery from sevoflurane anesthesia in a dose-dependent manner in children. METHODS: Sixteen children, aged 2.0 to 6.9 yr, scheduled for elective urological surgery were studied. Electromyogram recordings were acquired using intramuscular needle electrodes during spontaneous ventilation. After a 15-min period of equilibration, electromyogram activity was recorded over 30 s at each of three end-tidal concentrations, 1.5, 1.0, and 0.5 minimum alveolar concentration (MAC), administered in sequence. RESULTS: Phasic genioglossus activity was noted in four children at 1.5 MAC, five at 1.0 MAC, and six children at 0.5 MAC sevoflurane. Phasic palatoglossus activity was noted in 4 children at 1.5 MAC, 6 at 1.0 MAC, and 10 children at 0.5 MAC sevoflurane. Both the proportion of children exhibiting phasic activity, and the magnitude of phasic activity increased during recovery from anesthesia. For the genioglossus, decreasing the depth of sevoflurane anesthesia from 1.5 to 1.0 MAC increased phasic activity by approximately 35% and a further decrease to 0.5 MAC more than doubled activity (median [range] at 1.5 and 0.5 MAC: 2.7 µV [0 to 4.0 µV] and 8.6 µV [3.2 to 17.6], respectively; P = 0.029). A similar dose-related increase was recorded at the palatoglossus (P = 0.0002). CONCLUSIONS: Genioglossus and palatoglossus activity increases during recovery from sevoflurane anesthesia in a dose-dependent manner over the clinical range of sevoflurane concentrations in children.

Derquantel and abamectin: effects and interactions on isolated tissues of Ascaris suum.

Startect(®) is a novel anthelmintic combination of derquantel and abamectin. It is hypothesized that derquantel and abamectin interact pharmacologically. We investigated the effects of derquantel, abamectin and their combination on somatic muscle nicotinic acetylcholine receptors and pharyngeal muscle glutamate gated chloride receptor channels of Ascaris suum. We used muscle-strips to test the effects of abamectin, derquantel, and abamectin+derquantel together on the contraction responses to different concentrations of acetylcholine. We found that abamectin reduced the response to acetylcholine, as did derquantel. In combination (abamectin+derquantel), inhibition of the higher acetylcholine concentration response was greater than the predicted additive effect. A two-micropipette current-clamp technique was used to study electrophysiological effects of the anthelmintics on: (1) acetylcholine responses in somatic muscle and; (2) on l-glutamate responses in pharyngeal preparations. On somatic muscle, derquantel (0.1-30µM) produced a potent (IC50 0.22, CI 0.18-0.28µM) reversible antagonism of acetylcholine depolarizations. Abamectin (0.3µM) produced a slow onset inhibition of acetylcholine depolarizations. We compared effects of abamectin and derquantel on muscle preparations pretreated for 30min with these drugs. The effect of the combination was significantly greater than the predicted additive effect of both drugs at higher acetylcholine concentrations. On the pharynx, application of derquantel produced no significant effect by itself or on responses to abamectin and l-glutamate. Abamectin increased the input conductance of the pharynx (EC50 0.42, CI 0.13-1.36µM). Our study demonstrates that abamectin and derquantel interact at nicotinic acetylcholine receptors on the somatic muscle and suggested synergism can occur.

ALS dysphagia pathophysiology: differential botulinum toxin response.

OBJECTIVES: This study looked at the effect of botulinum toxin type A (BoTox-A) in patients with amyotrophic lateral sclerosis (ALS) with dysphagia due to isolated upper motor neuron (UMN) involvement or combined UMN/lower motor neuron (LMN) impairment associated with oral phase or oropharyngeal muscles involvement. Establishing whether different pathophysiologic mechanisms underlie different responses to BoTox-A treatment may have important implications for patient management. PATIENTS AND METHODS: We screened 35 patients with sporadic ALS with dysphagia and included in the study 20 out of 35 with upper esophageal sphincter (UES) hyperactivity. We divided these 20 patients into 2 groups, based on the presence or absence of LMN impairment. Irrespective of the groups, we treated all 20 patients with BoTox-A injected into the UES. The study outcome was dysphagia severity scored using the Penetration/Aspiration Scale (PAS), measured before and 2, 4, and 20 weeks after injection. RESULTS: Significant mean PAS reduction was noted at weeks 2 and 4. The botulinum-dependent PAS reduction was entirely associated with the variability shown by the group of patients with no sign of LMN impairment (group 2) and was not observed in group 1. CONCLUSIONS: The significant improvement observed in patients with isolated UES dysfunction suggests that a different pathophysiology of ALS dysphagia predisposes patients to a different response to treatment with BoTox-A. This treatment may represent an alternative treatment to percutaneous endoscopic gastrostomy (PEG) or prolong PEG-free time. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that botulinum is more effective at 2 and 4 weeks in improving dysphagia in patients with ALS with UES hyperactivity without LMN involvement (vs those with LMN involvement).