Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span.

Aging is an established risk factor for vascular diseases, but vascular aging itself may contribute to the progressive deterioration of organ function. Here, we show in aged mice that vascular endothelial growth factor (VEGF) signaling insufficiency, which is caused by increased production of decoy receptors, may drive physiological aging across multiple organ systems. Increasing VEGF signaling prevented age-associated capillary loss, improved organ perfusion and function, and extended life span. Healthier aging was evidenced by favorable metabolism and body composition and amelioration of aging-associated pathologies including hepatic steatosis, sarcopenia, osteoporosis, "inflammaging" (age-related multiorgan chronic inflammation), and increased tumor burden. These results indicate that VEGF signaling insufficiency affects organ aging in mice and suggest that modulating this pathway may result in increased mammalian life span and improved overall health.

Malignant salivary gland tumours of the larynx: a single institution review.

Malignant salivary gland tumours of the larynx are very rare, with limited reports of clinical outcomes. We present the decade-long experience of a single institution. A 10-year retrospective chart review of a tertiary head and neck cancer centre was performed. Index patients were identified from a review of a pathology database, and reviewed by a head and neck pathologist. Patient demographics, presenting signs and symptoms, treatment modalities and clinical outcomes were extracted from electronic medical records. Six patients were included, with an age range of 44 to 69. All six had malignant laryngeal salivary gland tumours. Pathologies included: three adenoid cystic carcinoma (2 supraglottic, 1 subglottic), one mucoepidermoid carcinoma (supraglottic), one epithelial-myoepithelial carcinoma (supraglottic) and one adenocarcinoma (transglottic). All were treated with surgery (2 endolaryngeal, 4 open) and five of six with the addition of adjuvant therapy (4 radiotherapy, 1 concurrent chemoradiation). One patient had smoking history; no patients had significant alcohol history. With 4.5 years of median follow-up, none of the patients has had recurrence or local/distant metastasis. Salivary gland tumours of the larynx present in mid to late-age, and can be successfully managed with a multi-modality approach, resulting in excellent local and regional control rates.

Non-epithelial tumors of the larynx: a single institution review.

AIM: Non-epithelial tumors of the larynx are rare and encompass a wide range of pathology. We present the decade-long experience of a single institution to define clinical presentations and outcomes. MATERIAL AND METHODS: This is a ten year retrospective chart review of a tertiary head and neck cancer center. Index patients were identified from a review of a pathology database, and patient demographics, presenting signs and symptoms, treatment modalities, and clinical outcomes were extracted from electronic medical records. Epithelial tumors (squamous cell carcinoma, spindle cell carcinoma, and salivary tumors), granulomas, sarcoidosis, papilloma, and amyloidosis were all excluded. RESULTS: Twenty-four patients with ages ranging from 2months-old to 84years were identified. Malignant lesions (11) included chondrosarcoma (6), Kaposi's sarcoma (2), metastatic melanoma, synovial cell sarcoma, and T cell neoplasm. Six were operated upon endolaryngeally, but four required either upfront or salvage total laryngectomy. Two received adjuvant therapy. Benign lesions (13) included hemangioma (4), granular cell tumor (3), myofibroblastic tumor (2), schwannoma (2), chondroma, and ossifying fibromyxoid tumor. Nine underwent endolaryngeal operations, and four were managed medically or with observation. None have required aggressive open resection or total laryngectomy. CONCLUSION: Treatment approach of non-epithelial tumors of the larynx depends on the site and extent of the tumor, histology, and sensitivity of adjuvant therapy. Benign tumors can be managed without need for aggressive resection thereby sparing laryngeal function.

Evaluation of the Genetic Basis of Familial Aggregation of Pacemaker Implantation by a Large Next Generation Sequencing Panel.

BACKGROUND: The etiology of conduction disturbances necessitating permanent pacemaker (PPM) implantation is often unknown, although familial aggregation of PPM (faPPM) suggests a possible genetic basis. We developed a pan-cardiovascular next generation sequencing (NGS) panel to genetically characterize a selected cohort of faPPM. MATERIALS AND METHODS: We designed and validated a custom NGS panel targeting the coding and splicing regions of 246 genes with involvement in cardiac pathogenicity. We enrolled 112 PPM patients and selected nine (8%) with faPPM to be analyzed by NGS. RESULTS: Our NGS panel covers 95% of the intended target with an average of 229x read depth at a minimum of 15-fold depth, reaching a SNP true positive rate of 98%. The faPPM patients presented with isolated cardiac conduction disease (ICCD) or sick sinus syndrome (SSS) without overt structural heart disease or identifiable secondary etiology. Three patients (33.3%) had heterozygous deleterious variants previously reported in autosomal dominant cardiac diseases including CCD: LDB3 (p.D117N) and TRPM4 (p.G844D) variants in patient 4; TRPM4 (p.G844D) and ABCC9 (p.V734I) variants in patient 6; and SCN5A (p.T220I) and APOB (p.R3527Q) variants in patient 7. CONCLUSION: FaPPM occurred in 8% of our PPM clinic population. The employment of massive parallel sequencing for a large selected panel of cardiovascular genes identified a high percentage (33.3%) of the faPPM patients with deleterious variants previously reported in autosomal dominant cardiac diseases, suggesting that genetic variants may play a role in faPPM.

Effects of adenotonsillectomy on plasma inflammatory biomarkers in obese children with obstructive sleep apnea: A community-based study.

BACKGROUND: Obesity and obstructive sleep apnea syndrome (OSA) are highly prevalent and frequently overlapping conditions in children that lead to systemic inflammation, the latter being implicated in the various end-organ morbidities associated with these conditions. AIM: To examine the effects of adenotonsillectomy (T&A) on plasma levels of inflammatory markers in obese children with polysomnographically diagnosed OSA who were prospectively recruited from the community. METHODS: Obese children prospectively diagnosed with OSA, underwent T&A and a second overnight polysomnogram (PSG) after surgery. Plasma fasting morning samples obtained after each of the two PSGs were assayed for multiple inflammatory and metabolic markers including interleukin (IL)-6, IL-18, plasminogen activator inhibitor-1 (PAI-1), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9), adiponectin, apelin C, leptin and osteocrin. RESULTS: Out of 122 potential candidates, 100 obese children with OSA completed the study with only one-third exhibiting normalization of their PSG after T&A (that is, apnea-hypopnea index (AHI) ≤1/hour total sleep time). However, overall significant decreases in MCP-1, PAI-1, MMP-9, IL-18 and IL-6, and increases in adropin and osteocrin plasma concentrations occurred after T&A. Several of the T&A-responsive biomarkers exhibited excellent sensitivity and moderate specificity to predict residual OSA (that is, AHI⩾5/hTST). CONCLUSIONS: A defined subset of systemic inflammatory and metabolic biomarkers is reversibly altered in the context of OSA among community-based obese children, further reinforcing the concept on the interactive pro-inflammatory effects of sleep disorders such as OSA and obesity contributing to downstream end-organ morbidities.

CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene.

BACKGROUND: Recently, mutations in the transient receptor potential cation channel, subfamily V, member 4 gene (TRPV4) have been reported in Charcot-Marie-Tooth Type 2C (CMT2C) with vocal cord paresis. Other mutations in this same gene have been described in separate families with various skeletal dysplasias. Further clarification is needed of the different phenotypes associated with this gene. METHODS: We performed clinical evaluation, electrophysiology, and genetic analysis of the TRPV4 gene in 2 families with CMT2C. RESULTS: Two multigenerational families had a motor greater than sensory axonal neuropathy associated with variable vocal cord paresis. The vocal cord paresis varied from absent to severe, requiring permanent tracheotomy in 2 subjects. One family with mild neuropathy also manifested pronounced short stature, more than 2 SD below the average height for white Americans. There was one instance of dolichocephaly. A novel S542Y mutation in the TRPV4 gene was identified in this family. The other family had a more severe, progressive, motor neuropathy with sensory loss, but less remarkable short stature and an R315W mutation in TRPV4. Third cranial nerve involvement and sleep apnea occurred in one subject in each family. CONCLUSION: CMT2C with axonal neuropathy, vocal cord paresis, and short stature is a unique syndrome associated with mutations in the TRPV4 gene. Mutations in TRPV4 can cause abnormalities in bone, peripheral nerve, or both and may result in highly variable orthopedic and neurologic phenotypes.

Modern pacemakers: hope or hype?

In recent years, the role of implantable pacing devices has expanded beyond the arrhythmia horizon and contemporary pacemakers' attempt to meet the physiological needs of patients. Modern pacemakers' functions include various modes of dual-chamber pacing, rate-response algorithms with dual sensors for optimum physiological response, cardiac resynchronization therapy (CRT), arrhythmia-prevention algorithms, antitachycardia pacing, and hemodynamic monitoring. The automaticity features of pacemakers enable continuous or intermittent monitoring of various pacemaker parameters including battery voltage, pacing impedance, sensing levels, pacing thresholds, and daily activity log. Modern pacemakers offer "physiological pacing" algorithms that minimize ventricular pacing and reduce the incidence of atrial fibrillation significantly. Ventricular pacing in patients with intact atrioventricular (AV) conduction or intermittent advanced AV block should be minimized with a hope to reduce heart failure hospitalization and mortality. A reduction in all-cause mortality due to physiological pacing, except for the CRT, has yet to be demonstrated in a randomized trial. Overall, modern pacemakers have acceptable performances to fulfill the clinical needs and have a reasonable safety margin. Promising new technologies are currently under development and offer hope to patients who may one day derive both symptomatic and mortality benefit from these devices.

The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection.

Desensitized patients are at high risk of developing acute antibody-mediated rejection (AMR). In most cases, the rejection episodes are mild and respond to a short course of plasmapheresis (PP) / low-dose IVIg treatment. However, a subset of patients experience severe AMR associated with sudden onset oliguria. We previously described the utility of emergent splenectomy in rescuing allografts in patients with this type of severe AMR. However, not all patients are good candidates for splenectomy. Here we present a single case in which eculizumab, a complement protein C5 antibody that inhibits the formation of the membrane attack complex (MAC), was used combined with PP/IVIg to salvage a kidney undergoing severe AMR. We show a marked decrease in C5b-C9 (MAC) complex deposition in the kidney after the administration of eculizumab.

Disparity in utilization of implantable cardioverter-defibrillators in treatment of heart failure based on sex and race.

Evaluation of: Hernandez AF, Fonarow GC, Lang L et al.:Sex and racial differences in the use of implantable cardioverter-defibrillators among patients hospitalized with heart failure.JAMA298(13), 1525-1532 (2007) [1] . Disparity of utilization of proven therapies for treatment of cardiac disease according to gender and ethnicity has been well documented in various aspects of cardiac care. Implanted cardiac defibrillators (ICDs) are devices that have been proven to prevent sudden cardiac death. This retrospective study examined ICD use in heart-failure patients who had an indication for ICD implantation, from the "Get with the Guidelines" program. The patients were stratified by gender and ethnicity (Black vs White). The overall rate of utilization (or intention for utilization) of ICDs was 35%, while among women and Black people the rate was significantly lower, at 27 and 23%, respectively, with the lowest rate being for Black women (28%). These findings suggest a bias against implantation of such devices in women and Black people, which is not explained by clinical variables.

Pharyngeal pH measurements in patients with respiratory symptoms before and during proton pump inhibitor therapy.

BACKGROUND: Pharyngeal pH monitoring is a diagnostic tool used to identify Gastroesophageal reflux disease (GERD) as an etiology of respiratory symptoms. We performed pharyngeal pH monitoring on 14 patients with respiratory symptoms thought to be induced by GERD. METHODS: Symptoms and pH monitoring (esophageal and pharyngeal) were assessed prior to and 3 months after the initiation of double-dose proton pump inhibitor therapy. RESULTS: Symptoms included cough, hoarseness, and throat clearing. Ten patients had at least one episode of pharyngeal reflux (PR+) and 4 patients had no pharyngeal reflux (PR-). Pharyngeal reflux episodes in PR+ patients decreased from 3.5 to 0.9 (P <0.05) per day with 8 of 10 (80%) patients having elimination or reduction of such episodes. Eight of 9 PR+ patients (89%) with suppressed pharyngeal reflux on medical therapy had resolution of respiratory symptoms. Three of 4 PR- patients (75%) had persistent symptoms on medical therapy. CONCLUSIONS: Proton pump inhibitor therapy improves clinical symptoms and decreases pharyngeal reflux episodes in patients with respiratory symptoms related to GERD. Direct measurement of pharyngeal pH is helpful in the identification of patients likely to respond to antireflux therapy.

Association of laryngopharyngeal reflux disease and subglottic stenosis.

Laryngopharyngeal reflux (LPR) disease and extraesophageal manifestations of gastroesophageal reflux have been recognized to have dramatic effects in the upper airways. Patient-reported symptoms alone underestimate the presence of LPR, making accurate clinical diagnosis difficult. Many previous studies examine populations with only standard dual-probe pH testing that does not include a test probe in the pharynx. Therefore, documentation of acid exposure at the laryngeal inlet is lacking. In adult patients with subglottic stenosis (SGS), whether due to granulomatous disease or presumed idiopathic causes, LPR is often a contributing or causative factor. A retrospective chart review from 1991 to 1999 identified 19 patients with SGS. Ten of the 19 patients had concomitant disease states, including sarcoidosis (3), Wegener's granulomatosis (3), laryngeal trauma (3), and a history of intubation (1). Fourteen patients underwent 24-hour ambulatory pH probe testing with 3- or 4-port probes. The proximal port in either catheter was positioned by manometric guidance directly behind the laryngeal inlet. Measurements of pH of less than 4 were recorded at the level of the larynx in 12 of the 14 patients tested (86%). This finding was noted in half of the patients despite empirical therapy with proton pump inhibitors at the time of the testing. Seven of 10 patients with underlying disease were studied, and all demonstrated acid reflux in the hypopharynx. In 9 patients, the stenosis was presumed to be idiopathic. Five of the 7 patients (71%) with idiopathic SGS tested had positive pH probe studies (pH below 4 in the pharyngeal probe). Our results demonstrate a strong association of LPR and SGS. In the idiopathic group, reflux is the probable cause of their stenosis. In the group of patients with underlying disease states, reflux was involved in all tested patients and likely acts as a synergistic factor that stimulates their granulomatous disease to react and subsequently result in the development of stenosis. Evaluation for LPR with pharyngeal pH testing should be performed in all patients with SGS.

The study of laryngeal muscle activity in normal human subjects and in patients with laryngeal dystonia using multiple fine-wire electromyography.

The normal human larynx performs numerous complex tasks with nearly complete reliability. These tasks require precise timing of movements that are effected by the laryngeal muscles. The most specific method to examine these muscles is by electromyography. Although many studies on laryngeal electromyography have been reported using multichannel recordings, none has provided a detailed analysis of each laryngeal muscle's role during a variety of common tasks and the spectrum of normative values. Simultaneous eight-channel, fine-wire electromyographic recordings were made in 11 human subjects. The timing patterns of the laryngeal muscles during the coordinated efforts for phonation and other common glottic functions were examined. In addition, normative values for latencies and amplitudes of response were determined. During simple phonation, a "set pattern" for the thyroarytenoid, lateral cricoarytenoid , and interarytenoid muscles was found. The thyroarytenoid and lateral cricoarytenoid muscles demonstrated a burst at onset preceding phonation and then decreased activity, whereas the interarytenoid sustained glottic position during phonation. The coordination of the laryngeal muscles was similarly determined for connected speech, respiration, Valsalva maneuver, cough, throat-clear task, and swallow. These patterns of response, the latencies for activities, and the amplitudes of response in normal subjects provided the basis to examine the abnormal laryngeal function in a group of 59 patients with four clinical varieties of laryngeal dystonia (adductor, tremor, abductor, and mixed). The findings include abnormal patterns of response, increased latencies, and increased amplitudes of recruitment in many tasks including nonphonatory tasks. Although specific distinctions were noted in each group, the responses were remarkably similar, indicating that all clinical varieties of laryngeal dystonia should be classified as mixed dystonia with a clinical preponderance for one or more types of behavior.

Pharyngeal pH monitoring in 222 patients with suspected laryngeal reflux.

To determine the existence of and characterize gastroesophagopharyngeal reflux in patients with symptoms of airway irritation, we monitored pharyngeal pH over a 24-hour period in 222 consecutive patients. Pharyngeal reflux was defined as a drop in pH to less than 4 at the pharyngeal sensor, which occurred simultaneously with acidification of the distal esophagus. Patients were divided into two groups: those with pharyngeal reflux (PR+) and those without (PR-). The Mann-Whitney U test and Student's t test were used to assess intergroup comparisons. Episodes of pharyngeal reflux (range 1 to 36, average 4.4) were identified in 90 PR+ patients (40%). No pharyngeal reflux was identified in the remaining 132 patients (PR-). Episodes of pharyngeal reflux were rapidly cleared (average duration 1.5 minutes), and occurred while in the upright position in 77 (86%) of 90 patients and while in the supine position in 11 (12%) of 90 patients. Twenty-three patients (25%) experienced symptoms in association with an episode of pharyngeal reflux. In the distal esophagus, the percentage of time the pH was below 4 during the upright position and the total percentage of time the pH was below 4 were greater in PR+ patients (6.4% and 5.8%, respectively) when compared to PR- patients (2.6% and 2.6%, respectively). Laryngoscopic findings did not distinguish PR+ from PR- patients. Pharyngeal reflux occurs most commonly in the upright position and can be identified in more than 40% of patients thought to have acid-induced laryngeal symptoms. Even though these episodes are short lived and rapidly cleared, symptoms occur concomitantly in 25% of patients with proven pharyngeal reflux. Patients with laryngeal symptoms and documented pharyngeal reflux have greater amounts of esophageal reflux when compared to patients with laryngeal symptoms and no demonstrable pharyngeal reflux.

The association of laryngoceles with ventricular phonation.

Laryngoceles represent dilatations of the laryngeal saccule that may extend internally into the airway, or externally through the thyrohyoid membrane. Unilateral laryngoceles are uncommon clinical entities and bilateral laryngoceles are rare. Certain activities like glass blowing and playing a wind instrument are associated with laryngocele development, as is laryngeal carcinoma in the ventricular area. This case describes development of bilateral laryngoceles in a patient who chronically uses ventricular phonation during speech. The pathogenesis involves repetitive elevation of intralaryngeal pressure during false vocal cord approximation, exposing the ventricles to abnormally high air pressures. The pathogenesis in this case, as well as in laryngoceles associated with occupational or anatomic risk factors, is discussed.

Evaluation and management of bilateral vocal cord immobility.

Bilateral vocal cord immobility can be life threatening for some patients. Others, who have an open glottic chink, may have a breathy dysphonia, intermittent dyspnea, and stridor. These signs and symptoms may also be found in a number of other conditions that cause weakness or paradoxical motion of the vocal cords that mimics paralysis. These other conditions include central nervous system diseases, neuromuscular disorders, laryngospasm, and psychogenic disorders. In addition, patients with cricoarytenoid joint immobility or interarytenoid scar can also have similar symptoms at presentation. It is critical to consider the differential diagnosis of an assumed bilateral vocal cord paralysis and understand the management of paradoxical movement, weakness, joint fixation, interarytenoid scar, laryngospasm, and psychogenic disorders. The treatment for bilateral immobility should proceed only after a thorough evaluation, which might include electromyography and/or examination during general anesthesia under dense anesthetic paralysis. Reconstructive procedures are the treatments of choice, and destructive procedures should be chosen only as a last resort.

Presentation of ALS to the otolaryngologist/head and neck surgeon: getting to the neurologist.

Patients with early symptoms of bulbar amyotrophic lateral sclerosis (ALS) are usually referred to the otolaryngologist without a diagnosis. Careful examination of the speech quality and a physical exam, including the vocal cords, should be undertaken. The emotional state of the patient should be considered, and a diagnosis should not be offered before a neurologic consultation has been obtained. Patients with late symptoms of bulbar ALS almost always present with both significant speech and swallowing abnormalities. Evaluation can be difficult because many abnormalities are found on examination. Advanced progression of symptoms is a clear indication for rapid referral to a neurologist if a diagnosis has not already been made. Supportive and symptomatic care should be offered to the patient immediately. The University of Washington Neuromuscular Clinic for Speech and Swallowing Disorders has seen 600 new neurologic patients since 1986, 211 of whom were ALS patients. The introduction of percutaneous gastrostomy has greatly changed the management of ALS patients, and 75 patients have undergone this procedure (32% because of inadequate swallowing, 68% for declining vital capacity). Medical management to improve symptoms may be indicated before surgery. Surgical options for patients with late salivary presentation are uncommon and include removal of the submaxillary glands, tracheostomy, and laryngeal or salivary diversion procedures. Laryngectomy or laryngeal diversion procedures are only very rarely indicated. Although tracheostomy usually interferes with swallowing and worsens aspiration, it may rarely be indicated in patients with late airway presentation for glottic narrowing or artificial respiratory support. Symptomatic management of patients with bulbar ALS is usually best undertaken by a multidisciplinary clinic that can provide a physically and psychologically supportive environment.