The relationship between chronic cough and paradoxical vocal fold movement: A review of the literature

Chronic cough (CC) and paradoxical vocal fold movement (PVFM) are debilitating conditions. PVFM has been given many labels,(1) including vocal cord dysfunction, Munchausen's stridor, functional inspiratory stridor, nonorganic functional or psychogenic upper airway obstruction, factitious asthma, psychogenic stridor, emotional laryngeal wheezing, and episodic laryngeal dyskinesia. 3 Although CC and PVFM have been considered separate entities in many reports, there is preliminary support for the notion that there may be an underlying link between these two conditions. Speech pathologists have become increasingly involved in the treatment of these patients and therefore need to understand the theoretical background of these disorders, the pathophysiological links between the two, and the impact of voice disorders on these populations. The aim of this article is to review the current literature on CC and PVFM from a speech pathology perspective to provide a model for defining and conceptualizing the disorders and to provide a framework for management and future research.

Water balance in goats subjected to feed restriction

The effect of feed restriction on water balance and nutrient utilization was investigated in individually penned Boer x Saanen kids. Twenty-two male Boer x Saanen kids with an initial average live weight (LW) of 15 kg were used. Seven kids were slaughtered at the beginning of the experiment (reference animals) and the remainders were allocated to one of the three treatments (0, 30 and 60% restriction) and therefore there were five kids per treatment. The feed intake for the 0% restriction treatment animals determined the intake for the animals in the 30 and 60% restriction treatment. When the animals in the 0% restriction treatment group reached 25 kg LW, the animals in the 30 and 60% restriction treatment groups were also slaughtered. There was a negative relationship between DMI and water intake. The digestibility coefficients for DM, OM, carbohydrates, ash, ether extract, energy, NDF, ADF and lignin did not differ between treatments, whereas the digestibility coefficient for CP was different between treatment groups. The highest metabolic water production was in animals in the 0% restriction treatment group. No significant differences were observed in the composition of gastro-intestinal tract contents of the goats in the different treatments. Lower water retention was found in the animals in the 60% restriction treatment group. The study showed that feed restriction affected water intake, CP digestibility and water retention in the body of the kid goats. This experiment demonstrated that DM:water intake ratio changed when severe feed restriction was applied (60% restriction) and water was freely available. It shows a different pattern of behaviour of penned goats, particularly if feed intake is restricted and perhaps caution is needed to extrapolate results from nutritional and physiological trials in pens to goats at pasture. (c) 2005 Elsevier BX All rights reserved.

Efficacy of speech pathology management for chronic cough: a randomised placebo controlled trial of treatment efficacy

Background: Chronic cough that persists despite medical treatment may respond to speech pathology intervention, but the efficacy of such treatment has not been investigated in prospective randomised trials. The aim of this study was to determine the efficacy of a speech pathology intervention programme for chronic cough. Methods: A single blind, randomised, placebo controlled trial was conducted in 87 patients with chronic cough that persisted despite medical treatment. Patients were randomly allocated to receive either a specifically designed speech pathology intervention or a placebo intervention. Participants in both groups attended four intervention sessions with a qualified speech pathologist. Results: Participants in the treatment group had a significant reduction in cough (8.9 to 4.6, p, 0.001), breathing (7.9 to 4.7, p < 0.001), voice (7.3 to 4.6, p < 0.001) upper airway (8.9 to 5.9, p < 0.001) symptom scores and limitation (2.3 to 1.6, p < 0.001) ratings following intervention. There was also a significant reduction in breathing (6.8 to 5.6, p=0.047), cough (7.6 to 6.3, p=0.014), and limitation ( 2.3 to 2.0, p=0.038) scores in the placebo group, but the degree of improvement was significantly less than in the treatment group (p < 0.01). Clinical judgement of outcome indicated successful ratings in 88% of participants in the treatment group compared with 14% in the placebo group ( p, 0.001). Conclusion: Speech pathology is an effective management intervention for chronic cough which may be a viable alternative for patients who do not respond to medical treatment.

Paracetamol [acetaminophen]-induced gastrotoxicity: Revealed by induced hyperacidity in combination with acute or chronic inflammation

Paracetamol is regarded as a relatively safe drug in the gastro-duodenal region of humans but recent epidemiological investigations have suggested that at high doses there may be an increased risk of ulcers and bleeding. To investigate the possibility that inflammatory conditions and gastric acidity may play a role in potentiating development of gastric mucosal injury from paracetamol in rats (as noted previously with various non-steroidal anti-inflammatory drugs) we studied the gastric irritant effects of paracetamol and some phenolic and non-phenolic analgesics and antipyretics in rats with adjuvant or collagen II induced arthritis or zymosan-induced paw inflammation and given 1.0 ml hydrochloric acid (HCl) 0.1 M and/or an i. p. injection of the cholinomimetic, acetyl-β-methyl choline chloride 5.0 mg/kg. Gastric lesions were determined 2 h after oral administration of 100 or 250 mg/kg paracetamol or at therapeutically effective doses of the phenolic or non-phenolic analgesics/antipyretics. The results showed that gastric mucosal injury occurred with all these agents when given to animals that received all treatments so indicating there is an adverse synergy of these three factors, namely: (i) intrinsic disease; (ii) hyperacidity; and (iii) vagal stimulation for rapidly promoting gastric damage, both in the fundic as well as the antral mucosa, for producing gastric damage by paracetamol, as well as the other agents. Removing one of these three predisposing factors effectively blunts/abolishes expression of this paracetamol-induced gastrotoxity in rats. These three factors, without paracetamol, did not cause significant acute gastropathy.

Strategies and therapeutic opportunities for the delivery of drugs to the esophagus

Targeting of drugs and therapies locally to the esophagus is an important objective in the development of new and more effective dosage forms. Therapies that are retained within the oral cavity for both local and systemic action have been utilized for many years, although delivery to the esophagus has been far less reported. Esophageal disease states, including infections, motility disorders, gastric reflux, and cancers, would all benefit from localized drug delivery. Therefore, research in this area provides significant opportunities. The key limitation to effective drug delivery within the esophagus is sufficient retention at this site coupled with activity profiles to correspond with these retention times; therefore, a suitable formulation needs to provide the drug in a ready-to-work form at the site of action during the rapid transit through this organ. A successfully designed esophageal-targeted system can overcome these obstacles. This review presents a range of dosage form approaches for targeting the esophagus, including bioadhesive liquids and orally retained lozenges, chewing gums, gels, and films, as well as endoscopically delivered therapeutics. The techniques used to measure efficacy both in vitro and in vivo are also discussed. Drug delivery is a growing driver within the pharmaceutical industry and offers benefits both in terms of clinical efficacy, as well as in market positioning, as a means of extending a drug's exclusivity and profitability. Emerging systems that can be used to target the esophagus are reported within this review, as well as the potential of alternative formulations that offer benefits in this exciting area.

Investigating the functional properties of the somatosensory cortex during experimental visceral pain using magnetoencephalography

Background The somatosensory cortex has been inconsistently activated in pain studies and the functional properties of subregions within this cortical area are poorly understood. To address this we used magnetoencephalography (MEG), a brain imaging technique capable of recording changes in cortical neural activity in real-time, to investigate the functional properties of the somatosensory cortex during different phases of the visceral pain experience. Methods In eight participants (4 male), 151-channel whole cortex MEG was used to detect cortical neural activity during 25 trials lasting 20 seconds each. Each trial comprised four separate periods of 5 seconds in duration. During each of the periods, different visual cues were presented, indicating that period 1=rest, period 2=anticipation, period 3=pain and period 4=post pain. During period 3, participants received painful oesophageal balloon distensions (four at 1 Hz). Regions of cortical activity were identified using Synthetic Aperture Magnetometry (SAM) and by the placement of virtual electrodes in regions of interest within the somatosensory cortex, time-frequency wavelet plots were generated. Results SAM analysis revealed significant activation with the primary (S1) and secondary (S2) somatosensory cortices. The time-frequency wavelet spectrograms showed that activation in S1 increased during the anticipation phase and continued during the presentation of the stimulus. In S2, activation was tightly time and phase-locked to the stimulus within the pain period. Activations in both regions predominantly occurred within the 10–15 Hz and 20–30 Hz frequency bandwidths. Discussion These data are consistent with the role of S1 and S2 in the sensory discriminatory aspects of pain processing. Activation of S1 during anticipation and then pain may be linked to its proposed role in attentional as well as sensory processing. The stimulus-related phasic activity seen in S2 demonstrates that this region predominantly encodes information pertaining to the nature and intensity of the stimulus.

The co-ordination chemistry of tellurium and related selenium ligands

2-(2-pyridyl)phenyl(p-ethoxyphenyl)tellurium(II), (RR1Te) reacts with HgC12 at room temperature to give white HgCl2.RR1Te. On setting aside, or on warming the reaction mixture a yellow material, [R1HgCl.(RTeCl)2] is formed. Multinuclear NMR(125Te, 199Hg, 1H) and mass spectroscopy confirm the formulation, and confirm the ease of transfer of the p-ethoxyphenyl group (R1) between the metal centres. The crystal structure of the yellow material consists of two discrete RTeCl molecules together with a R1HgCl molecule. There is no dative bond formation between these species, hence the preferred description of the formation of an inclusion complex. The reaction of RR1Te with Copper(I) chloride in the cold gives an air sensitive yellow product Cu3Cl3(RR1Te)2(0.5CH3CN); under reflux in air changes to the green Cu2Cl(RR1Te)(0.5 EtOH). By contrast, the reaction of RR1Te with acetonitrile solution of Copper(II) salts under mild conditions affords the white materials CuCl(RR1Te) and CuBr(RR1Te)H2O. RR1Te reacts with PdCl2 and PtCl2 to give materials albeit not well defined, can be seen as intermediates to the synthesis of inorganic phase of the type M3XTe2XCl2X. Paramagnetism is associated with some of the palladium and platinum products. The 195Pt NMR measurement in DMSO establishes the presence of six platinum species, which are assigned to Pt(IV), Pt(III) or Pt(II). The reactions show that in the presence of PdCl2 or PtCl2 both R and R1 are very labile. The reaction of RHgCl(R= 2-(2-pyridyl)phenyl) with SeX4(X= Cl, Br) gives compounds which suggest that both Trans-metallation and redox processes are involved. By varying reaction conditions materials which appear to be intermediates in the trans-metallation process are isolated. Potentially bidentate tellurium ligands having molecular formula RTe(CH2)nTeR,Ln, (R= Ph,(t-Bu). C6H4, n = 5,10) are prepared. Palladium and Platinum complexes containing these ligands are prepared. Also complex Ph3SnC1L(L = p-EtO.C6H4) is prepared.

Hypervalent iodine in synthesis 93. A facile synthesis of 2-substituted imidazo[1,2-a]pyrimidines by cyclocondensation of alkynyl(phenyl)iodonium salts and 2-aminopyrimidine

Simple stirring of a mixture of the alkynyl(phenyl)iodonium salts 1 with 2-aminopyrimidine 2 in chloroform under reflux for two hours in the presence of K2CO3 gave, after workup, the 2-substituted imidazo[1,2-]pyrimidines 3 in moderate to good yields. A possible mechanism for the formation of 3 involves the intramolecular cyclization of the intermediate alkylidenecarbene 6.

The design of a high pressure solvent extraction process using liquid ammonia as solvent

The literature on the potential use of liquid ammonia as a solvent for the extraction of aromatic hydrocarbons from mixtures with paraffins, and the application of reflux, has been reviewed. Reference is made to extractors suited to this application. A pilot scale extraction plant was designed comprising a Scm. diameter by 12Scm. high, 50 stage Rotating Disc Contactor with 2 external settlers. Provision was made for operation with, or without, reflux at a pressure of 10 bar and ambient temperature. The solvent recovery unit consisted of an evaporator, compressor and condenser in a refrigeration cycle. Two systems were selected for study, Cumene-n-Heptane-Ammonia and Toluene-Methylcyclohexane-Ammonia. Equlibrium data for the first system was determined experimentally in a specially-designed, equilibrium bomb. A technique was developed to withdraw samples under pressure for analysis by chromatography and titration. The extraction plant was commissioned with a kerosine-water system; detailed operating procedures were developed based on a Hazard and Operability Study. Experimental runs were carried out with both ternary ammonia systems. With the system Toluene-Methylcyclohexane-Ammonia the extraction plant and the solvent recovery facility, operated satisfactorily, and safely,in accordance with the operating procedures. Experimental data gave reasonable agreement with theory. Recommendations are made for further work with plant.

Investigation of the absorption pathways of some poorly absorbed drugs using human intestinal (CAC0-2) cell monolayers

Absorption across the gastro-intestinal epithelium is via two pathways; the transcellular and paracellular pathway. Caco-2 cells, when cultured on polycarbonate filters, formed a confluent monolayer with many properties of differentiated intestinal epithelial cells, As a model of human gastro-intestinaJ tract epithelia they were used to elucidate and characterise the transepithelial transport of two protein kinase C inhibitors, N-(3-chlorophenyl)-4-[2-(3-hydroxypropylamino)-4-pyridyl]-2-pyrimidinamin (CHPP) and N-benzoyl-staurosporine (NBS), and the polypeptide, human calcitonin. Lanthanum ions are proposed as a paracellular pathway inhibitor and tested with D-mannitol permeability and transepithelial electrical resistance measurements. The effect La3+ has on the carrier-mediated transport of D-glucose and Sodium taurocholate as well as the vesicularly transcytosed horseradish peroxidase was also investigated. As expected, 2 mM apical La3+ increases transepithelial electrical resistance 1.S-fold and decreases mannitol permeability by 63.0 % ± 1.37 %. This inhibition was not repeated by other cations. Apical 2 mM La3+ was found to decrease carrier-mediated D-glucose and taurocholate permeability by only 8.7 % ± 1.6 %, 26.3 % ± 5.0 %. There was no inhibitory effect on testosterone or PEG 4000 permeability observed with La3+. However, for horseradish peroxidase and human calcitonin permeability was decreased by 98.7 % ± 11.7%, and 96.2 % ± 0.8 % respectively by 2 mM La3+. Indicating that human calcitonin could also be transported by vesicular transcytosis. The addition of 2 mM La3+ to the apical surface of Caco-2 monolayers produces a paracellular pathway inhibition. Therefore, La3+ could be a useful additional tool in delineating the transepithelial pathway of passive drug absorption.

Oscillatory dynamics in the perception of pain investigated using magnetoencephalography

This thesis investigates changes in the oscillatory dynamics in key areas of the pain matrix during different modalities of pain. Gamma oscillations were seen in the primary somatosensory cortex in response to somatic electrical stimulation at painful and non-painful intensities. The strength of the gamma oscillations was found to relate to the intensity of the stimulus. Gamma oscillations were not seen during distal oesophageal electrical stimulation or the cold pressor test. Gamma oscillations were not seen in all participants during somatic electrical stimulation, however clear evoked responses from SI were seen in everyone. During a train of electrical pulses to the median nerve and the digit, a decrease in the frequency of the gamma oscillations was seen across the duration of the train. During a train of electrical stimuli to the median nerve and the digit, gamma oscillations were seen at ~20-100ms following stimulus onset and at frequencies between 30-100Hz. This gamma response was found to have a strong evoked component. Following a single electrical pulse to the digit, gamma oscillations were seen at 100-250ms and between 60-95Hz and were not temporally coincident with the main components of the evoked response. These results suggest that gamma oscillations may have an important role in encoding different aspects of sensory stimuli within their characteristics such as strength and frequency. These findings help to elucidate how somatic stimuli are processed within the cortex which in turn may be used to understand abnormal cases of somatosensory processing.

Primary and secondary somatosensory cortex responses to anticipation and pain: a magnetoencephalography study

Several brain regions, including the primary and secondary somatosensory cortices (SI and SII, respectively), are functionally active during the pain experience. Both of these regions are thought to be involved in the sensory-discriminative processing of pain and recent evidence suggests that SI in particular may also be involved in more affective processing. In this study we used MEG to investigate the hypothesis that frequency-specific oscillatory activity may be differentially associated with the sensory and affective components of pain. In eight healthy participants (four male), MEG was recorded during a visceral pain experiment comprising baseline, anticipation, pain and post-pain phases. Pain was delivered via intraluminal oesophageal balloon distension (four stimuli at 1 Hz). Significant bilateral but asymmetrical changes in neural activity occurred in the beta-band within SI and SII. In SI, a continuous increase in neural activity occurred during the anticipation phase (20-30 Hz), which continued during the pain phase but at a lower frequency (10-15 Hz). In SII, oscillatory changes only occurred during the pain phase, predominantly in the 20-30 Hz beta band, and were coincident with the stimulus. These data provide novel evidence of functional diversity within SI, indicating a role in attentional and sensory aspects of pain processing. In SII, oscillatory changes were predominantly stimulus-related, indicating a role in encoding the characteristics of the stimulus. We therefore provide objective evidence of functional heterogeneity within SI and functional segregation between SI and SII, and suggest that the temporal and frequency dynamics within cortical regions may offer valuable insights into pain processing.

Strategies for local drug delivery targeting the oesophagus

Localised, targeted drug delivery to the oesophagus offers the potential for more effective delivery and reduced drug dosages, coupled with increased patient compliance. This thesis considers bioadhesive liquids, orally retained tablets and films as well as chewable dosage forms as drug delivery systems to target the oesophagus. Miconazole nitrate was used as a model antifungal agent. Chitosan and xanthan gum hydrogels were evaluated as viscous polymer viables with the in vitro retention, drug release and minimum inhibitory concentration values of the formulations measured. Xanthan showed prolonged retention on the oesophageal surface in vitro yet chitosan reduced the MIC value; both polymers offer potential for local targeting to the oesophagus. Cellulose derivatives were investigated within orally retained dosage forms. Both drug and polymer dissolution rates were measured to investigate the drug release mechanism and to develop a formulation with concomitant drug and polymer release to target the oesophagus with solubilised drug within a viscous media. Several in vitro dissolution methods were evaluated to measure drug release from chewable dosage forms with both drug and polymer dissolution quantified to investigate the effects of dissolution apparatus on drug release. The results from this thesis show that a range of drug delivery strategies that can be used to target drug to the oesophagus. The composition of these formulations as well as the methodology used within the development are crucial to best understand the formulation and predict its performance in vivo.

Characterization and optimization of bilosomes for oral vaccine delivery

Oral vaccines offer significant benefits due to the ease of administration, better patient compliance and non-invasive, needle-free administration. However, this route is marred by the harsh gastro intestinal environment which is detrimental to many vaccine formats. To address this, a range of delivery systems have been considered including bilosomes; these are bilayer vesicles constructed from non-ionic surfactants combined with the inclusion of bile salts which can stabilize the vesicles in the gastro intestinal tract by preventing membrane destabilization. The aim of this study was to investigate the effect of formulation parameters on bilosome carriers using Design of Experiments to select an appropriate formulation to assess in vivo. Bilosomes were constructed from monopalmitoylglycerol, cholesterol, dicetyl phosphate and sodium deoxycholate at different blends ratios. The optimized bilosome formulation was identified and the potential of this formulation as an oral vaccine delivery system were assessed in biodistribution and vaccine efficacy studies. Results showed that the larger bilosomes vesicles (~6 µm versus 2 µm in diameter) increased uptake within the Peyer's patches and were able to reduce median temperature differential change and promote a reduction in viral cell load in an influenza challenge study. © 2013 Informa UK, Ltd.

SGLT inhibitors in management of diabetes

The two main sodium-glucose cotransporters (SGLTs), SGLT1 and SGLT2, provide new therapeutic targets to reduce hyperglycaemia in patients with diabetes. SGLT1 enables the small intestine to absorb glucose and contributes to the reabsorption of glucose filtered by the kidney. SGLT2 is responsible for reabsorption of most of the glucose filtered by the kidney. Inhibitors with varying specificities for these transporters (eg, dapagliflozin, canagliflozin, and empagliflozin) can slow the rate of intestinal glucose absorption and increase the renal elimination of glucose into the urine. Results of randomised clinical trials have shown the blood glucose-lowering efficacy of SGLT inhibitors in type 2 diabetes when administered as monotherapy or in addition to other glucose-lowering therapies including insulin. Increased renal glucose elimination also assists weight loss and could help to reduce blood pressure. Effective SGLT2 inhibition needs adequate glomerular filtration and might increase risk of urinary tract and genital infection, and excessive inhibition of SGLT1 can cause gastro-intestinal symptoms. However, the insulin-independent mechanism of action of SGLT inhibitors seems to offer durable glucose-lowering efficacy with low risk of clinically significant hypoglycaemia at any stage in the natural history of type 2 diabetes. SGLT inhibition might also be considered in conjunction with insulin therapy in type 1 diabetes. © 2013 Elsevier Ltd.