The plasmin system is induced by and degrades amyloid-beta aggregates.

Amyloid-beta (Abeta) appears critical to Alzheimer's disease. To clarify possible mechanisms of Abeta action, we have quantified Abeta-induced gene expression in vitro by using Abeta-treated primary cortical neuronal cultures and in vivo by using mice transgenic for the Abeta precursor (AbetaP). Here, we report that aggregated, but not nonaggregated, Abeta increases the level of the mRNAs encoding tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Moreover, tPA and uPA were also upregulated in aged AbetaP overexpressing mice. Because others have reported that Abeta aggregates can substitute for fibrin aggregates in activating tPA post-translationally, the result of tPA induction by Abeta would be cleavage of plasminogen to the active protease plasmin. To gain insights into the possible actions of plasmin, we evaluated the hypotheses that tPA and plasmin may mediate Abeta in vitro toxicity or, alternatively, that plasmin activation may lead to Abeta degradation. In evaluating these conflicting hypotheses, we found that purified plasmin degrades Abeta with physiologically relevant efficiency, i.e., approximately 1/10th the rate of plasmin on fibrin. Mass spectral analyses show that plasmin cleaves Abeta at multiple sites. Electron microscopy confirms indirect assays suggesting that plasmin degrades Abeta fibrils. Moreover, exogenously added plasmin blocks Abeta neurotoxicity. In summation, we interpret these results as consistent with the possibility that the plasmin pathway is induced by aggregated Abeta, which can lead to Abeta degradation and inhibition of Abeta actions.

The expression of key oxidative stress-handling genes in different brain regions in Alzheimer's disease.

Alzheimer's disease (AD) has been hypothesized to be associated with oxidative stress. In this study, the expression of key oxidative stress-handling genes was studied in hippocampus, inferior parietal lobule, and cerebellum of 10 AD subjects and 10 control subjects using reverse transcriptase-polymerase chain reaction (RT-PCR). The content of Mn-, Cu,Zn-superoxide dismutases (Mn- and Cu,Zn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GSSG-R) mRNAs, and the "marker genes" (beta-actin and cyclophilin) mRNAs was determined. This study suggests that gene responses to oxidative stress can be significantly modulated by the general decrease of transcription in the AD brain. To determine if the particular oxidative stress handling gene transcription was induced or suppressed in AD, the "oxidative stress-handling gene/beta-actin" ratios were quantified and compared with control values in all brain regions studied. The Mn-SOD mRNA/beta-actin mRNA ratio was unchanged in all regions of the AD brain studied, but an increase of the Cu,Zn-SOD mRNA/beta-actin mRNA ratio was observed in the AD inferior parietal lobule. The levels of peroxidation handling (CAT, GSHPx, and GSSG-R) mRNAs normalized to beta-actin mRNA level were elevated in hippocampus and inferior parietal lobule, but not in cerebellum of AD patients, which may reflect the protective gene response to the increased peroxidation in the brain regions showing severe AD pathology. The results of this study suggest that region-specific differences of the magnitude of ROS-mediated injury rather than primary deficits of oxidative stress handling gene transcription are likely to contribute to the variable intensity of neurodegeneration in different areas of AD brain.

Reinnervation of the paralyzed larynx: a review.

Our high-speed and increasingly aggressive society, coupled with a continuing rise in necessary surgery of the neck and adjacent areas, accounts for the current increase in patients affilicted with vocal-cord paralysis. Such patients may sustain relatively little persistent loss of function (e.g., when only one cord is involved, which then regains function or becomes compensated) or considerable loss (as in cases of bilateral vocal-cord paralysis). To improve on existing methods of dealing with these problems, the author has developed and refined the nerve-muscle-pedicle technique for reinnervating paralyzed muscles. A nerve-muscle pedicle obtained from the ansa hypoglossi branch to the omohyoid muscle or another strap muscle can be used to selectively reinnervate the posterior cricoarytenoid muscle in cases of bilateral-cord paralysis, or for selective reinnervation of the lateral thyroarytenoid muscle in cases of unilateral-cord paralysis. The bilateral reinnervation technique showed a 90% success rate in 90 patients, as demonstrated by their ability to sustain reasonable day-to-day activity without needing a tracheotomy tube and without manifesting further loss of voice. The unilateral technique has yielded promising results in a limited number of carefully selected patients.

Incidence of cranial nerve dysfunction following carotid endarterectomy.

An analysis of postoperative injuries to the recurrent laryngeal, hypoglossal, marginal mandibular, and superior laryngeal nerves was undertaken in 517 patients who underwent 535 carotid endarterectomies between April 1978 and March 1981 at The Cleveland Clinic Foundation. A review of the literature is presented followed by the results of this analysis and a discussion of the findings. Suggestions for decreasing or avoiding such injuries are made. Conclusions are drawn to help the otolaryngologist identify the endarterectomized patient with an impaired upper aerodigestive tract.

Management of the congenital midline nasal mass: a review.

The nasal encephalocele, the glioma, and the dermoid are the most common of the congenital midline nasal masses. Due to similar embryologic development, each of these lesions may be associated with bony cranial defects and intracranial abnormalities, as well as CSF leakage and the potential for fatal meningitis if not handled properly. Properative manipulation should be avoided. Radiologic studies are instructive only if they are positive. If intracranial attachments are identified radiologically or suspected clinically, neurosurgical consultation should be obtained, and intracranial exploration and resection should be carried out as the initial procedure. Extra-cranial resection of the remaining mass may be performed immediately after intracranial resection, may be postponed, or may become unnecessary.

Approach to and reconstruction for lesions of the posterior third of the tongue via midline labiomandibular glossotomy.

Most benign and malignant lesions of the posterior third of the tongue may be approached through a median labiomandibular glossotomy. This is accomplished by splitting the lower lip, mandible, floor of the mouth, and tongue in the midline to expose such areas as the posterior tongue, pharynx, and nasopharynx. This technique is useful for lesions of the posterior third of the tongue for several reasons: 1) it provides excellent exposure, 2) it is cosmetically superior to most other approaches, 3) it allows for several alternatives to reconstruction, such as retrusion or rotation tongue flaps, 4) the procedure sustains minimum blood loss since the tongue is bisected in the midline in an avascular plane, (5) when preoperative radiation therapy has been included, this approach minimizes the amount of surgery performed through the radiated field, and 6) postoperative tongue mobility is usually sufficient to permit articulation and deglutition to approach normal. The Cleveland Clinic Foundation's experience with this approach is reviewed, the technique is described, and a variety of cases are presented to illustrate its applicability.

Tumors of the carotid body. Experience with 41 operative cases.

Evaluation of a patient with a carotid body tumor requires a complete head and neck examination with special attention to the cranial nerves and careful search for additional paragangliomas in other sites. Angiography is very helpful in making the diagnosis and assessing the ipsilateral and contralateral carotid artery. Surgery should be performed early, since group I tumors are easily excised and are associated with a low surgical morbidity. Surgical excision shoud be performed by head and neck and vascular surgeons applying shunting or reconstructive techniques when appropriate. With improved diagnostic and surgical techniques, the morbidity and mortality should continue to approach zero.

Human laryngeal reinnervation.

Bilateral vocal cord paralysis is fortunately an uncommon occurrence although the incidence of this injury secondary to external neck trauma is increasing. In general, a patient with this lesion is faced with the choice between adequate airway at the expense of a breathy, weak voice or a fairly good voice with the need for a permanent tracheotomy. In an effort to provide a better solution to this dilemma, an attempt has been made to develop a means of reinnervation of at least one vocal cord without the problems inherent in the usual nerve anastomosis techniques. After extensive preliminary work in dogs the nerve-muscle pedicle technique for reinnervation has been developed. In this procedure the branch of the ansa hypoglossi to the anterior belly of the omohyoid is mobilized and a small block of muscle containing the terminal branches is freed from the muscle proper. Using an approach similar to the Woodman arytenoidectomy, the posterior cricoarytenoid muscle is exposed, and its fibers are partially incised. The previously prepared nerve-muscle pedicle is sutured to it. In the first five patients subjected to this procedure, return of spontaneous abduction of the reinnervated vocal cord was noted between six and eight weeks post surgery. In no case was the voice weakened nor was there any problem with aspiration. All five patients have achieved sufficient airway so that exercise tolerance for daily activities is adequate without a tracheotomy. The physiologic and histologic background of this technique is discussed in detail.

Conservation laryngeal surgery in the elderly patient.

In the 100 years since Bilroth first undertook a total laryngectomy, general improvements in the prevention and management of childhood and adult disease have led to continuing increase in life expectancy to the point that, in many developed countries, 25% or more of the population is over the age of 65. Although many of these individuals are in otherwise reasonable health, major head and neck procedures are often not performed in favor of radiation therapy for cure, even for lesions that would otherwise be considered amenable to surgery in younger patients, on the grounds that the patient is too old to tolerate the necessary procedure. The same argument has been employed in favoring total laryngectomy over subtotal procedures in the older patient. Review of the author's experience (27 cases) with conservation laryngeal surgery in patients over the age of 65 at the time treatment was undertaken reveals that such procedures are well tolerated in this age group. There were no mortalities and an overall complication rate of 11.1% resulted. These findings compare favorably with complication rates reported for similar patients and surgery in the under 65 age group and strongly suggest that chronologic age alone need not be a contraindication to such surgery.

The management of facial paralysis due to extracranial injuries.

Improvements in surgical capabilities in the management of malignancies about the ear and parotid gland, increasing vehicular and interpersonal trauma, and greater concern with cosmetic factors by the public at large, have led to increasing need for the surgeon's ability to manage injuries to the facial nerve. Several important anatomic, physiologic and technical factors bear upon a logical approach to repair of such facial nerve injuries. Careful attention to these concepts had led to satisfactory return of facial function in most cases managed by the author.

Laryngeal transplantation: current status 1974.

There are four major areas of concern that must be examined before human laryngeal transplantation can be considered feasible in clinical practice. These are: 1. surgical mechanics of revascularization; 2. reinnervation; 3. prevention of host rejection; and 4. justification. Of these criteria, the first two habe been met sucessfully at present. Safe suppression of rejection without increased risk of cancer recurrence remains to be achieved. Until this third criterion is satisfied, one is probably not justified to make further attempts at laryngeal transplantation in humans.

Complications after surgical management of the paralyzed larynx.

Patients suffering from uni or bilateral laryngeal paralysis frequently require surgical management for best possible rehabilitation. As with any surgical procedure the potential for complications or less than optimal results exists. The Otolaryngologist-Head and Neck Surgeon who wishes to provide best possible care for his patient must understand not only the indications for these surgical procedures, but also the complications that may be expected, so that every possible effort can be made to avoid or minimize them.

Congenital bilateral recurrent nerve paralysis and ptosis: a new syndrome?

Bilateral vocal cord paralysis is a rare, but not unheard of, occurrence in the perinatal period. It is often incompatible with life unless the problem is recognized promptly, the child intubated, and--following this--a tracheotomy performed. Bilateral congenital ptosis is a very rare occurrence and is almost always associated with either significant central nervous system deficit or with other oculomotor problems. The combination of congenital bilateral recurrent nerve paralysis and congenital ptosis has not been previously reported in the English language literature. The author has had the opportunity to manage two patients, a father and his daughter, both of whom manifested this unusual combination of symptoms. Detailed case histories are presented. Both of the patients were successfully managed by temporary tracheotomy followed by reinnervation of the larynx, with eventual extubation and satisfactory day-to-day airway. Although only two cases represent an inadequate number to determine a new syndrome, these striking findings in a father and his only offspring suggest the possibility that this may, indeed, represent a new symptom complex of congenital origin.

Vocal cord paralysis--1979: etiology and management.

Because of the development of reinnervation surgery, approximately 400 patients have been seen by the author with a referral diagnosis of vocal cord paralysis. Because these patients were being entered into a research protocol to evaluate the efficacy of reinnervation surgery, very careful evaluation and records have been kept. Retrospective analysis of these records has permitted an up-to-date evaluation of the epidemiology, natural history, symptoms, signs and presenting complaints, as well as the status of treatment of vocal cord paralysis at the present time. Since this subject has received only limited treatment in the recent literature, it was felt that such an opportunity to evaluate a large personal experience might be a worthwhile addition to current knowledge of the subject.

Human laryngeal reinnervation: long-term experience with the nerve-muscle pedicle technique.

The nerve-muscle pedicle technique for reinnervation of bilateral vocal cord paralysis has now been applied in 45 cases over the past four years. EMG studies, volume flow loop, pulmonary function studies, and the ability to extubate the patient with good to excellent exercise tolerance for day-to-day activity have been used as parameters to judge success or failure of this procedure. To date there has been a primary success rate of 91.1% (41/45) and a long-term success rate of 88.8% (40/45). There has been one serious complication in the entire series and no significant morbidity other than this. Age of the patient and length of paralysis are not necessarily contraindications to the procedure. These results suggest that the nerve-muscle pedicle technique may be successfully used for reinnervation of bilaterally paralyzed vocal cords without sacrificing residual voice, as is the case with arytenoidectomy type procedures.

Transnasal, transeptal sphenoidal approach to hypophysectomy.

Since 1960 the most useful and widely employed technique for transphenoidal hypophysectomy has generally been via the sublabial, transeptal approach. This procedure has offered excellent exposure, limited blood loss and a direct, midline approach through the sphenoid to the hypophysis, thus preserving certain midline structures as a guide to the appropriate point of entry into the sella turcica. This approach has certain drawbacks, however, not the least of which is the extensive sublabial incision that must be made and the need to remove or otherwise interfere with the nasal spine. This maneuver can result in changes in the vertical dimension of the septal-collumellar area and, more important, often results in permanent numbness of the upper teeth. In patients who wear dentures, it will sometimes produce a bothersome scar which will require refitting or change in wearing patterns for these dentures. It also requires surgical closure. For the past two years at the Cleveland Clinic Foundation a modified transeptal, transphenoidal approach to hypophysectomy has been undertaken conjointly between the Department of Otolaryngology and Communicative Disorders and the Department of Neurosurgery. This approach to hypophysectomy may offer a good alternative to the sublabial approach, and in competent hands avoids some of the complications of the latter procedure.

Recurrent laryngeal nerve pathology in spasmodic dysphonia.

Since it was first described in 1871, spasmodic (spastic) dysphonia has been considered a disease of psychogenic origin. Unsupported theories of possible organic etiology have appeared sporadically in the literature. In 1976 sectioning of the recurrent laryngeal nerve for patients with this disease was reported with resultant improvement in voice production. This was attempted because the spasmodic dysphonic has, in effect, already compensated vocal cords bilaterally. It was reasoned, therefore, that if one of these was paralyzed the patient would immediately be converted to a state approximating that of well-compensated unilateral vocal cord paralysis which situation, as is well known, usually carries with it a fairly good voice. A controlled study to evaluate the efficacy of this surgical approach has been undertaken at the Cleveland Clinic during the past year. In an attempt to elucidate the possible organic etiology of spasmodic dysphonia, a section of nerve was removed in every case and examined by both light and electron microscopy. Special stains for myelin were also used on the light microscopy specimens. Demyelinization has been found in most of the cases examined by electron microscopy. Possible correlation between this disease entity and other cranial nerve syndromes of unknown etiology is noted. Such conditions as trigeminal neuralgia, glossopharyngeal neuralgia, belpharospasm, hemifacial spasm, and even possibly Bell's palsy may exhibit a similar etiology.

Speech development in aphonic children.

It has been well established that pre-lingually hearing-impaired children experience difficulties in speech development. Little appears in the literature, however, about speech development in aphonic children. The authors have had the opportunity to manage several children who, for various reasons, were unable to phonate from a pre-lingual age to approximately the age of 5 or 6 years. The children in this report developed various compensatory means of communication, including unusual laryngeal, non-laryngeal and nonverbal communication. Representative cases are reviewed and observations are made regarding the effects of aphonia on speech development.

Laryngeal pacemaker. II. Electronic pacing of reinnervated posterior cricoarytenoid muscles in the canine.

A fully reliable means of rehabilitating patients with bilateral vocal cord paralysis has not yet been developed. In order to improve upon existing solutions to this problem, the authors have recently described a laryngeal pacemaker, initially tested through stimulation of a cross-over nerve-muscle pedicle from one sternohyoid muscle to the other in the canine. Afferent stimuli, initiated through elongation of the airway during inspiration, were detected by a linear strain gauge sutured to the tracheal rings and appropriately amplified. The current report deals with the application of this concept to pace a nerve-muscle pedicle reinnervating the posterior cricoarytenoid muscle. Videoscopic and cinematographic documentation of electrically paced abduction of the reinnervated vocal fold, synchronous with inspiration, was clearly demonstrated. Only miniaturization of an implantable electronic amplifier remains to permit an attempt at pacing of the paralyzed larynx in humans.

Complications of laryngeal framework surgery (phonosurgery).

The rising popularity of surgery involving the laryngeal framework (surgical medialization of immobile vocal folds, vocal fold tightening, pitch variation, etc.) has resulted in increasing case experience. Little has appeared in the literature regarding complications or long-term results of this type of surgery. Several years' experience in a major referral center with various types of laryngeal framework surgery has led to a small number of complications. These have included late extrusion of the prosthesis and delayed hemorrhage. A review of these complications and recommendations for modification of technique to minimize them in the future are discussed.