TRPM8, ASIC1, and ASIC3 localization and expression in the human oropharynx.

BACKGROUND: Oropharyngeal dysphagia (OD) is a prevalent disease with poor prognosis among older people and has no pharmacological treatment. Polymodal sensory receptors like the TRP or ASIC family receptors are potential targets to treat OD. TRPM8 agonists and acidic solutions can improve the swallow response in patients with OD, but little is known about the expression of TRPM8, ASIC1, and ASIC3 in the human oropharynx. The aim of this study was to assess the expression and localization of TRPM8, ASIC1, and ASIC3 in human samples of the oropharynx to lay the basis for new pharmacological treatments for OD. METHODS: Pathology-free samples from oropharyngeal regions innervated by cranial nerves V, IX, and X were obtained during major ENT surgery and processed to obtain mRNA (20 patients) or to be used in immunohistochemical assays (12 patients). TRPM8, ASIC1, and ASIC3 expression and localization were studied with RT-qPCR and fluorescent immunohistochemistry. KEY RESULTS: ASIC3 was expressed in the 3 regions studied with similar levels and was localized on sensory fibers innervating the mucosa below the basal lamina of all studied regions. TRPM8 was also co-localized on the sensory fibers innervating the mucosa below the basal lamina of all studied regions. In contrast, ASIC1 was only found in the nerves innervating the tongue muscular fibers. CONCLUSIONS & INFERENCES: TRPM8 and ASIC3 are found on submucosal sensory nerves in the human oropharynx. Our study lays the basis to use oropharyngeal TRPM8 and ASIC3 receptors as therapeutic targets to develop new active pharmacological treatments for OD patients.

Increased levels of substance P in patients taking beta-blockers are linked with a protective effect on oropharyngeal dysphagia.

BACKGROUND: We have recently found a potential protective effect of beta-blockers on oropharyngeal dysphagia (OD). The action mechanism by which beta-blockers could wield this protective effect is unknown, but the neurotransmitter substance P (SP) could play a key role. The aim of this study was to analyze serum and saliva SP levels in patients taking beta-blockers (TBB), and to explore its relationship with OD. METHODS: Adult (>50 year) patients TBB were randomly recruited from the primary care setting and 1:1 matched by age, sex, and Barthel Index (BI) with patients not taking beta-blockers (NTBB). Serum and saliva samples were taken and analyzed for their SP levels using an enzyme-linked immunosorbent assay (ELISA). Socio-demographic and clinical variables were collected. Dysphagia was evaluated in all patients using the clinical volume-viscosity swallow test (V-VST). KEY RESULTS: We studied 28 patients TBB (64.96 ± 7.31 years, 57.1% women, BI 99.6 ± 1.31, carvedilol-equivalent dose 24.11 ± 18.12 mg) and 28 patients NTBB (65.61 ± 6.43 years, 57.1% women, BI 99.6 ± 1.31). SP serum levels were significantly higher in patients TBB (260.68 ± 144.27 vs 175.46 ± 108.36 pg/mL, P = .009) as were SP saliva levels (170.34 ± 146.48 vs 102.73 ± 52.28 pg/mL, P < .001) compared with patients NTBB. The prevalence of OD was 32.1% in patients TBB and 67.9% in patients NTBB (P = .015). Moreover, patients with OD had significantly lower SP saliva levels in comparison with patients without clinical signs of OD (98.39 ± 43.25 vs 174.69 ± 147.21 pg/mL) P < .001. CONCLUSIONS & INFERENCES: We have found that serum and saliva SP levels are greater in patients TBB. This increase in SP levels could be the action mechanism by which beta-blockers protect patients from OD.

Prevalence, risk factors and complications of oropharyngeal dysphagia in stroke patients: A cohort study.

BACKGROUND: Oropharyngeal dysphagia (OD) is a prevalent poststroke condition with severe complications and increased mortality. Poststroke OD prevalence varies among studies and there is little evidence of its related risk factors and associated complications. OBJECTIVE: to evaluate the prevalence of OD after stroke and the risk factors and associated complications. METHODS: We performed a prospective longitudinal study of stroke patients consecutively admitted to a general hospital. OD was diagnosed with the volume-viscosity swallow test (V-VST). Demographic, functional status and topographical and clinical variables of stroke were collected to assess risk factors for OD. We evaluated functional status, mortality, respiratory infections, and readmissions 3 and 12 months after stroke. A multivariate regression analysis determined associated risk factors for OD and for each outcome variable. KEY RESULTS: We included 395 stroke patients with a 45.06% prevalence of OD on admission. OD was independently associated with age (OR = 1.05; CI = 1.02-1.08), previous stroke (OR = 2.40; CI = 1.00-5.79), severity using the National Institute of Health Stroke Scale (OR = 3.52; CI = 1.57-7.87) and volume of the lesion (OR = 1.02; CI = 1.01-1.03). OD after stroke was an independent risk factor for prolonged hospital stay (P = .049; ß = 0.938) and institutionalization after discharge (OR = 0.47; CI = 0.24-0.92); OD was an independent risk factor for poorer functional capacity (OR = 3.00; CI = 1.58-5.68) and increased mortality (HR = 6.90; CI = 1.57-30.34) 3 months after stroke. CONCLUSIONS & INFERENCES: Poststroke OD is prevalent and associated with poor short and long term prognosis. Stroke severity and patient status before stroke were more relevant to OD than lesion location. Systematic screening programs and early OD management could significantly improve poststroke patient outcome.

A comparative study on the therapeutic effect of TRPV1, TRPA1, and TRPM8 agonists on swallowing dysfunction associated with aging and neurological diseases.

BACKGROUND: Oropharyngeal sensory impairment is a potential target to treat swallowing dysfunction in patients with oropharyngeal dysphagia (OD). AIM: To assess the therapeutic effect of stimulating oropharyngeal sensory afferents with TRPV1, TRPA1, or TRPM8 agonists vs increasing bolus viscosity in older and neurologic patients with OD by comparing four studies of similar experimental design. METHODS: Swallow function of 142 older patients with impaired safety of swallow at nectar ([50-350] mPa·s) viscosity was evaluated with videofluoroscopy (VFS) while treated with TRPV1 (150 µmol/L), TRPV1/A1 (150 µmol/L and 1 mmol/L), or TRPM8 (1 mmol/L or 10 mmol/L) agonists or modified starch (MS) at spoon thick viscosity (>1750 mPa·s). RESULTS: TRPV1 stimulation with capsaicinoids reduced penetrations by 50%, pharyngeal residue by 80%, and LVC time by 24.38% and increased bolus velocity by 36.51%. TRPV1/A1 stimulation with piperine reduced penetrations by 56.32%, LVC time by 25.55% and increased bolus velocity by 23.63%. TRPM8 stimulation with menthol 1 mmol/L reduced penetrations by 37.5% while 10 mmol/L reduced LVC time by 18.44%. Thickeners reduced penetrations by 77.11%, but increased pharyngeal residue by 19.89%, delayed LVC by 41.73%, and reduced bolus velocity by 13.44%. CONCLUSION: Natural capsaicinoids have a stronger therapeutic effect on VFS signs and swallow response by stimulating TRPV1 than TRPV1/A1 or TRPM8 agonists. While TRP stimulants increased bolus velocity and reduced swallow response times, thickeners reduced bolus velocity and further delayed the swallow response. This study sets the bases to develop new pharmacologic strategies for older patients with OD, moving away from compensation toward the recovery of swallow function.

Chronic post-stroke oropharyngeal dysphagia is associated with impaired cortical activation to pharyngeal sensory inputs.

BACKGROUND AND PURPOSE: The role of afferent sensory pathways in the pathophysiology of post-stroke oropharyngeal dysphagia is not known. We hypothesized that patients with chronic post-stroke dysphagia (PSD) would show impaired sensory cortical activation in the ipsilesional hemisphere. METHODS: We studied 28 chronic unilateral post-stroke patients [17 PSD and 11 post-stroke non-dysphagic patients (PSnD)] and 11 age-matched healthy volunteers. Event-related sensory-evoked potentials to pharyngeal stimulation (pSEP) and sensory thresholds were assessed. We analyzed pSEP peak latency and amplitude (N1, P1, N2 and P2), and neurotopographic stroke characteristics from brain magnetic resonance imaging. RESULTS: Healthy volunteers presented a highly symmetric bihemispheric cortical pattern of brain activation at centroparietal areas (N1-P1 and N2-P2) to pharyngeal stimuli. In contrast, an asymmetric pattern of reduced ipsilesional activation was found in PSD (N2-P2; P = 0.026) but not in PSnD. PSD presented impaired safety of swallow (penetration-aspiration score: 4.3 ± 1.6), delayed laryngeal vestibule closure (360.0 ± 70.0 ms) and higher National Institute of Health Stroke Scale (7.0 ± 6.2 vs. 1.9 ± 1.4, P = 0.001) and Fazekas scores (3.0 ± 1.4 vs. 2.0 ± 1.1; P < 0.05) than PSnD. pSEP showed a unilateral delay at stroke site exclusively for PSD (peak-latency interhemispheric difference vs. PSnD: N1, 6.5 ± 6.7 vs. 1.1 ± 1.0 ms; N2, 32.0 ± 15.8 vs. 4.5 ± 4.9 ms; P < 0.05). CONCLUSIONS: Chronic post-stroke oropharyngeal dysphagia is associated with stroke severity and degree of leukoaraoisis. Impaired conduction and cortical integration of pharyngeal sensory inputs at stroke site are key features of chronic PSD. These findings highlight the role of sensory pathways in the pathophysiology of post-stroke oropharyngeal dysphagia and offer a potential target for future treatments.

Videofluoroscopic assessment of the pathophysiology of chronic poststroke oropharyngeal dysphagia.

BACKGROUND AND PURPOSE: Oropharyngeal dysphagia (OD) is a major complaint following stroke, associated with poor clinical outcome and high mortality rates. We aimed at characterizing the kinematics of swallow response associated with unsafe swallowing in chronic poststroke patients with OD. PATIENTS AND METHODS: Consecutive poststroke patients with a positive volume-viscosity swallow test for OD 3 months following stroke were studied by videofluoroscopy (VFS). Demographical and clinical factors and kinematics of swallow response were compared between those poststroke patients with safe swallow (penetration-aspiration scale, PAS≤2) and those with unsafe swallow (PAS≥3). Receiver operating characteristic (ROC) curves were drawn for laryngeal vestibule closure (LVC) time which predicts unsafe swallow. RESULTS: We studied 73 poststroke patients (76.7±9.3 years, 53.4% male) by VFS (60.4% with impaired safety, PAS=4.47±1.44, and 95.9% with impaired efficacy of swallow). Poststroke patients with unsafe swallow presented a poorer functional (Rankin 2.2±1.6 vs 1.2±1.0, P<.012) and nutritional status (MNA-sf≤11, 34.2% vs 7.4%, P<.05) than poststroke patients with safe swallow. Poststroke patients with unsafe swallow presented a significant delay in LVC time (406.4±99.5 ms vs 318.9±80.4 ms; P<.05) and weaker tongue bolus propulsion forces (0.771±0.450 mJ vs 1.638±3.212 mJ; P=.043). LVC time ≥340 ms predicts unsafe swallow in chronic poststroke patients with a diagnostic accuracy of 0.78. CONCLUSIONS: Impaired safety of swallow in chronic poststroke patients is caused by specific impairments in swallow response including delayed timing of airway protection mechanisms and weak tongue propulsion forces. Treatments aiming to restore swallowing function in poststroke patients with OD should be targeted to improve these critical biomechanical events.

Cough reflex attenuation and swallowing dysfunction in sub-acute post-stroke patients: prevalence, risk factors, and clinical outcome.

BACKGROUND: Cough and swallowing impairments in post-stroke patients (PSP) have been associated with increased risk for respiratory complications. AIMS: To assess the prevalence of alterations in protective cough responses in subacute PSP and its association with oropharyngeal dysphagia (OD), clinical, and neurotopographic stroke factors and clinical outcomes. METHODS: Three months after stroke, the cough reflex test (CRT) was performed by nebulizing incremental citric acid concentrations (7.8-1000 mmol L-1 ) to determine the concentration that elicited two and five coughs; OD was assessed by the volume-viscosity swallow test. Clinical and neurotopographic stroke risk factors and complications (readmissions, respiratory infections, institutionalization, and mortality) were recorded from 3 to 12 months post-stroke. RESULTS: We included 225 PSP. Prevalence of impaired CRT was 5.8%, that of OD was 40.4% (20.4% with impaired safety of swallow), and of both impairments was, 1.8%. No specific risk factors associated with impaired CRT were found; however, hemorrhagic, wide circulation infarction (TACI), and brainstem strokes delayed the cough response. OD was associated with age, TACI and poor functional and nutritional status. Outcome of PSPs was unaffected by impaired CRT but OD and impaired safety of swallow increased institutionalization, respiratory infections, and mortality with the poorest outcome for those with both impairments. CONCLUSIONS: Prevalence of subacute post-stroke OD and swallow safety impairments was much higher than CRT attenuation, and risk factors strongly differed suggesting that the swallow response receives a stronger cortical control than the cough reflex. OD has a greater impact on PSP clinical outcome than impaired cough, the poorest prognosis being for patients with both airway protective dysfunctions.

Spatiotemporal characteristics of the pharyngeal event-related potential in healthy subjects and older patients with oropharyngeal dysfunction.

BACKGROUND: Oropharyngeal dysphagia (OD) is a highly prevalent symptom in older people. Appropriate oropharyngeal sensory feedback is essential for safe and efficient swallowing. However, pharyngeal sensitivity decreases with advancing age and could play a fundamental role in the physiopathology of swallowing dysfunction associated with aging. We aimed to characterize pharyngeal sensitivity and cortical response to a pharyngeal electrical stimulus in healthy volunteers (HV) and older patients with and without OD. METHODS: Eight young HV, eight older HV without OD, and 14 older patients with OD were studied by electroencephalography through 32 scalp electrodes. Pharyngeal event-related potentials (ERP) were assessed following electrical stimulation of the pharynx. Sensory and tolerance thresholds to the electrical stimulus and latency, amplitude, and scalp current density of each ERP component were analyzed and compared. An ERP source localization study was also performed using the sLORETA software. KEY RESULTS: Older participants (with and without OD) presented an increased sensory threshold to pharyngeal electrical stimulation (10.2 ± 1.7 mA and 11.5 ± 1.9 mA respectively), compared with young HV (6.0 ± 1.2 mA). The cortical activation of older HV in response to pharyngeal electrical stimulus was reduced compared with young HV (N2 amplitude: 0.22 ± 0.79 vs -3.10 ± 0.59, P<.05). Older patients with OD also presented disturbances to the pharyngo-cortical connection together with disrupted pattern of cortical activation. CONCLUSIONS AND INFERENCES: Older people present a decline in pharyngeal sensory function, more severe in older patients with OD. This sensory impairment might be a critical pathophysiological element and a potential target for treatment of swallowing dysfunction in older patients.

Localization and expression of TRPV1 and TRPA1 in the human oropharynx and larynx.

BACKGROUND: Previous studies have found that TRPV1 and TRPA1 receptor agonists improve swallow response in patients with oropharyngeal dysphagia (OD), but little is known about the expression of these receptors in the human oropharynx. The aim of this study was to assess the expression and localization of TRPV1 and TRPA1 in human samples from the oropharynx of healthy patients, to provide the basis for new pharmacological treatments for OD. METHODS: Samples from oropharyngeal regions innervated by cranial nerves V, IX, and X (tongue, pharynx, and epiglottis) were obtained during ENT surgery and processed either for mRNA (21 patients) or for immunohistochemical assays (seven patients). The expression analysis was performed with RT-qPCR using ACTBh as reference gene. Hemotoxylin and eosin staining was used to study the histology; the immunohistochemical assay used (i) neuron-specific enolase to detect nerve fibers or (ii) fluorescent probes to locate TRPV1 and TRPA1. RESULTS: TRPV1 was expressed in the three studied regions, with higher levels in CN V region (tongue) than in CN X region (epiglottis; p < 0.05), and was localized at epithelial cells and nociceptive fibers in all studied regions. TRPA1 was also expressed in all studied regions, but was always localized below the basal lamina. No immunoreactivity for TRPA1 was found on epithelial cells. CONCLUSIONS & INFERENCES: TRPV1 and TRPA1 are widely expressed in the human oropharynx with two distinct patterns. Our study further confirms that TRPV1/A1 receptors are promising therapeutic targets to develop active treatments for OD patients.

A Comparative Study Between Modified Starch and Xanthan Gum Thickeners in Post-Stroke Oropharyngeal Dysphagia.

Thickeners are used in post-stroke oropharyngeal dysphagia (OD) as a compensatory therapeutic strategy against aspirations. To compare the therapeutic effects of modified starch (MS) and xanthan gum (XG) thickeners on swallow safety and efficacy in chronic post-stroke OD patients using clinical and videofluoroscopic (VFS) assessment. Patients were studied by clinical assessment (volume-viscosity swallow test, V-VST) and VFS using 3 volumes (5, 10, 20 mL) and 3 viscosities (liquid, nectar and spoon thick), comparing MS and XG. We studied 122 patients (46MS, 76XG). (A) V-VST showed that both thickeners similarly improved safety of swallow. Prevalence of safe swallowing significantly increased with enhanced viscosity (P < 0.001 vs liquid), MS: 47.83 % at liquid, 84.93 % at nectar and 92.96 % at spoon thick; XG: 55.31 % at liquid, 77.78 % at nectar and 97.84 % at spoon thick. Patients on MS reported higher prevalence of pharyngeal residue at spoon-thick viscosities. (B) VFS: increasing bolus viscosity with either thickener increased prevalence of safe swallows (P < 0.001 vs liquid), MS: 30.25 % liquid, 61.07 % nectar and 92.64 % spoon thick; XG: 29.12 % liquid, 71.30 % nectar and 89.91 % spoon thick. Penetration-aspiration scale score was significantly reduced with increased viscosity with both thickeners. MS increased oral and pharyngeal residues at nectar and spoon-thick viscosities but XG did not. Timing of airway protection mechanisms and bolus velocity were not affected by either thickener. Increasing bolus viscosity with MS and XG thickeners strongly and similarly improved safety of swallow in chronic post-stroke OD by a compensatory mechanism; in contrast only MS thickeners increased oropharyngeal residue.

Nitrergic neuro-muscular transmission is up-regulated in patients with diverticulosis.

BACKGROUND: Neuro-transmission impairment could be associated to motility changes observed in patients with diverticular disease. Therefore, the objective was to characterize the inhibitory neuro-muscular transmission and gene expression changes of the enteric inhibitory pathways in patients with diverticulosis (DS). METHODS: Circular muscle strips from sigmoid colon of patients with DS and controls were studied using the organ bath technique to evaluate spontaneous contractility and enteric motor neurons stimulated by electrical field and qRT-PCR to assess the expression of nNOS, iNOS, P2Y1 R and PGP9.5. KEY RESULTS: Patients with DS presented decreased spontaneous rhythmic contractions (SRC) that were significantly enhanced after incubation with L-NNA (1 mM) and TTX (1 µM), and unaffected by the P2Y1 antagonist MRS2500 (1 µM). Stimulation on enteric motor neurons caused an increased duration of the latency of OFF-contractions in DS group (p < 0.001), antagonized by L-NNA and slightly affected by MRS2500 (1 µM). No differences in the IC50 between controls and DS patients were observed on inhibition of SRC for the NO-donor sodium nitroprusside (SNP) and the preferential P2Y agonist ADPßS. Moreover, nNOS relative expression was also up-regulated 2.3-fold in the DS group (p < 0.05) whereas there was no significant difference in relative expression of iNOS, P2Y1 R and the neuronal marker PGP9.5 between groups. CONCLUSIONS & INFERENCES: Patients with DS presented an over-expression of nNOS with increased endogenously NO-mediated responses suggesting enhanced NO-release. Up-regulation in the nitrergic pathway in early stages of the disease might play a role in colonic motor disorders associated to diverticular disease.

Sensitivity and specificity of the Eating Assessment Tool and the Volume-Viscosity Swallow Test for clinical evaluation of oropharyngeal dysphagia.

BACKGROUND: Oropharyngeal dysphagia (OD) is an underdiagnosed digestive disorder that causes severe nutritional and respiratory complications. Our aim was to determine the accuracy of the Eating Assessment Tool (EAT-10) and the Volume-Viscosity Swallow Test (V-VST) for clinical evaluation of OD. METHODS: We studied 120 patients with swallowing difficulties and 14 healthy subjects. OD was evaluated by the 10-item screening questionnaire EAT-10 and the bedside method V-VST, videofluoroscopy (VFS) being the reference standard. The V-VST is an effort test that uses boluses of different volumes and viscosities to identify clinical signs of impaired efficacy (impaired labial seal, piecemeal deglutition, and residue) and impaired safety of swallow (cough, voice changes, and oxygen desaturation ≥3%). Discriminating ability was assessed by the AUC of the ROC curve and sensitivity and specificity values. KEY RESULTS: According to VFS, prevalence of OD was 87%, 75.6% with impaired efficacy and 80.9% with impaired safety of swallow including 17.6% aspirations. The EAT-10 showed a ROC AUC of 0.89 for OD with an optimal cut-off at 2 (0.89 sensitivity and 0.82 specificity). The V-VST showed 0.94 sensitivity and 0.88 specificity for OD, 0.79 sensitivity and 0.75 specificity for impaired efficacy, 0.87 sensitivity and 0.81 specificity for impaired safety, and 0.91 sensitivity and 0.28 specificity for aspirations. CONCLUSIONS & INFERENCES: Clinical methods for screening (EAT-10) and assessment (V-VST) of OD offer excellent psychometric proprieties that allow adequate management of OD. Their universal application among at-risk populations will improve the identification of patients with OD at risk for malnutrition and aspiration pneumonia.

The effects of a xanthan gum-based thickener on the swallowing function of patients with dysphagia.

BACKGROUND: Increasing bolus viscosity of thin liquids is a basic therapeutic strategy to protect patients with oropharyngeal dysphagia (OD) from aspiration. However, conventional starch thickeners increase post-deglutitive residue. AIM: To assess the therapeutic effect of a new xanthan gum-based thickener, Resource ThickenUp Clear (Nestlé Health Science, Vevey, Switzerland) on patients with oropharyngeal dysphagia. METHODS: We studied the effect of Resource ThickenUp Clear using a clinical method and videofluoroscopy on 120 patients with oropharyngeal dysphagia (66 with stroke, 41 older and 13 with neurodegenerative diseases) and 14 healthy volunteers while swallowing thin-liquid, nectar-like and spoon-thick boluses. We assessed the prevalence of signs of impaired safety and efficacy of swallow and the physiology of the swallow response. RESULTS: Increasing bolus viscosity with Resource ThickenUp Clear: (i) improved safety of swallow demonstrated by a reduction in the prevalence of cough and voice changes in the clinical study and penetrations and aspirations during video fluoroscopy. Prevalence of aspirations was 12.7% with thin liquid, 7.7% with nectar-like (P < 0.01) and 3.4% with spoon-thick (P < 0.01) viscosities. Penetration-Aspiration Scale was reduced from 3.24 ± 0.18 at thin liquid to 2.20 ± 0.18 at nectar-like (P < 0.001) and to 1.53 ± 0.13 at spoon-thick (P < 0.001) viscosities; (ii) did not enhance pharyngeal residue; (iii) nectar-like viscosity did not affect bolus velocity nor timing of swallow response and (iv) spoon-thick viscosity reduced bolus velocity. CONCLUSIONS: Resource ThickenUp Clear improves the safety of swallow without increasing residue providing a viscosity-dependent therapeutic effect for patients with oropharyngeal dysphagia. At nectar viscosity, the effect is due to intrinsic texture properties, spoon-thick viscosity adding changes in swallow physiology. NCT01158313.

Effect of surface sensory and motor electrical stimulation on chronic poststroke oropharyngeal dysfunction.

BACKGROUND: Chronic poststroke oropharyngeal dysfunction (OD) is a common condition, leading to severe complications, including death. Treatments for chronic poststroke OD are scarce. The aim of our study was to assess and compare the efficacy and safety of treatment with surface electrical stimulation (e-stim) at sensory and motor intensities in patients with chronic poststroke OD. METHODS: Twenty chronic poststroke patients with OD were randomly assigned to (i) sensory e-stim (treatment intensity: 75% of motor threshold) or (ii) motor e-stim (treatment intensity: motor threshold). Patients were treated during 10 days, 1 h/day. Videofluoroscopy was performed at the beginning and end of the study to assess signs of impaired efficacy and safety of swallow and timing of swallow response. KEY RESULTS: Patients presented advanced age (74.95 ± 2.18), 75% were men. The mean days poststroke was 336.26 ± 89.6. After sensory stimulation, the number of unsafe swallows was reduced by 66.7% (p < 0.001), the laryngeal vestibule closure time by 22.94% (p = 0.027) and maximal vertical hyoid extension time by 18.6% (p = 0.036). After motor stimulation, the number of unsafe swallows was reduced by 62.5% (p = 0.002), the laryngeal vestibule closure time by 38.26% (p = 0.009) and maximal vertical hyoid extension time by 24.8% (p = 0.008). Moreover, the motor stimulus reduced the pharyngeal residue by 66.7% (p = 0.002), the upper esophageal sphincter opening time by 39.39% (p = 0.009), and increased bolus propulsion force by 211.1% (p = 0.008). No serious adverse events were detected during the treatment. CONCLUSIONS & INFERENCES: Surface e-stim is a safe and effective treatment for chronic poststroke dysphagic patients.

Post-stroke dysphagia: progress at last.

Oropharyngeal Dysphagia (OD) is both underestimated and underdiagnosed as a cause of malnutrition and respiratory complications following stroke. OD occurs in more than 50% of stroke patients. Aspiration pneumonia (AP) occurs in up to 20% of acute stroke patients and is a major cause of mortality after discharge. Systematic screening for OD should be performed on every patient with stroke before starting oral feeding, followed, if appropriate by clinical and instrumental (videofluroscopy and/or fiberoptic endoscopy) assessment. Bolus modification with adaptation of texture and viscosity of solids and fluids and postural adjustments should be part of the minimal treatment protocol, but they do not change the impaired swallow physiology nor promote recovery of damaged neural swallow networks in stroke patients. To this purpose, two new neurostimulation approaches are being developed to stimulate cortical neuroplasticity to recover swallowing function: (i) those aimed at stimulating the peripheral oropharyngeal sensory system by chemical, physical or electrical stimulus; and (ii) those aimed at directly stimulating the pharyngeal motor cortex, such as repetitive transcranial magnetic stimulation (rTMS). The study of Park et al. in this issue of Neurogastroenterology and Motility evaluated the effect of rTMS in dysphagic stroke patients and showed a marked improvement in swallow physiology. Other studies also using rTMS showed plastic changes in pharyngeal motor cortical areas relevant to swallowing function. If further randomized controlled trials confirm these initial results, the neurorehabilitation strategies will be introduced to clinical practice sooner rather than later, improving the recovery of dysphagic stroke patients. Progress at last.

Pathophysiology of oropharyngeal dysphagia in the frail elderly.

BACKGROUND: Oropharyngeal dysphagia is a major complaint among the elderly. Our aim was to assess the pathophysiology of oropharyngeal dysphagia in frail elderly patients (FEP). METHODS: A total of 45 FEP (81.5 +/- 1.1 years) with oropharyngeal dysphagia and 12 healthy volunteers (HV, 40 +/- 2.4 years) were studied using videofluoroscopy. Each subject's clinical records, signs of safety and efficacy of swallow, timing of swallow response, hyoid motion and tongue bolus propulsion forces were assessed. KEY RESULTS: Healthy volunteers presented a safe and efficacious swallow, faster laryngeal closure (0.157 +/- 0.013 s) upper esophageal sphincter opening (0.200 +/- 0.011 s), and maximal vertical hyoid motion (0.310 +/- 0.048 s), and stronger tongue propulsion forces (22.16 +/- 2.54 mN) than FEP. By contrast, 63.63% of FEP presented oropharyngeal residue, 57.10%, laryngeal penetration and 17.14%, tracheobronchial aspiration. Frail elderly patients with impaired swallow safety showed delayed laryngeal vestibule (LV) closure (0.476 +/- 0.047 s), similar bolus propulsion forces, poor functional capacity and higher 1-year mortality rates (51.7%vs 13.3%, P = 0.021) than FEP with safe swallow. Frail elderly patients with oropharyngeal residue showed impaired tongue propulsion (9.00 +/- 0.10 mN), delayed maximal vertical hyoid motion (0.612 +/- 0.071 s) and higher (56.0%vs 15.8%, P = 0.012) 1-year mortality rates than those with efficient swallow. CONCLUSION & INFERENCES: Frail elderly patients with oropharyngeal dysphagia presented poor outcome and high mortality rates. Impaired safety of deglutition and aspirations are mainly caused by delayed LV closure. Impaired efficacy and residue are mainly related to weak tongue bolus propulsion forces and slow hyoid motion. Treatment of dysphagia in FEP should be targeted to improve these critical events.

Effect of otilonium bromide on contractile patterns in the human sigmoid colon.

BACKGROUND: The mechanism of action of the spasmolytic compound otilonium bromide (OB) on human colonic motility is not understood. The aim of our study was to characterize the pharmacological effects of OB on contractile patterns in the human sigmoid colon. METHODS: Circular sigmoid strips were studied in organ baths. Isolated smooth muscle cells from human sigmoid colon were examined using the calcium imaging technique. KEY RESULTS: Otilonium bromide inhibited by 85% spontaneous non-neural rhythmic phasic contractions (RPCs), (IC(50) = 49.9 nmol L(-1)) and stretch-induced tone (IC(50) = 10.7 nmol L(-1)) with maximum effects at micromolar range. OB also inhibited by 50% both on- (IC(50) = 38.0 nmol L(-1)) and off-contractions induced by electrical stimulation of excitatory motor neurons. In contrast, the inhibitory latency period prior to off-contractions was unaffected by OB. OB inhibited acetylcholine-, substance P-, and neurokinin A-induced contractions. The L-type Ca(2+) channel agonist BayK8644 reversed the effects of OB on RPCs, on- and off-contractions. Hexamethonium, atropine, the NK(2) antagonist, or depletion of intracellular Ca(2+) stores by thapsigargin did not prevent the inhibitory effect of OB on RPCs and electrical contractions. KCl-induced calcium transients in isolated smooth muscle cells were also inhibited by OB (IC(50) = 0.2 micromol L(-1)). CONCLUSIONS & INFERENCES: Otilonium bromide strongly inhibited the main patterns of human sigmoid motility in vitro by blocking calcium influx through L-type calcium channels on smooth muscle cells. This pharmacological profile may mediate the clinically observed effects of the drug in patients with irritable bowel syndrome.

[Retrospective study of prodromal symptoms in schizophrenia]. / Estudio retrospectivo de los síntomas prodrómicos en la esquizofrenia.

INTRODUCTION: There are some non-psychotic symptoms that can forecast the onset of psychosis. Discovering the differences between the symptoms that lead to disease and those that do not makes it possible to identify them and permits early treatment of the disease. METHODS: A sample of 689 schizophrenic patients was analyzed retrospectively. This sample was obtained from the clinical records database of the University Psychiatric Hospital Institut Pere Mata. Data were analyzed with the SPSS version 9.0 statistical package. RESULTS: The most frequent prodromal symptoms of the sample were the delusional ones, the disorganized ones and the neurotic ones. The prodromal symptoms were equally distributed in both genders. In the subtypes, paranoids showed more delusional symptoms, whereas the nonparanoids presented more disorganized symptoms. Acute onsets had more delusional prodromal symptoms whereas the insidious onsets showed more disorganized ones. CONCLUSIONS: In the prodromal stages of shizophrenia, we can also find the community neurotic prevalences regarding gender. The higher rate of neurotic symptoms in the nonparanoid subtype would be explained by the inclusion of the schizoaffective category, whereas the higher rate of disorganized symptoms categories would be due to the hebephrenic and simple categories. The latter would also explain the prodromal differences in the onset type.

Estudio retrospectivo de los síntomas prodrómicos en la esquizofrenia / Retrospective study of prodromal symptoms in schizophrenia

Introducción. Existen unos síntomas prodrómicos que pueden anunciar el inicio de las psicosis, entre ellas, la esquizofrenia. Descubrir la diferencia entre los síntomas que conducen a la enfermedad de los que no, permitiría identificarlos y empezar a tratar la enfermedad de forma precoz. Métodos. Análisis retrospectivo de una muestra extraída de la base de datos informatizada de las historias clínicas del Hospital Psiquiátrico Universitario Instituto Pere Mata. Esta muestra consta de 689 pacientes esquizofrénicos. Los datos se analizan con el paquete estadístico SPSS versión 9.0.Resultados. En esta muestra los síntomas prodrómicos más frecuentes son los delirantes, los desorganizados y los neuróticos. Respecto al sexo, los síntomas prodrómicos se distribuyen de forma uniforme. En cuanto al subtipo, los paranoides muestran más síntomas delirantes y los no paranoides presentan más síntomas desorganizados. Los inicios agudos tienen síntomas prodrómicos más delirantes y los insidiosos más desorganizados. Conclusiones. En las fases prodrómicas de la esquizofrenia también se reflejan las prevalencias neuróticas comunitarias en cuanto al género. La mayor frecuencia de síntomas neuróticos en el subtipo no paranoide se explicaría por la inclusión de la categoría esquizoafectiva, mientras que la mayor frecuencia de síntomas desorganizados se debería a las categorías hebefrénica y simple. Esto último también explicaría las diferencias prodrómicas del tipo de inicio (AU)