Sandra M. Reynolds

Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea‐pigs

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 Aδ‐ 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 Aδ‐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 mechanoreceptors 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 COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: IV. Local treatment failure and enucleation in the first 5 years after brachytherapy. COMS report no. 19.

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 I(125) 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 [CI], 10.0%-15.6%); the risk of treatment failure was 10.3% (95% CI, 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). CONCLUSIONS Local treatment failure and enucleation were relatively infrequent events after I(125) 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.

Screening for Metastasis From Choroidal Melanoma: The Collaborative Ocular Melanoma Study Group Report 23

PURPOSE To describe the predictive value of liver function tests (LFTs), chest x-ray, and diagnostic imaging for detecting melanoma metastasis during routine follow-up after treatment for choroidal melanoma. MATERIALS AND METHODS Prospective longitudinal follow-up of patients enrolled onto two randomized trials was conducted by the Collaborative Ocular Melanoma Study (COMS) Group. Baseline and annual or semiannual systemic and laboratory evaluations were performed according to a standard protocol for 2320 patients enrolled on the COMS. RESULTS COMS patients were screened annually for metastasis and new cancers using LFTs (alkaline phosphatase, AST, ALT, or bilirubin). Elevated findings (1.5 to 2 times upper limit of normal) on LFT prompted a diagnostic or imaging test to confirm or rule out cancer recurrence. Of 714 patients with clinical reports of metastasis, 675 patients died. Of these 675 patients, all but four had either histopathologically confirmed or clinically suspected metastatic melanoma present at the time of death. Among all patients, the 5-year cumulative diagnosis rate of metastatic melanoma was 24% (95% CI, 22% to 27%). Based on all patients with reported metastasis, the sensitivity, specificity, positive predictive value and negative predictive value associated with at least one abnormal LFT before first diagnosis of metastasis at any site was 14.7%, 92.3%, 45.7% and 71.0%, respectively. CONCLUSION Use of LFTs results followed by diagnostic tests has high specificity and predictive values but low sensitivity. Better tests are needed to identify earlier metastatic disease associated with choroidal melanoma.

Multisite Comparison of High-Sensitivity Multiplex Cytokine Assays†

ABSTRACT The concentrations of cytokines in human serum and plasma can provide valuable information about in vivo immune status, but low concentrations often require high-sensitivity assays to permit detection. The recent development of multiplex assays, which can measure multiple cytokines in one small sample, holds great promise, especially for studies in which limited volumes of stored serum or plasma are available. Four high-sensitivity cytokine multiplex assays on a Luminex (Bio-Rad, BioSource, Linco) or electrochemiluminescence (Meso Scale Discovery) platform were evaluated for their ability to detect circulating concentrations of 13 cytokines, as well as for laboratory and lot variability. Assays were performed in six different laboratories utilizing archived serum from HIV-uninfected and -infected subjects from the Multicenter AIDS Cohort Study (MACS) and the Womens Interagency HIV Study (WIHS) and commercial plasma samples spanning initial HIV viremia. In a majority of serum samples, interleukin-6 (IL-6), IL-8, IL-10, and tumor necrosis factor alpha were detectable with at least three kits, while IL-1β was clearly detected with only one kit. No single multiplex panel detected all cytokines, and there were highly significant differences (P < 0.001) between laboratories and/or lots with all kits. Nevertheless, the kits generally detected similar patterns of cytokine perturbation during primary HIV viremia. This multisite comparison suggests that current multiplex assays vary in their ability to measure serum and/or plasma concentrations of cytokines and may not be sufficiently reproducible for repeated determinations over a long-term study or in multiple laboratories but may be useful for longitudinal studies in which relative, rather than absolute, changes in cytokines are important.

Limited inferior macular translocation for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration.

PURPOSE To review a series of patients with age-related macular degeneration undergoing limited macular translocation for the treatment of subfoveal choroidal neovascularization, to determine short-term visual acuity outcomes, to measure amounts of attainable retinal movement, and to identify prognostic factors. METHODS A retrospective review was conducted on a consecutive series of patients undergoing inferior limited macular translocation with scleral imbrication for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration. The main outcome measures investigated were distance of macular translocation, visual acuity at 3 and 6 months after surgery, change in visual acuity from baseline, and the development of intraoperative and postoperative complications. Univariate and multivariate analyses of a number of potential prognostic factors were undertaken. RESULTS Macular translocation was achieved in all 102 eyes (101 patients) included in this study. The range of movement varied from 200 to 2,800 microm with a median movement of 1, 200 microm. Nearly 33% of the study group achieved a visual acuity better than 20/100 at 3 months, and 49% achieved this vision at 6 months. At 3 and 6 months, 37% and 48% of the study group, respectively, experienced 2 or more lines of improvement on visual acuity testing, and by 6 months 16% experienced greater than 6 lines of visual improvement. Good baseline vision, achieving the desired amount of macular translocation, a greater amount of macular translocation, and recurrent choroidal neovascularization at baseline were associated with better visual acuities at 3 and 6 months. Poor preoperative vision and the development of complications were associated with worse vision at 3 and 6 months. CONCLUSIONS Limited macular translocation is a technically feasible procedure that can lead to significant visual improvement and good visual acuity in some patients presenting with subfoveal choroidal neovascularization associated with age-related macular degeneration. A randomized prospective clinical trial of this surgical technique is warranted.

Complications associated with limited macular translocation

PURPOSE To report the ocular complications associated with the limited macular translocation procedure. METHODS Retrospective review of 153 consecutive eyes of 151 patients that had the limited macular translocation procedure for subfoveal choroidal neovascularization between April 1996 and February 1999. The major study variables investigated included the incidence of specific ocular complications and their impact on visual acuity at 3 months after the surgery. In addition, baseline patient characteristics and operative factors were evaluated to determine whether they were significant risk factors for the development of an ocular complication. The existence of a surgical procedure learning process was investigated. RESULTS One hundred forty-one (92.15%) of 153 eyes achieved at least 3-month follow-up. At least one complication occurred in 53 of 153 eyes (34.6%) and in 51 of these 53 eyes (96. 22%) the complications occurred before 3 months of postoperative follow-up. The intraoperative and postoperative complications included retinal detachment (17.4%), retinal breaks (13.4%), macular holes (7.8%), macular fold (4.6%), and intraocular hemorrhage (vitreous, subretinal, or choroidal; 9.2%). Eyes that developed retinal detachment, subretinal hemorrhage, and macular fold had significantly more loss of visual acuity than eyes without each of these complications (P =.0001, P =.038, and P =.027, respectively). The presence of predominantly classic choroidal neovascularization, the occurrence of an intraoperative retinal break, any intraocular hemorrhage, or macular fold formation were significantly associated with retinal detachment (P =.021, P =.025, P =.013, and P =.014, respectively). The incidence of any complication, retinal detachment, and hemorrhage significantly decreased during the study period, suggesting a learning process (P =.03, P =.006, P =.027, respectively). CONCLUSIONS A variety of ocular complications can occur during or after limited macular translocation, and some are associated with reduced postoperative visual acuity. Improved surgical techniques and experience may significantly reduce the incidence of these complications.

Selective Expression of a Sodium Pump Isozyme by Cough Receptors and Evidence for Its Essential Role in Regulating Cough

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 α3 subunit of Na+-K+ ATPase. Intravital staining of cough receptors by FM2-10, cough receptor excitability in vitro, and coughing in vivo are 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.

Inferior limited macular translocation for subfoveal choroidal neovascularization secondary to age-related macular degeneration: 1-year visual outcome and recurrence report.

PURPOSE To report the 1-year visual outcomes and incidence of persistent and recurrent choroidal neovascularization (CNV) after limited macular translocation (LMT) for subfoveal CNV in patients with age-related macular degeneration (ARMD). DESIGN Interventional case series. METHODS Retrospective review of 102 consecutive eyes of 101 patients that had the inferior limited macular translocation procedure for subfoveal choroidal neovascularization secondary to ARMD. The outcome measures were visual acuity at 12 months after surgery, change in visual acuity from baseline, the proportion of eyes with moderate (3 or more lines) or severe (6 or more lines) visual acuity loss, and cumulative incidence of persistent or recurrent CNV and its impact on visual acuity. Cumulative incidence was estimated using Kaplan-Meier survival analysis methods. Association between persistence and recurrence of CNV and the Snellen visual acuity recorded at each follow-up visit was evaluated using the Wilcoxon rank-sum test. RESULTS Eighty-six (84.3%) of 102 eyes completed the 1-year follow-up. By 12 months postoperatively, 35 (40.7%) of the 86 eyes achieved visual acuity of 20/100 or better while 34 (39.5%) of the 86 eyes experienced 2 or more Snellen lines of visual improvement. In the 52 eyes with effective translocation and complete laser photocoagulation of the CNV complex with sparing of the sensory fovea, the estimated incidence of recurrence was 34.6% at 12 months (95% confidence interval of 21%-48%). Sixty-five percent of the recurrences were subfoveal and caused a decrease in visual acuity. There was a trend toward worse median change in visual acuity in eyes with persistent or recurrent CNV. CONCLUSIONS Limited macular translocation for the treatment of subfoveal CNV secondary to ARMD is associated with improvement in visual acuity in approximately 39.5% of eyes and enables complete laser photocoagulation of the neovascular complex with sparing of the sensory macula in approximately 60.4% of eyes that complete 1 year follow-up. Persistence and recurrence of CNV are common after LMT and are important causes of vision loss. Further studies are warranted to more precisely evaluate the risks and benefits of LMT in ARMD.

Histopathologic Characteristics of Choroidal Melanoma in Eyes Enucleated After Iodine 125 Brachytherapy in the Collaborative Ocular Melanoma Study

OBJECTIVE To describe the histopathologic findings in eyes with uveal melanoma that had secondary enucleation after failed brachytherapy plaque treatment. METHODS Histopathologic findings in eyes that had secondary enucleation after plaque radiation therapy in the Collaborative Ocular Melanoma Study (COMS) were reported on a standardized data form. The findings were compared with eyes that had primary enucleation for uveal melanoma. RESULTS Seventy-five eyes that had secondary enucleation were studied. Compared with primary enucleations, tumors in the irradiated eyes had lower mitotic activity, a smaller proportion of histologically intact tumor, more inflammation, more fibrosis, and more vascular damage within the tumor. In addition, compared with primary enucleations, eyes previously irradiated had a higher frequency of retinal invasion by the tumor and greater damage to the retinal vasculature, consistent with radiation retinopathy; neovascularization of the iris; and vitreous hemorrhage. Tumor growth or extrascleral extension was confirmed histopathologically in 25 of 42 eyes (60%) enucleated because of a reported failure of local control. CONCLUSIONS Eyes with secondary enucleation after brachytherapy differ histopathologically from eyes with primary enucleation for uveal melanoma. These histopathologic differences may be due to the effects of radiation, tissue conditions related to plaque failure, and, in some cases, tumor growth. In 40% of eyes enucleated because of suspected failure of local control, increased tumor size could not be histologically confirmed.

I-125 brachytherapy for choroidal melanoma photographic and angiographic abnormalities: the Collaborative Ocular Melanoma Study: COMS Report No. 30.

OBJECTIVES (1) To summarize the protocol used for grading features of postradiation abnormalities from fundus photographs and fluorescein angiograms of patients enrolled in the Collaborative Ocular Melanoma Study (COMS); (2) to document the prevalence of features of interest in the posterior pole of these eyes during 8 years of follow-up; and (3) to investigate baseline patient, tumor, and treatment characteristics associated with posterior pole features. DESIGN Observational case series within a randomized, multicenter clinical trial. PARTICIPANTS We evaluated 650 patients who were assigned to and received iodine-125 brachytherapy in the COMS for medium-sized tumors. METHODS Color fundus photographs and fluorescein angiograms were taken at baseline and 2, 5, and 8 years; 30 features were graded according to a standard protocol. MAIN OUTCOME MEASURES Prevalence at selected time intervals of fundus photographic features associated with retinopathy and optic neuropathy. RESULTS The percentage of patients with >/=1 feature of interest was 49.2% at baseline, 84.4% at 2 years, 91.2% at 5 years, and 90.7% at 8 years. The most frequent findings across all follow-up examinations were macular microaneurysms (75.6% of examinations), macular angiographic leakage (75.1%), and optic disc hyperfluorescence (62.8%). The median number of features present increased significantly with each follow-up to a maximum of 7 features at 8 years. The prevalence of neovascularization of the disc at 5 years was 5.2%. The prevalence of optic neuropathy at 5 years was 27.4%. Prognostic factors for more prevalent and severe posterior pole abnormalities were diabetes, tumor location close to both optic nerve and foveal avascular zone, and greater dose of radiation to the foveola and optic nerve head. CONCLUSIONS The amount and severity of retinopathy and optic neuropathy after iodine-125 brachytherapy increased through 8 years of follow-up. Assessment of photographs and angiograms taken in accord with a standard protocol provided reliable estimates of rates of development of features of retinopathy and optic neuropathy in eyes treated using the COMS brachytherapy protocol. Our findings support earlier reports that tumor factors in addition to radiation treatment may contribute to posterior pole abnormalities. FINANCIAL DISCLOSURE(S) The authors have no proprietary or commercial interest in any materials discussed in this article.