Oropharyngeal Secretions Research Articles

Management of Oropharyngeal and Tracheobronchial Secretions in Patients with Neurologic Disease

Neurologic disorders may impair the normal clearance of secretions. Effective palliation requires the management of excessive oral, pharyngeal and/or tracheobronchial secretions. This requires an understanding of underlying mechanisms and familiarity with the many available medical and surgical treatment options. The authors intend to review the relevant anatomy and physiology along with the available medical, surgical and physical therapies available to treat this commonly encountered problem. A review of current management and the supporting literature. Clinicians have many effective therapeutic options to choose from when managing the excessive oral, pharyngeal and/or tracheobronchial secretions caused by neurologic disorders. Treatment choices that are predicated upon pathophysiologic causes and patient status are the most likely to succeed.

Descending polyneuropathy in an intravenous drug user

A 27-year-old male intravenous drug user presented to the Emergency Department of St James's Hospital with a 1-week history of progressive dysphasia, dysphagia and difficulty 'holding his head up' and 'keeping his eyes open'. He also complained of increasing weakness in his upper limbs, as a result of which he kept dropping things. He was on a methadone program but was using both intravenous heroin and cocaine at the time of presentation. Examination of his motor function revealed generalized hypotonia, hyporeflexia and reduced power in both upper limbs. No sensory loss was observed. Co-ordination was intact. The clinical picture of a proximal symmetrical descending weakness and an absence of sensory loss was suggestive of botulism. Clostridium botulinum is a spore-forming, obligate anaerobe. The three forms of human botulism are food-borne, wound and intestinal. A fourth man-made form is produced from aerosolized botulinum toxin and results in inhalational botulism. A little as 1 g of aerosolized botulinum toxin has the potential to kill 1.5 million people. Toxin is detected in serum or stool specimens in only approximately 46% of clinically diagnosed cases. Treatment involves supportive care and early passive immunization with equine antitoxin. Patients should be regularly assessed for loss of gag and cough reflex, control of oropharyngeal secretions, oxygen saturation, vital capacity and inspiratory force. When respiratory function begins to deteriorate, anticipatory intubation is indicated. Early symptom recognition and early treatment with antitoxin are essential in order to prevent mortality, and to prevent additional cases, it is important to ascertain the presence of similar symptoms in contacts of the patient and local public health officials must be notified as one case may herald an outbreak. Given the continued threat of bioterrorism, the Centre for Disease Control Surveillance System in the United States must also be notified of any cases of botulism.

Nevirapine Concentration in Cervicovaginal and Oropharyngeal Secretions after Single-Dose Administration to the Mother

Nevirapine Concentration in Cervicovaginal and Oropharyngeal Secretions after Single-Dose Administration to the Mother

Nosocomial Pneumonia and Oral Health

This article will critically review the evidence linking pneumonia to the aspiration of microbe-laden oropharyngeal secretions and tie that to the predisposition for these processes to affect dependent, medically compromised individuals. The goal of this review is to alert the reader to the role that oral disease and oral health play in fostering and preventing, respectively, widespread and potentially fatal pulmonary disease among high-risk individuals.

Haemophilus influenzae type b carriage among 3- to 24-month-old Turkish children

There are few studies from developing countries on the epidemiology of Haemophilus influenzae (Hib) infections among infants and children. We set out to determine the prevalence of oropharyngeal Hib colonization among Turkish children younger than two years of age and to identify antimicrobial resistance among the isolates. A cross-sectional study was conducted on 818 healthy children and oropharyngeal secretions were sampled. The carriage rate of Hib was found to be 7.2% and this increased significantly with age. Carriage of Hib among 3- to 6-month-old children (3.5%) was higher than expected and was significantly higher among children who were passive smokers (P=0.04). Logistic regression analysis showed that breastfeeding status was the sole significant factor for colonization (OR 2.2, 95% CI 1.26-3.82). Antimicrobial susceptibility tests on 56 isolates of H. influenzae showed that 51.8% and 21.4% were resistant to trimethoprim-sulphamethoxazole and ampicillin respectively. Other notable resistances were to cefalexin (10.7%) and chloramphenicol (3.6%); no isolates were resistant to ceftriaxone.

Model of experimental infection in healthy and immunosuppressed swiss albino mice (Mus musculus) using Candida albicans strains with different patterns of enzymatic activity

With the purpose to evaluate Candida albicans virulence in vivo, two strains selected were based on their phospholipase and proteinase activity, and used in a model of experimental infection. One strain, isolated from vaginal secretion, was stocked at the URM Culture Collection for 43 years and presented high phospholipase (Pz=0.217) and proteinase (1.386 U.mL-1) activity. The other strain was a fresh strain isolated from oropharyngeal secretion of an AIDS patient, and presented low phospholipase (Pz=0.482) and proteinase (0.780 U.mL-1) activity. The strains were inoculated via intraperitoneum in immunosuppressed and non-immunosuppressed mice (Mus musculus) and the infection was evaluated over a period of 21 days. Liver, spleen, lungs and kidneys were aseptically removed and the blood of the animals was collected every 72 h. The number of colony forming units (c.f.u) isolated from each organ was counted and a histopathologic examination was performed. The freshly isolated strain was more virulent than the stocked strain, as shown by the number of positive cultures and severity of the lesions observed at the histopathologic examination. A correlation between the in vitro enzymatic activity and the in vivo virulence was not observed.

SDS-Page and numerical analysis of Candida albicans from human oral cavity and other anatomical sites

The aim of the present research was to evaluate the protein polymorphism degrees among forty-eight C. albicans isolates from fourteen anatomical sites of clinical patients by polyacrylamide gel electrophoresis (SDS-PAGE) and numerical analyzes, in order to identify subspecies and their similarities in some infectious niches. Cell cultures were grown in YEPD medium, collected by centrifugation, and washed in cold saline solution. The whole-cell proteins were extracted by cell disruption using glass beads and submitted to SDS-PAGE technique. After electrophoresis, the protein bands were stained with coomassie-blue and analyzed by statistics package NTSYS-pc version 1.70 software. Similarity matrixes and dendrograms were generated by application of similarity coefficient of simple matching and UPGMA algorithm, respectively. The results obtained showed several C. albicans subtypes and their similarity degrees (80% to 100%). Such data showed that same patients may be infected by two or more C. albicans subtypes in certain anatomical sites (i.e. only in oral cavity of immunocompromised patients, blood, or tracheal secretion), or yet, two or more patients can be infected in identical anatomical sites (i.e. bronchial washing, urine, oral cavity, tracheal secretion, vaginal secretion, and healthy saliva) with a same C. albicans subtype. However, two or more patients also can show infections in corresponding sites (i.e. oral cavity of immunocompromised patients, blood, oropharyngeal secretion, oral cavity, tracheal secretion, vaginal secretion, and healthy saliva) by different C. albicans subtypes. Besides, two or more patients also can be infected with identical or different C. albicans subtypes in different anatomical sites (i.e.1. identical subtypes in vaginal secretion, tracheal secretion, and urine; abdominal secretion and spittle; drainage and oral cavity; catheter and healthy saliva - i.e.2. subtypes different in bronchial washing, oropharyngeal secretion, pulmonary secretion, oral cavity of immunocompromised patients, and blood). Complementary studies involving C. albicans sample isolated from several anatomical sites of immunocompetent or immunocompromised patients (before, during and after specifics therapies) and their families or hospital workers must be done in order to establish the sources of C. albicans colonization. The whole-cell proteins profile performed by SDS-PAGE associated with computer-assisted numerical analysis may provide preliminary criteria for taxonomic and epidemiological studies of such microorganisms.

Risk factors for ventilator-associated pneumonia: from epidemiology to patient management.

Risk factors for the development of ventilator-associated pneumonia (VAP), as identified in epidemiological studies, have provided a basis for testable interventions in randomized trials. We describe how these results have influenced patient treatment. Single interventions in patients undergoing intubation have focused on either reducing aspiration of oropharyngeal secretions, modulation of colonization (in either the oropharynx, the stomach, or the whole digestive tract), use of systemic antimicrobial prophylaxis, or ventilator circuit changes. More recently, multiple simultaneously implemented interventions have been used. In general, routine measures to decrease oropharyngeal aspiration and antibiotic-containing prevention strategies appear to be the most effective, and the latter were associated with improved rates of patient survival in recent trials. These benefits must be balanced against the widespread fear of emergence of antibiotic resistance. In hospital settings with low baseline levels of antibiotic resistance, however, the benefits to patient outcome may outweigh this fear of resistance. In settings with high levels of antibiotic resistance, combined approaches of non-antibiotic using strategies and education programs might be most beneficial.

HIV infection and human herpesvirus-8 oral shedding among men who have sex with men.

Human herpesvirus-8 (HHV-8) is frequently detected in oropharyngeal secretions from HIV-infected men who have sex with men (MSM), and contact with saliva may be an important mode of HHV-8 transmission. A total of 196 MSM were followed over 2 years to determine the correlates of HHV-8 oropharyngeal shedding. A total of 134 (68%) of 196 participants were HHV-8 seropositive upon enrollment, and 9 (15%) of 62 participants seroconverted to HHV-8 during follow-up. HHV-8 DNA was detected in 43 (22%) of 196 participants: 39 (27%) of 134 HHV-8 seropositive, 4 (8%) of 53 HHV-8 seronegative, and 5 (56%) of 9 seroconverters to HHV-8. HHV-8 was detected in 101 (15%) of 696 total oral specimens: 84 (17%) of 481 samples from HHV-8-seropositive men, 6 (3%) of 180 samples from HHV-8-seronegative men, and 11 (31%) of 35 samples from seroconverters. Using adjusted marginal structural models, HHV-8 shedding was higher in men not receiving highly active antiretroviral therapy (odds ratio 2.4, 95% CI 1.0-6.0, P = 0.06), with CD4 counts > 200 cells/mm (odds ratio 4.8, 95% CI 1.0-22.8, P = 0.05), or with detectable oral leukocyte esterase (odds ratio 5.0, 95% CI 2.0-12.5, P < 0.01). CD4 count, antiretroviral therapy, and oral inflammation may influence HHV-8 oropharyngeal shedding.

Rapid antigen-capture assay to detect West Nile virus in dead corvids.

The utility of the VecTest antigen-capture assay to detect West Nile virus (WNV) in field-collected dead corvids was evaluated in Manitoba and Ontario, Canada, in 2001 and 2002. Swabs were taken from the oropharynx, cloaca, or both of 109 American Crows, 31 Blue Jays, 6 Common Ravens, and 4 Black-billed Magpies from Manitoba, and 255 American Crows and 28 Blue Jays from Ontario. The sensitivity and specificity of the antigen-capture assay were greatest for samples from American Crows; oropharyngeal swabs were more sensitive than cloacal swabs, and interlaboratory variation in the results was minimal. The sensitivity and specificity of the VecTest using oropharyngeal swabs from crows were 83.9% and 93.6%, respectively, for Manitoba samples and 83.3% and 95.8%, respectively, for Ontario birds. The VecTest antigen-capture assay on oropharyngeal secretions from crows is a reliable and rapid diagnostic test that appears suitable for incorporation into a WNV surveillance program.

Detection of Group A beta-hemolytic Streptococcus employing three different detection methods: culture, rapid antigen detecting test, and molecular assay.

In order to study the prevalence of Group A beta-hemolytic Streptococcus (GABHS) pharyngotonsillitis in our pediatric population and to compare different sampling methods of GABHS detection, oropharyngeal swabs from 50 children with acute pharyngotonsillitis, between 1 and 12 years old, were used simultaneously for culture, molecular assay and rapid GABHS antigen detection tests. All children were clinically examined at the Division of Pediatric Otorhinolaryngology of the Federal University of São Paulo. Diagnostic criteria were based on signs and symptoms, including sore throat, fever and oropharyngeal purulent secretion. Children that had been treated with antibiotics were excluded. Overall, combining the three methods, the prevalence of GABHS was 34%. GABHS was diagnosed in 30% of the bacterial cultures, in 25% of the samples tested with the molecular nucleic acid hybridization method and in 26% of the cases tested with the rapid antigen detection test. There was no significant difference between these three methods.

Predictive value of accumulated oropharyngeal secretions for aspiration during video nasal endoscopic evaluation of the swallow.

The purpose of this prospective study was to investigate the predictive value of oropharyngeal secretions by use of 5-point and modified 3-point secretion scales for aspiration of food or liquid and diet recommendation outcomes. One hundred consecutive patients and 4 control subjects participated. The 5-point secretion severity scale correlated highly to aspiration (Spearman's rho = .516, p < .0001) and to diet recommendation outcomes (Spearman's rho = .72, p < .0001). Patients who received tube feedings were more likely to demonstrate a higher secretion level than patients who received oral feedings (Pearson chi squared analysis value = 25.461, p < .0001). Patients with a tracheotomy tube tended to demonstrate higher secretion levels than patients without a tracheotomy tube (Spearman's rho = .446, p < .0001). The relationship of the 3-point secretion severity scale level with aspiration was .488, p < .0001 (Spearman's rho), and that with diet recommendation outcomes was .746, p < .0001 (Spearman's rho).

A Multisite Survey of Suctioning Techniques and Airway Management Practices

Ventilator-associated pneumonia, common in critically ill patients, is associated with microaspiration of oropharyngeal secretions and may be related to suctioning and airway management practices. To describe institutional policies and procedures related to closed-system suctioning and airway management of intubated patients, and to compare practices of registered nurses and respiratory therapists. A descriptive, comparative, multisite study of facilities that use closed-system suctioning devices on most intubated adults was conducted. Nurses and respiratory therapists who worked at the sites completed surveys related to their practices. A total of 1665 nurses and respiratory therapists at 27 sites throughout the United States responded. The typical respondent had at least 6 years' experience with patients receiving mechanical ventilation (61%) and a baccalaureate degree or higher (54%). Most sites had policies for management of endotracheal tube cuffs (93%), hyperoxygenation (89%) and use of gloves (70%) with closed-system suctioning, and instillation of isotonic sodium chloride solution for thick secretions (74%). Only 48% of policies addressed oral care and 37% addressed oral suctioning. Nurses did more oral suctioning and oral care than respiratory therapists did, and respiratory therapists instilled sodium chloride solution more and rinsed the suctioning device more often than nurses did. Policies vary widely and do not always reflect current research. Consistent performance of practices such as wearing gloves for airway management and maintaining endotracheal cuff pressures must be evaluated. Collaborative, research-based policies and procedures must be developed and implemented to ensure best practices for intubated patients.

Manejo clínico de las neumonías adquiridas en la comunidad

Streptococcus pneumoniae is the most common cause of CAP, at a rate of 9.6% to 48.8% of cases with an etiologic diagnosis. Mycoplasma pneumoniae is one of the primary causes of pneumonia in young patients, mainly those under 20 years old. Chlamydia pneumoniae can affect young patients and adults with underlying diseases, causing 5%-15% of CAP episodes. Chlamydia psittaci and Coxiella burnetii are uncommon causes of CAP, as are viral influenza and respiratory syncytial virus, which can cause pneumonia in adults during the cold months. Legionella pneumophila accounts for 2%-6% of CAP in the majority of series of hospitalized patients. Haemophilus influenzae is an infrequent cause of pneumonia in adults, affecting mainly elderly people and patients with underlying diseases, such as chronic airway obstruction and tobacco use. Moraxella catarrhalis mainly affects patients with underlying bronchopulmonary disease, such as chronic airway obstruction. Staphylococcus aureus is also an uncommon causal agent, accounting for 1.7% of 2145 cases of pneumonia,5 although it is more frequent in patients with severe CAP. Aerobic gram-negative bacilli, such as Klebsiella spp. (1.2% of 2458 cases of CAP) and Escherichia coli (0.8%) are infrequent causes of CAP5. In severe cases, the frequency of enterobacteria is higher, causing 11.8% of the episodes. Pseudomonas aeruginosa is a quite infrequent causal agent, accounting for 0.5% of cases without criteria of severity and with an etiologic diagnosis, and 3.8% of severe cases5. The frequency of CAP involving anaerobic microorganisms is unknown, though it has been estimated at about 10%. The most common predisposing factor is the aspiration of oropharyngeal secretions during episodes of altered mental status or other circumstances favoring this event, such as dysphagia, intestinal obstruction, periodontal disease, tonsillectomy or dental extractions. In series of patients with severe community pneumonia, the most frequent agents are S. pneumoniae, followed by Legionella spp. and H. influenzae6 and other gram-negative bacilli, and aspiration pneumonia, whereas in series of cases treated on an outpatient basis, pneumococcus, Chlamydia spp. and M. pneumoniae predominate. The relationships among the various etiologic agents and predisposing factors are summarized in Table 1.

Nosocomial pneumonia.

Nosocomial pneumonia, or terminal pneumonia as it was formerly called, results from the repetitive microaspiration of contaminated oropharyngeal secretions into the lungs in the presence of impaired host defenses. This pathophysiologic sequence was suggested by the observations of Osler but clarified by the seminal work of Rouby and colleagues. The enormous impact of antimicrobial agents on the organisms responsible for nosocomial pneumonias was first identified by Kneeland and Price who found that organisms of the normal pharyngeal flora virtually disappeared in terminal pneumonias following administration of these drugs, being replaced by gram-negative bacilli. The remarkable susceptibility of seriously ill patients to becoming colonized by exogenous organisms, even in the absence of antimicrobial therapy, was shown by Johanson et al. These factors, antibiotics and the change in bacterial binding receptors in the airways associated with illness, lead to infections caused by exogenous organisms that are frequently resistant to antimicrobial agents. Clinical findings that usually identify patients with respiratory infections are unreliable for the diagnosis of nosocomial pneumonias as shown by Andrews et al. Invasive techniques, especially the protected specimen brush (PSB) technique, avoid contamination of the specimen by proximal secretions and accurately reflect the bacterial burden of the lung, as first shown by Chastre et al. Quantitation of such specimens serves as an excellent proxy for direct cultures of the lung and are the current gold standard for diagnosis.

Yeasts isolated from clinical samples of AIDS patients

In order to investigate yeasts in oropharyngeal secretion, urine, sputum and inguinal scales from AIDS patients, clinical samples were collected from one hundred patients interned in the Infectious and Parasitic Diseases Sector of the Hospital das Clinicas of the Universidade Federal de Pernambuco and in Hospital Universitario Osvaldo Cruz of the Universidade de Pernambuco. Yeasts were isolated from seventy-two out of one hundred and eight clinical samples. The isolated yeasts were: Candida albicans (sixty-two isolates), Candida tropicalis (four isolates), Candida glabrata (two isolates), Candida parapsilosis (two isolates), Candida krusei (one isolate) and Trichosporon pullulans (one isolate).

Physiology of the aerodigestive system and aberrations in that system resulting in aspiration.

Aspiration pneumonia remains a significant and often devastating problem in critically ill patients. It is unclear whether aspiration pneumonia occurs because of problems in the handling of oropharyngeal secretions or if the reflux of gastric contents is the major etiological factor. Additionally, the obvious breakdown of upper aerodigestive protective mechanisms in the critically ill patient population is largely unstudied. Finally, the impact and contribution of tubes, both endotracheal and nasoenteral, on aspiration pneumonia is unclear. A Medline literature search on scientific and review articles concerning the normal physiology of the aerodigestive tract and factors that compromised normal physiology was undertaken. Readings were supplemented by expert outside opinion from researchers in these fields and from the combined expertise from a multidisciplinary panel of experts assembled at a recent summit on aspiration pneumonia. Changes in the normal physiology of the aerodigestive tract are vast and varied and dependent on the response to injury, iatrogenic interventions, and the use of nasoenteral and endotracheal tubes. The effects on gastric and esophageal motility are likely dynamic and represent an ongoing but changing risk of reflux for the patient. Nasoenteral and endotracheal tubes likely compromise upper aerodigestive protective mechanisms. More research is needed on the functioning of the aerodigestive protective mechanisms in critically ill patients. Understanding of the dynamic changes in gastrointestinal motility will also be an important factor to decrease the incidence of aspiration pneumonia in this patient population.

Trichosporon pullulans (Lidner) Diddens &amp; Lodder isolated from the oral cavity of AIDS patient

Trichosporon has been reported as a remarkable emerging pathogen and usually occurs in imunodrepressed patients. An oropharyngeal secretion sample was collected from a patient with AIDS, at the Sector of Infectious and Parasitic Diseases, Osvaldo Cruz University Hospital, Pernambuco State, Brazil. No yeast cells or arthroconidia were observed in the direct exam, but a culture was positive for Trichosporon pullulans, which is being reported in an AIDS patient for the first time.

Experimental infection of the Sigmodon alstoni cotton rat with Caño Delgadito virus, a South American hantavirus.

Forty-eight Sigmodon alstoni (Alston's cotton rat) were inoculated with Caño Delgadito (CDG) virus to extend our knowledge and understanding of the natural host relationships of the hantaviruses indigenous to the Americas. Infectious CDG virus was recovered from oropharyngeal secretions, urine, or solid tissues of nine of 12 animals killed on day 9 post-inoculation (PI), 14 of 24 animals killed on day 18 or 27 PI, and none of 12 animals killed on day 54 PI. In addition, virus-specific RNA was detected in the kidneys of six of the 12 animals killed on day 54 PI, and adult cotton rats inoculated with the kidneys of four animals killed on day 54 PI developed antibody to CDG virus. Collectively, the results indicate that CDG virus can establish lengthy (perhaps lifelong) infections in Alston's cotton rat and thus support the concept that S. alstoni is the principal host of CDG virus.

Preventing Enteral Tube Feeding–Associated Aspiration: Something No One Should Get Blue in the Face Over

In this issue of Nutrition in Clinical Practice, Maloney et al review the use of blue food dye for coloring enteral tube feeding and make a plea for the discontinuation of this practice. This popular technique has been used for nearly two decades to detect early evidence of pulmonary aspiration in an attempt to prevent the regurgitation of a large volume of enteral tube feeding from the gastrointestinal tract into the respiratory tree. To put this paper into context, I feel it is important to understand the pathophysiologic events that surround the development of aspiration pneumonia in patients receiving enteral tube feeding so that methods to prevent this complication can be appropriately applied. Nearly 50% of normal adults aspirate oropharyngeal secretions while they are sleeping. Lung injury generally does not occur because only a small volume is inhaled, most of these secretions are cleared by coughing and normal mucociliary function, and an intact immune system clears any bacteria that find their way into the lower respiratory tract. Aspiration pneumonia occurs when oropharyngeal material is not readily cleared from the lung or contains pathogenic microorganisms. Aspiration pneumonitis is the result of the inhalation of acidic gastric contents and particulate material that cause a chemical injury to the lung. Aspiration pneumonia usually occurs in elderly patients with dysphagia or gastric dysmotility, whereas aspiration pneumonitis occurs at any age in patients with a marked decrease in their sensorium. This latter group is most often composed of patients who receive general anesthesia or experience events that include drug overdose, seizure, and cerebrovascular accident. Hospitalized patients, especially those who are critically ill, are at the greatest risk for aspiration and aspiration pneumonia. There are several factors that contribute to this higher risk, including prolonged maintenance of a supine position, gastroparesis as a result of the underlying illness, and nasogastric intubation. Hospitalized patients are also more likely to develop aspiration pneumonia because the gastric contents may be colonized by pathogenic microorganisms when the pH of the stomach is increased by the use of histamine-2 receptor blocking agents, proton-pump inhibitors, and enteral tube feeding. Finally, the prevalence of aspiration associated with enteral tube feeding is approximately 5% with an incidence of 2.4 events per 1000 tube-feeding days. Fortunately for many of these patients, the event is not life-threatening, and enteral nutrition may be safely continued. Maloney et al focus their attention on FD&C Blue No. 1, the most commonly used coloring agent that is added to enteral feeding. They describe why FD&C Blue No. 1 rapidly gained acceptance over the last two decades as a means of detecting early aspiration, and the response by the manufacturers to develop supplies that make the addition of FD&C Blue No. 1 to enteral formula relatively easy. He summarized the rationale that has been used to justify the addition of coloring agents to enteral formula and the research that generally does not lend great support to the use of this technique in identifying clinically important aspiration. Two case reports are described where mortality is attributed to FD&C No. 1. This is followed by summaries of seven other cases reported in the medical literature where it is suggested that FD&C Blue No. 1 resulted in significant morbidity and mortality. The implication that FD&C Blue No. 1 was responsible for the injury experienced by these patients is substantiated by the demonstration that FD&C Blue No. 1 was present in the serum of three patients, a finding that should not have occurred with the use of a “nonabsorbable” dye. It is suggested that FD&C Blue No. 1 acts as a mitochondrial toxin and that an increase in gut permeability is necessary for this dye to be absorbed into the circulation in amounts that are sufficient to cause this problem. It is concluded that the addition of blue dye and specifically the use of FD&C Blue No. 1 should be abandoned as a means of monitoring enteral tube feeding tolerance Correspondence and reprint requests: Douglas L. Seidner, MD, Digestive Disease Center, The Cleveland Clinic Foundation, 9500 Euclid Ave, A30, Cleveland, OH 44195.