We have identified a distinct subtype of airway vagal afferent nerve that plays an essential role in regulating the cough reflex. These afferents are exquisitely sensitive to punctate mechanical stimuli, acid, and decreases in extracellular chloride concentrations, but are insensitive to capsaicin, bradykinin, histamine, adenosine, serotonin, or changes in airway intraluminal pressures. In this study we used intravital imaging, retrograde neuronal tracing, and electrophysiological analyses to characterize the structural basis for their peculiar mechanical sensitivity and to further characterize the regulation of their excitability. In completing these experiments, we uncovered evidence for an essential role of an isozyme of Na+-K+ATPase in regulating cough. These vagal sensory neurons arise bilaterally from the nodose ganglia and are selectively and brilliantly stained intravitally with the styryl dye FM2-10. Cough receptor terminations are confined and adherent to the extracellular matrix separating the airway epithelium and smooth muscle layers, a site of extensive remodeling in asthma and chronic obstructive pulmonary disease. The cough receptor terminals uniquely express the α3subunit of Na+-K+ATPase. Intravital staining of cough receptors by FM2-10, cough receptor excitabilityin vitro, and coughingin vivoare potently and selectively inhibited by the sodium pump inhibitor ouabain. These data provide the first detailed morphological description of the peripheral terminals of the sensory nerves regulating cough and identify a selective molecular target for their modulation.

The diagnosis and management of small choroidal melanoma remains controversial.1Gass J.D. Problems in the differential diagnosis of choroidal nevi and malignant melanoma XXXIII Edward Jackson Memorial lecture.Trans Sect Ophthalmol Am Acad Ophtalmol Otolaryngol. 1977; 83: 19-48Google Scholar There are several reasons for this controversy; first and foremost is the lack of any uniformly accepted terminology or diagnostic criteria for small choroidal melanoma.2Singh A.D. Mokashi A.A. Bena J.F. et al.Small choroidal melanocytic lesions: features predictive of growth.Ophthalmology. 2006; 113: 1032-1039Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar The second issue is the lack of a randomized, prospective trial that compares prompt treatment with deferred treatment until the diagnosis is confirmed (documented growth).3Kupfer C. Discussion: risk factors for growth and metastasis of small choroidal melanocytic lesions.Trans Am Ophthalmol Soc. 1995; 93: 277-278Google ScholarTherefore, as an initial step, we sought to develop objective inclusion criteria for a randomized clinical trial of prompt treatment versus deferred treatment for small choroidal melanoma. Data from the small melanoma prospective study component of the Collaborative Ocular Melanoma Study (COMS) were used for this supplemental analysis.4Group COMSFactors predictive of growth and treatment of small choroidal melanoma: COMS Report No. 5. The Collaborative Ocular Melanoma Study Group.Arch Ophthalmol. 1997; 115: 1537-1544Crossref PubMed Scopus (191) Google Scholar Observation was chosen initially for 188 tumors and the data related to these tumors forms the basis for this supplemental analysis. Forty-four tumors not scheduled for treatment at the time of their evaluation for the COMS substudy grew during follow-up. Growth was defined as an increase to a size eligible for 1 of the COMS randomized trials.4Group COMSFactors predictive of growth and treatment of small choroidal melanoma: COMS Report No. 5. The Collaborative Ocular Melanoma Study Group.Arch Ophthalmol. 1997; 115: 1537-1544Crossref PubMed Scopus (191) Google ScholarThe baseline clinical and photographic features associated with time to growth included baseline apical height (>2.0 mm), basal diameter (>8.0 mm), presence of drusen, retinal pigment epithelium changes adjacent to the tumor, and overlying orange pigment.4Group COMSFactors predictive of growth and treatment of small choroidal melanoma: COMS Report No. 5. The Collaborative Ocular Melanoma Study Group.Arch Ophthalmol. 1997; 115: 1537-1544Crossref PubMed Scopus (191) Google Scholar Multivariable analysis of these 5 features was performed in a stratified manner. Kaplan–Meier estimates of time to growth to medium or large tumor size as defined for the COMS trials, were calculated for all subgroups of patients categorized by the cumulative number of baseline risk factors (1–5); 5-year estimates and their corresponding 95% confidence intervals were computed and compared.The analysis of the distribution of these 5 risk factors in the 188 tumors revealed that the majority (159; 84.5%) of the tumors were 2.0–3.0 mm in height but only 10 (5.3%) were 12.0–16.0 mm in diameter (Table 1 [available online at http://aaojournal.org]). Various combinations of risk factors were observed in the 188 tumors; any 2 risk factors were present in 179 tumors (95.2%) and none had all 5 factors (Fig 1 [available online at http://aaojournal.org]). The Kaplan–Meier 5-year growth rate was low when only drusen (9.7%; 95% confidence interval [CI], 2.2 –17.1) or retinal pigment epithelium changes were present (17.3%; 95% CI, 4.2–30.4) and high when the tumor diameter was 12.1–16.0 mm (63.0%; 95% CI, 26.3–99.7) or orange pigment was present (56.9%; 95% CI, 39.5–74.3; Table 1; Fig 2 [available online at http://aaojournal.org]). The Kaplan–Meier estimate of the 5-year growth rate of >50% was observed with the combination of 2 risk factors; height (2.0–3.0 mm) and diameter (12.1–16.0 mm), and height (2.0–3.0 mm) and presence of orange pigment, and diameter (12.1–16.0 mm) and presence of orange pigment (Table 1). Because of the small number of tumors with >2 risk factors, no meaningful conclusion could be drawn about the contribution of risk factors for growth in several subgroups (data not shown). Similarly, because of the low number of melanoma-related deaths in the study subjects, no formal statistical analysis could be performed of the relationship between baseline risk factors for growth and time to death.Table 1Estimates of 5-Year Tumor Growth by Tumor Features: Collaborative Ocular Melanoma Study Small Tumor Patients Untreated at Baseline (n = 188)FeaturesNo. with FeatureNo. without FeatureKaplan-Meier Estimate of 5-Year Growth in Those with Feature (95% CI)With GrowthWithout GrowthWith GrowthWithout Growthn%n%n%n%One Ht43271167313289734.5(25.7–43.4) Dia55055039221397863.0(26.3–99.7) Dru687493383863629.7(2.2–17.1) RPE61436863828997217.3(4.2–30.4) Org1853164726181208256.9(39.5–74.3)Two Ht + Dia45045040221407857.1(20.5–93.8) Ht + Dru586192393476669.0(1.4–16.6) Ht + RPE615338538271027318.4(4.7–32.1) Ht + Org1860124026171248363.0(45.1–80.9) Dia + Dru23346742241337644.4(0–93.1) Dia + RPE13326743241337633.3(0–86.7) Dia + Org1100——432413676100— Dru + RPE——17100442711873—— Dru + Org——4100442513275—— RPE + Org24036042241327646.7(0–95.3)Dia = largest basal diameter of 12.1 to 16.0 mm; Dru = Drusen present; Ht = apical height of 2.0 to 3.0 mm; Org = orange pigment present; RPE = retinal pigment epithelial changes present. Open table in a new tab Figure 2Kaplan–Meier estimates of the cumulative number of tumors with growth within 5 years by tumor diameter (A, diameter of 12.1–16.0 mm) versus a diameter of ≤12.0 mm), height (B, height 2.0–3.0 mm vs height ≤2.0 mm), and presence versus absence of orange pigment (C).View Large Image Figure ViewerDownload (PPT)Overall, factors that were associated with a Kaplan–Meier estimate of ≥50% rate of growth may be considered as inclusion criteria for a randomized treatment trial (Table 2 [available online at http://aaojournal.org]). Although 5-year estimate of tumor growth for tumor thickness (2.0–3.0 mm) alone was only 35%, we selected tumor thickness (2.0–3.0 mm) as an inclusion criterion because tumor thickness (2.0–3.0 mm) in combination with larger diameter (12.1–16.0 mm) or in presence of orange pigmentation was associated with 5-year growth rate of 57%–100%. In addition, several previous studies have also suggested greater tumor thickness as an important risk factor for growth.2Singh A.D. Mokashi A.A. Bena J.F. et al.Small choroidal melanocytic lesions: features predictive of growth.Ophthalmology. 2006; 113: 1032-1039Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Because the risk of tumor growth in patients with risk factors exceeded the risk of no or trivial growth within 5 years, such patients could be ethically entered into a randomized trial; they have a higher probability of the lesion representing a small melanoma than a large nevus. Our data analysis also lends support to the designation of these lesions as indeterminate choroidal melanocytic lesions rather than small melanoma or suspicious nevus, thus highlighting the ambiguity in identifying the true nature of these lesions.5Butler P. Char D.H. Zarbin M. Kroll S. Natural history of indeterminate pigmented choroidal tumors.Ophthalmology. 1994; 101: 710-716Abstract Full Text PDF PubMed Scopus (97) Google ScholarTable 2Choroidal Indeterminate Melanocytic Lesions: Prompt versus Deferred Treatment Trial: Inclusion CriteriaFeatureDimensions1Diameter 5.0–16.0 mm and height 1.0–3.0 mm2Presence of any 1 of the 3 risk factorsLargest basal diameter 12.1–16.0 mmThickness 2.0–3.0 mm⁎The 5-year estimate of tumor growth for tumor thickness (2.0–3.0 mm) alone was 35%; in combination with larger diameter (12.1–16.0 mm) or in presence of orange pigmentation, the risk was 57%–100%.Orange pigmentation presentFeatures 1 and 2 must be present. The 5-year estimate of tumor growth for tumor thickness (2.0–3.0 mm) alone was 35%; in combination with larger diameter (12.1–16.0 mm) or in presence of orange pigmentation, the risk was 57%–100%. Open table in a new tab The diagnosis and management of small choroidal melanoma remains controversial.1Gass J.D. Problems in the differential diagnosis of choroidal nevi and malignant melanoma XXXIII Edward Jackson Memorial lecture.Trans Sect Ophthalmol Am Acad Ophtalmol Otolaryngol. 1977; 83: 19-48Google Scholar There are several reasons for this controversy; first and foremost is the lack of any uniformly accepted terminology or diagnostic criteria for small choroidal melanoma.2Singh A.D. Mokashi A.A. Bena J.F. et al.Small choroidal melanocytic lesions: features predictive of growth.Ophthalmology. 2006; 113: 1032-1039Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar The second issue is the lack of a randomized, prospective trial that compares prompt treatment with deferred treatment until the diagnosis is confirmed (documented growth).3Kupfer C. Discussion: risk factors for growth and metastasis of small choroidal melanocytic lesions.Trans Am Ophthalmol Soc. 1995; 93: 277-278Google Scholar Therefore, as an initial step, we sought to develop objective inclusion criteria for a randomized clinical trial of prompt treatment versus deferred treatment for small choroidal melanoma. Data from the small melanoma prospective study component of the Collaborative Ocular Melanoma Study (COMS) were used for this supplemental analysis.4Group COMSFactors predictive of growth and treatment of small choroidal melanoma: COMS Report No. 5. The Collaborative Ocular Melanoma Study Group.Arch Ophthalmol. 1997; 115: 1537-1544Crossref PubMed Scopus (191) Google Scholar Observation was chosen initially for 188 tumors and the data related to these tumors forms the basis for this supplemental analysis. Forty-four tumors not scheduled for treatment at the time of their evaluation for the COMS substudy grew during follow-up. Growth was defined as an increase to a size eligible for 1 of the COMS randomized trials.4Group COMSFactors predictive of growth and treatment of small choroidal melanoma: COMS Report No. 5. The Collaborative Ocular Melanoma Study Group.Arch Ophthalmol. 1997; 115: 1537-1544Crossref PubMed Scopus (191) Google Scholar The baseline clinical and photographic features associated with time to growth included baseline apical height (>2.0 mm), basal diameter (>8.0 mm), presence of drusen, retinal pigment epithelium changes adjacent to the tumor, and overlying orange pigment.4Group COMSFactors predictive of growth and treatment of small choroidal melanoma: COMS Report No. 5. The Collaborative Ocular Melanoma Study Group.Arch Ophthalmol. 1997; 115: 1537-1544Crossref PubMed Scopus (191) Google Scholar Multivariable analysis of these 5 features was performed in a stratified manner. Kaplan–Meier estimates of time to growth to medium or large tumor size as defined for the COMS trials, were calculated for all subgroups of patients categorized by the cumulative number of baseline risk factors (1–5); 5-year estimates and their corresponding 95% confidence intervals were computed and compared. The analysis of the distribution of these 5 risk factors in the 188 tumors revealed that the majority (159; 84.5%) of the tumors were 2.0–3.0 mm in height but only 10 (5.3%) were 12.0–16.0 mm in diameter (Table 1 [available online at http://aaojournal.org]). Various combinations of risk factors were observed in the 188 tumors; any 2 risk factors were present in 179 tumors (95.2%) and none had all 5 factors (Fig 1 [available online at http://aaojournal.org]). The Kaplan–Meier 5-year growth rate was low when only drusen (9.7%; 95% confidence interval [CI], 2.2 –17.1) or retinal pigment epithelium changes were present (17.3%; 95% CI, 4.2–30.4) and high when the tumor diameter was 12.1–16.0 mm (63.0%; 95% CI, 26.3–99.7) or orange pigment was present (56.9%; 95% CI, 39.5–74.3; Table 1; Fig 2 [available online at http://aaojournal.org]). The Kaplan–Meier estimate of the 5-year growth rate of >50% was observed with the combination of 2 risk factors; height (2.0–3.0 mm) and diameter (12.1–16.0 mm), and height (2.0–3.0 mm) and presence of orange pigment, and diameter (12.1–16.0 mm) and presence of orange pigment (Table 1). Because of the small number of tumors with >2 risk factors, no meaningful conclusion could be drawn about the contribution of risk factors for growth in several subgroups (data not shown). Similarly, because of the low number of melanoma-related deaths in the study subjects, no formal statistical analysis could be performed of the relationship between baseline risk factors for growth and time to death. Dia = largest basal diameter of 12.1 to 16.0 mm; Dru = Drusen present; Ht = apical height of 2.0 to 3.0 mm; Org = orange pigment present; RPE = retinal pigment epithelial changes present. Overall, factors that were associated with a Kaplan–Meier estimate of ≥50% rate of growth may be considered as inclusion criteria for a randomized treatment trial (Table 2 [available online at http://aaojournal.org]). Although 5-year estimate of tumor growth for tumor thickness (2.0–3.0 mm) alone was only 35%, we selected tumor thickness (2.0–3.0 mm) as an inclusion criterion because tumor thickness (2.0–3.0 mm) in combination with larger diameter (12.1–16.0 mm) or in presence of orange pigmentation was associated with 5-year growth rate of 57%–100%. In addition, several previous studies have also suggested greater tumor thickness as an important risk factor for growth.2Singh A.D. Mokashi A.A. Bena J.F. et al.Small choroidal melanocytic lesions: features predictive of growth.Ophthalmology. 2006; 113: 1032-1039Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Because the risk of tumor growth in patients with risk factors exceeded the risk of no or trivial growth within 5 years, such patients could be ethically entered into a randomized trial; they have a higher probability of the lesion representing a small melanoma than a large nevus. Our data analysis also lends support to the designation of these lesions as indeterminate choroidal melanocytic lesions rather than small melanoma or suspicious nevus, thus highlighting the ambiguity in identifying the true nature of these lesions.5Butler P. Char D.H. Zarbin M. Kroll S. Natural history of indeterminate pigmented choroidal tumors.Ophthalmology. 1994; 101: 710-716Abstract Full Text PDF PubMed Scopus (97) Google Scholar Features 1 and 2 must be present.

Adenosine induces dyspnea, cough, and airways obstruction in asthma, a phenomenon that also occurs in various sensitized animal models in which a neuronal involvement has been implicated. Although adenosine has been suggested to activate cholinergic nerves, the precise mechanism has not been established. In the present study, the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) induced a cholinergic reflex, causing tracheal smooth muscle contraction that was significantly inhibited by the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 100 microg/kg) (P < 0.05) in anesthetized animals. Furthermore, the adenosine A(2) agonist 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680) induced a small reflex, whereas the A(3) selective agonist N(6)-(3-iodobenzyl)-5'-N-methylcarbamoyladenosine (IB-MECA) was without effect. The tracheal reflex induced by CPA was also inhibited by recurrent nerve ligation or muscarinic receptor blockade (P < 0.001), indicating that a cholinergic neuronal mechanism of action accounted for this response. The cholinergic reflex in response to aerosolized CPA was significantly greater in passively sensitized compared with naive guinea pigs (P < 0.01). Chronic capsaicin treatment, which inhibited sensory nerve function, failed to inhibit CPA-induced reflex tracheal contractions in passively sensitized guinea pigs, although the local anesthetic lidocaine inhibited CPA-induced tracheal contractions. The effects of CPA on the reflex response was not dependent on the release of histamine from tissue mast cells or endogenous prostaglandins as shown by the lack of effect of the histamine H(1) receptor antagonist pyrilamine (1 mg/kg) or the cyclooxygenase inhibitor meclofenamic acid (3 mg/kg), respectively. In conclusion, activation of pulmonary adenosine A(1) receptors can stimulate cholinergic reflexes, and these reflexes are increased in allergic guinea pigs.

BACKGROUND:Since 1992 the Office of Research Integrity (ORI) had reviewed investigations of scientific misconduct in research funded by the US Public Health Service (PHS). ORI defined scientific misconduct as "fabrication, falsification, plagiarism, or other practices that seriously deviate from those that are commonly accepted within the scientific community for proposing, conducting, or reporting research".PURPOSE:The purpose of this study was to summarize the findings and administrative actions reported in ORI notices of scientific misconduct in clinical trials occurring between May 1992 and 2002.METHODS:Findings of misconduct were gathered from publicly available sources: the ORI annual reports and the NIH Guide to Grants and Contracts.RESULTS:Clinical trials accounted for 17 (13%) of the 136 investigations that resulted in findings of scientific misconduct, and they were noted in 12 (11%) of the 113 brief reports of investigations closed with findings of no scientific misconduct. In clinical trials, the most severe sanction, debarment from US Government funding, was applied in six (35%) of the cases of misconduct compared to 79 (66%) of 119 cases from all other types of research combined. Of individuals cited for misconduct in clinical trials, three (18%) held doctorates in contrast to 81 (68%) in other types of research.CONCLUSIONS:In clinical trials, junior employees may bear the burden of sanction for scientific misconduct. The most frequently applied sanction was the requirement that a plan of supervision of the sanctioned employees accompany any future application for funding which would include them. This imposition of sanction on an individual employee does not address possible causes of misconduct which may be inherent in the overall pattern of leadership, training and supervision in the trial. Furthermore, the definition of misconduct, as interpreted by the Departmental Appeals Board, excludes carelessness and other poor research practices that may lead to dissemination of more incorrect data than misconduct.

Cough is an indispensable defensive reflex. Although generally beneficial, cough is also a common symptom of diseases such as asthma, chronic obstructive pulmonary disease (COPD) and lung cancer. Cough remains a major unmet medical need and, although the centrally acting opioids have remained the antitussive drug of choice for decades, such opioids possess many unwanted side-effects. However, new research into the behaviour of airway sensory nerves has provided greater insight into the mechanisms of cough and new avenues for the discovery of novel non-opioid antitussive drugs. In this article, the pathophysiological mechanisms of cough and the implications of this research for the development of novel antitussive drugs will be discussed. A poster depicting the pharmacology of cough is available online and in print as supplementary material to this article. Cough is an indispensable defensive reflex. Although generally beneficial, cough is also a common symptom of diseases such as asthma, chronic obstructive pulmonary disease (COPD) and lung cancer. Cough remains a major unmet medical need and, although the centrally acting opioids have remained the antitussive drug of choice for decades, such opioids possess many unwanted side-effects. However, new research into the behaviour of airway sensory nerves has provided greater insight into the mechanisms of cough and new avenues for the discovery of novel non-opioid antitussive drugs. In this article, the pathophysiological mechanisms of cough and the implications of this research for the development of novel antitussive drugs will be discussed. A poster depicting the pharmacology of cough is available online and in print as supplementary material to this article. Erratum: The pharmacology of cough: 25 (2004), 569–576 et al.Trends in Pharmacological SciencesJanuary, 2005In BriefIn the article ‘The pharmacology of cough’ by Reynolds et al., which was published in the November 2004 issue of TiPS, there were three errors. In Box 1, sibenadet was incorrectly cited (in the text and table) as a dopamine D2 receptor and β2-adrenoceptor antagonist. It is in fact a D2 receptor and β2-adrenoceptor agonist. In the section ‘GABA receptors’ on p. 574, baclofen was incorrectly cited as a GABAB receptor antagonist. It is in fact a GABAB receptor agonist. In addition, Ref. 36 should have been cited as Adcock, J.J. Full-Text PDF

We have identified the tracheal and laryngeal afferent nerves regulating cough in anaesthetized guinea-pigs. Cough was evoked by electrical or mechanical stimulation of the tracheal or laryngeal mucosa, or by citric acid applied topically to the trachea or larynx. By contrast, neither capsaicin nor bradykinin challenges to the trachea or larynx evoked cough. Bradykinin and histamine administered intravenously also failed to evoke cough. Electrophysiological studies revealed that the majority of capsaicin-sensitive afferent neurones (both Adelta- and C-fibres) innervating the rostral trachea and larynx have their cell bodies in the jugular ganglia and project to the airways via the superior laryngeal nerves. Capsaicin-insensitive afferent neurones with cell bodies in the nodose ganglia projected to the rostral trachea and larynx via the recurrent laryngeal nerves. Severing the recurrent nerves abolished coughing evoked from the trachea and larynx whereas severing the superior laryngeal nerves was without effect on coughing. The data indicate that the tracheal and laryngeal afferent neurones regulating cough are polymodal Adelta-fibres that arise from the nodose ganglia. These afferent neurones are activated by punctate mechanical stimulation and acid but are unresponsive to capsaicin, bradykinin, smooth muscle contraction, longitudinal or transverse stretching of the airways, or distension. Comparing these physiological properties with those of intrapulmonary mechano-receptors indicates that the afferent neurones mediating cough are quite distinct from the well-defined rapidly and slowly adapting stretch receptors innervating the airways and lungs. We propose that these airway afferent neurones represent a distinct subtype and that their primary function is regulation of the cough reflex.

The physiology of cough has become one of the primary focuses of recent research into the cough reflex. Peripherally, interest in differentiating subtypes of airway afferent fibres to determine their contributions to the cough reflex has led to the discovery of an RAR-fibre subtype that responds exclusively to tussive stimuli in the anaesthetized guinea pig and has been hypothesized to initiate the normal defensive cough reflex. Further investigations have begun to more fully differentiate these and other afferent fibre types pharmacologically. Centrally, investigations into the involvement of respiratory networks and gating mechanisms in the cough reflex have contributed to our understanding of the control of cough. Pathological changes in the cough reflex resulting from disease are also beginning to be elucidated. Further research in this area should lead to a more complete understanding of cough and a more rational approach to its treatment.

Background The purpose of this analysis was to examine and quantify the coordinating center workload in regard to certification and turnover of clinical personnel who participated in the Collaborative Ocular Melanoma Study (COMS). Methods The COMS was a set of multicenter, multidisciplinary randomized clinical trials conducted to evaluate radiotherapy for initial treatment of choroidal melanoma, a primary eye cancer. Patients were screened, enrolled, treated, and followed for mortality and clinical outcomes at 43 clinical centers in the United States and Canada, beginning late in 1986. Clinical centers were added to the COMS during three calendar periods. Training and certification of clinical personnel was performed by five resource centers and coordinated at the COMS coordinating center. A personnel database was maintained at the coordinating center for tracking certification progress, recertification, transfers and resignations. Certification records were analyzed for the period 1986 through 1998 when patient accrual and treatment were completed. Results Clinical personnel (929 individuals) were certified for one or more of nine distinct roles in the COMS, resulting in 1342 certifications; 26% were certified for two or more positions. The total number certified for each role ranged from 114 to 208. Certifications per year ranged from 260 in 1987 to 35 in 1997. The certification workload at the coordinating center rose following addition of each group of new clinical centers. It also increased in 1995 as a result of recertification of current personnel mandated by the external data monitoring committee. Conclusions This analysis documented that training and certification were continuing tasks, and not limited to initiation of the study. Resignations and reassignments of certified personnel were responsible for 642 decertifications.

Cough is an indispensable defensive reflex. Although generally beneficial, cough is also a common symptom of diseases such as asthma, chronic obstructive pulmonary disease (COPD) and lung cancer. Cough remains a major unmet medical need and, although the centrally acting opioids have remained the antitussive drug of choice for decades, such opioids possess many unwanted side-effects. However, new research into the behaviour of airway sensory nerves has provided greater insight into the mechanisms of cough and new avenues for the discovery of novel non-opioid antitussive drugs. In this article, the pathophysiological mechanisms of cough and the implications of this research for the development of novel antitussive drugs will be discussed. A poster depicting the pharmacology of cough is available online and in print as supplementary material to this article.

Neurokinin-containing nerve fibers were localized to guinea pig airway parasympathetic ganglia in control tissues but not in tissues pretreated with capsaicin. The purpose of the present study was to determine whether neurokinins, released during axonal reflexes or after antidromic afferent nerve stimulation, modulate ganglionic synaptic neurotransmission. The neurokinin type 3 (NK3) receptor antagonists SB-223412 and SR-142801 inhibited vagally mediated cholinergic contractions of bronchi in vitro at stimulation voltages threshold for preganglionic nerve activation but had no effect on vagally mediated contractions evoked at optimal voltage or field stimulation-induced contractions. Intracellular recordings from the ganglia neurons revealed that capsaicin-sensitive nerve stimulation potentiated subsequent preganglionic nerve-evoked fast excitatory postsynaptic potentials. This effect was mimicked by the NK3 receptor agonist senktide analog and blocked by SB-223412. In situ, senktide analog markedly increased baseline tracheal cholinergic tone, an effect that was reversed by atropine and prevented by vagotomy or SB-223412. Comparable effects of intravenous senktide analog on pulmonary insufflation pressure were observed. These data highlight the important integrative role played by parasympathetic ganglia and indicate that activation of NK3 receptors in airway ganglia by endogenous neurokinins facilitates synaptic neurotransmission.

Objective: To describe the frequency and predictors of local treatment failure and enucleation after iodine 125 (I-125) brachytherapy in patients with choroidal melanoma treated and followed up in a large randomized clinical trial.Design: Prospective, noncomparative, interventional case series within a randomized, multicenter clinical trial.Participants: Patients enrolled in the Collaborative Ocular Melanoma Study (COMS) trial of enucleation versus brachytherapy between February 1987 and July 1998; tumors measured 2.5 to 10.0 mm in apical height and no more than 16.0 mm in longest basal dimension.Methods: 1125 brachytherapy was administered via episcleral plaque according to a standard protocol. Follow-up ophthalmic evaluations, including ophthalmic ultrasound and fundus photography, were performed according to a standard protocol at baseline, every 6 months thereafter for 5 years, and subsequently at annual intervals. Survival analysis methods were used to estimate the cumulative risk of postirradiation treatment failure and enucleation. Factors associated with treatment failure and enucleation of plaqued eyes were evaluated using Cox proportional hazards analysis.Main Outcome Measures: Reports of enucleation and of local treatment failure, defined as tumor growth, recurrence, or extrascleral extension, derived from clinical reports based on echographic and photographic documentation.Results: As of September 30, 2000, 638 of the 650 patients randomized to brachytherapy and so treated had been followed up for 1 year or longer, and 411 had been followed up for at least 5 years. Sixty-nine eyes were enucleated during the first 5 years after brachytherapy, and treatment failure was reported for 57 eyes. The Kaplan-Meier estimate of proportion of patients undergoing enucleation by 5 years was 12.5% (95% confidence interval [Cl], 10.0%-15.6%); the risk of treatment failure was 10.3% (95% Cl, 8.0%-13.2%). Treatment failure was the most common reason for enucleation within 3 years of treatment; beyond 3 years, ocular pain was most common. Risk factors for enucleation were greater tumor thickness, closer proximity of the posterior tumor border to the foveal avascular zone, and poorer baseline visual acuity in the affected eye. Risk factors for treatment failure were older age, greater tumor thickness, and proximity of the tumor to the foveal avascular zone. Local treatment failure was associated weakly with reduced survival after controlling for baseline tumor and personal characteristics (adjusted risk ratio, 1.5; P = 0.08). 1125Conclusions. Local treatment failure and enucleation were relatively infrequent events after brachytherapy within the COMS. Treatment failure typically occurred early and was associated weakly with poorer survival. The COMS randomized trial documented the absence of a clinically or statistically significant difference in survival for patients randomly assigned to enucleation versus brachytherapy. This analysis documents the efficacy of brachytherapy to achieve sustained local tumor control and to conserve the globe. Ophthalmology 2002,109:2197-2206 (C) 2002 by the American Academy of Ophthalmology.