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Macroautophagy/autophagy is suppressed by MTOR (mechanistic target of rapamycin kinase) and is an anticancer target under active investigation. Yet, MTOR-regulated autophagy remains incompletely mapped. We used proteomic profiling to identify proteins in the MTOR-autophagy axis. Wild-type (WT) mouse cell lines and cell lines lacking individual autophagy genes (Atg5 or Ulk1/Ulk2) were treated with an MTOR inhibitor to induce autophagy and cultured in media with either glucose or galactose. Mass spectrometry proteome profiling revealed an elevation of known autophagy proteins and candidates for new autophagy components, including CALCOCO1 (calcium binding and coiled-coil domain protein 1). We show that CALCOCO1 physically interacts with MAP1LC3C, a key protein in the machinery of autophagy. Genetic deletion of CALCOCO1 disrupted autophagy of the endoplasmic reticulum (reticulophagy). Together, these results reveal a role for CALCOCO1 in MTOR-regulated selective autophagy. More generally, the resource generated by this work provides a foundation for establishing links between the MTOR-autophagy axis and proteins not previously linked to this pathway. Abbreviations: ATG: autophagy-related; CALCOCO1: calcium binding and coiled-coil domain protein 1; CALCOCO2/NDP52: calcium binding and coiled-coil domain protein 2; CLIR: MAP1LC3C-interacting region; CQ: chloroquine; KO: knockout; LIR: MAP1LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MLN: MLN0128 ATP-competitive MTOR kinase inhibitor; MTOR: mechanistic target of rapamycin kinase; reticulophagy: selective autophagy of the endoplasmic reticulum; TAX1BP1/CALCOCO3: TAX1 binding protein 1; ULK: unc 51-like autophagy activating kinase; WT: wild-type.

Chronic hepatitis C is associated with health-related quality of life and cognitive impairments, even in mild disease. Recent evidence demonstrating hepatitis C virus (HCV) neurotropism has strengthened a neuropathophysiological hypothesis. However, sample heterogeneity confounds study outcomes. A uniquely homogeneous cohort of Irish women, following an iatrogenic HCV outbreak, offers a rare opportunity to control for HCV chronicity and the virus' purported impact on quality of life and cognition. A multi site, three-group, cross-sectional design was employed. Noncirrhotic, iatrogenically infected women, developing either acute or chronic infection, were recruited from prospective tertiary-care liver clinics and the community. Well-matched healthy controls were also recruited. All participants completed a psychosocial survey and were invited to undergo a comprehensive neuropsychological test battery. Significantly distressed psychosocial symptom profiles were observed in those with an iatrogenic HCV exposure history, which was independent of viral chronicity. Chronic and cleared HCV cohorts were not differentiated from each other. Two distinct subgroups, demarcated along 'impaired' vs 'nonimpaired' quality-of-life reports, were clearly identified and logistic regression analysis identified depressed mood and cognitive fatigue, rather than viral status, as statistically significant predictors of group membership. Compared with matched controls, significant cognitive impairments were not observed in either HCV cohort. Our findings provide strong evidence of nonviral factors accounting for quality of life impairment in chronic HCV and they also appear to question existing reports of cognitive dysfunction in mild disease. Depressed mood and cognitive fatigue appear to be critical psychosocial mediators of reduced quality-of-life and we hypothesize that metabolite abnormalities reported in HCV samples may also be confounded by these factors, given the associated literature.

Objective: To compare growth of infants fed goat milk infant formula (GMF) or cow milk infant formula (CMF) and to compare tolerability and safety of the two formulas. Methods: The study was conducted in Auckland, New Zealand. This was a double-blind randomized controlled trial. Newborn term infants were randomized within 72 h of birth to GMF or CMF. Milk formula powder in single serve sachets were reconstituted and fed to infants from trial commencement until age 168 days. No other formula given from randomization until age 168 days. Infant weight, length and head circumference were measured at birth and age 14, 28, 56, 84, 112, 140 and 168 days. Bowel motion frequency and consistency, sleeping and crying patterns and adverse events were also measured. Results: Seventy-two infants were randomized, 36 each to GMF or CMF, with 62 infants completing the intervention. At enrolment the average weight of infants in the GMF group (mean ± SD) was 3.33 ± 0.43 kg and in the CMF group 3.43 ± 0.47 kg; and at study completion 8.07 ± 0.90 kg (GMF) and 7.87 ± 0.99 kg (CMF). The difference in average weight gain over the study period for the GMF group versus the CMF group was not significant (+309 g; 95% CI = −49 to +668, P = 0.09). Median daily bowel motion frequency was greater in the GMF group than the CMF group (2.4 vs 1.7, P = 0.01). There were no group differences in bowel motion consistency, duration of crying, ease of settling, or frequency of adverse events. Conclusion: Growth of infants fed GMF is not different to that of infants-fed CMF.

Vagal paraganglioma is a rare tumor of neural crest origin. Although the literature is in agreement with regard to epidemiology, diagnosis, and tumor biology, there is some controversy over treatment modalities for these patients. We performed a nonrandomized retrospective study in a large single-institution series of patients (n = 19) in whom vagal paraganglioma was diagnosed. General statistics included age, male/female ratio, tumor size, and duration of follow-up. Other variables such as signs and symptoms at presentation, family history, multicentricity, metastatic disease, and secretion of catecholamines were included. CT scan, MRI, and angiography were used in combination for diagnostic purposes as well as for treatment planning. Preoperative embolization was performed in 5 of the more recently treated patients. Current issues regarding the use of preoperative embolization and choice of surgical approach were analyzed. In this article the possibility and sequela of vagus nerve-sparing procedures will be presented. Operative complications and postoperative morbidity related to cranial neuropathies will be discussed. The rationale for performing adjunct procedures, including cricopharyngeal myotomy and vocal fold medialization, to facilitate the rehabilitation of patients with postoperative cranial nerve deficits will be given. Our findings and recommendations will be compared with currently accepted treatment protocols in conjunction with a review of the literature.

Olfactory neuroblastoma is a rare malignancy of the olfactory mucosa that may be derived from the olfactory epithelium. To characterize this tumor, we cultured olfactory neuroblastoma cells in the presence or absence of growth factors (transforming growth factor alpha and basic fibroblast growth factor) known to affect olfactory tissue and assessed their responsiveness to known odorants by measuring changes in intracellular calcium. Untreated cells did not respond to odorants. Basic fibroblast growth factor treatment had cytotoxic effects, and treated cells did not respond to odorants. Transforming growth factor alpha treatment resulted in the induction of odor responsiveness in these cells. Cells responded to odorants at 100 nM to 100 microM concentrations and responded with both increases and decreases in intracellular calcium. Increases in intracellular calcium were mediated by a calcium influx and were reversibly blocked by compounds known to inhibit second messenger pathways in olfactory receptor neurons. The calcium responses of the olfactory neuroblastoma cells were thus specific to the odorants and similar to those found in olfactory receptor neurons. The results support the notion that olfactory neuroblastoma cells may be of olfactory origin and thus they can be used as a model cell line to study human olfaction.

Patients with Kallmann syndrome (KS) exhibit hypogonadotropic hypoganadism and anosmia [Kallmann et al., Am. J. Mental Def., 48 (1944) 203–236] secondary to failure of gonadotropin-releasing hormone (GnRH)-producing neurons to migrate from the olfactory placode to the brain, and to agenesis of the olfactory bulbs. It has been hypothesized that olfactory neurons (ON) from individuals with KS are immature partly on the basis of studies in animals showing that lack of synaptic connection of ON with the olfactory bulb results in expression of immature ON [Schwob et al., J. Neurosci., 12 (1979) 880–883]. To test this assumption, we obtained olfactory tissue samples from two males diagnosed with KS on the basis of medical history and MRI studies. Both patients were anosmic. The functioning of cells isolated from biopsies taken from the upper middle turbinate and septum was studied by measuring changes in intracellular Ca2+ concentration ([Cai]) using dual excitation fluorescence microscopy. Biopsies from both patients yielded cells that morphologically appeared to be ON. Seven of 16 cells that morphologically resembled ON responded with a change in [Cai] upon stimulation with an odorant mixture. These studies show that at least some ON in KS individuals are functionally mature and suggest that complete development of the olfactory bulbs is not required for differentiation of mature human ON.

The association between nasal allergy and loss or diminution of smell is frequently alluded to in the literature; however, neither the true prevalence of hyposmia in individuals with allergic rhinitis nor its bases have been established.We assessed olfactory threshold for phenylethyl alcohol in 91 patients with symptoms of allergic rhinitis and 80 nonatopic control subjects. To determine the degree to which nasal congestion contributes to hyposmia in allergic rhinitis, total nasal resistance was measured in 64 of the patients and 72 of the control subjects.Olfactory thresholds were significantly higher in allergic patients than in control subjects (p0.001), with 23.1% of the patients demonstrating a clinically significant smell loss (defined as threshold at or above the 2.5th percentile of control values). Although nasal resistance was significantly higher among patients than among controls (p0.001), it was not related to olfactory threshold in either group. Clinical or radiographic evidence of sinusitis or nasal polyps or both in allergy patients was found to be significantly associated with hyposmia (p0.006).The observed prevalence of hyposmia among patients with allergic rhinitis suggests that this is a major etiologic factor contributing to smell disorders. Sinusitis or nasal polyps or both may underlie many cases of allergy-related hyposmia.

Whiplash injuries of the cervical spine comprise 30% of injuries reported following motor vehicle accident (MVA) and often progress to chronic painful conditions. The purpose of this case report is to describe the management of a 37-year-old female referred to physical therapy with neck and shoulder pain after whiplash injury. The patient demonstrated limited cervical and shoulder active range of motion as well as quantitative sensory testing (QST) results consistent with central nervous system sensitization. She was treated for 11 visits over a 6-week period with manual therapy and specific exercise directed to the cervicothoracic spine. Her pain decreased from 9/10 to 2/10 by the end of treatment and remained improved at 1/10 at the 6-month follow-up. Her Copenhagen Neck Functional Disability Scale decreased from 23/30 to 4/30 by the 11th visit. In addition, she demonstrated clinically significant increases in cervical active range of motion and normal somatosensation. Manual therapy of the cervicothoracic spine may be a beneficial adjunct to the standard care of patients with signs and symptoms of central sensitization after whiplash-associated disorder and primary report of neck and shoulder pain.

Pain is a common complaint among clients seeking physical therapy services, yet interpretation of associated sensory changes can be difficult for the clinician. Musculoskeletal injury typically results in nociceptive pain due to noxious stimuli of the damaged muscle or joint tissues. However, with progression from acute to chronic stages, altered nociceptive processing can give rise to an array of sensory findings. Specifically, patients with chronic joint injury may present with signs and symptoms typically associated with neuropathic injury, due to changes in nociceptive processing. Clinical presentation may include expansion of hyperalgesia into adjacent and remote areas, allodynia, dysesthesias, and perceptual deficits. Quantitative sensory testing (QST) may provide an objective method of examining sensation and, thereby, of recognizing potential changes in the nociceptive pathways. The purpose of this paper is to provide an overview of altered nociceptive processing and somatosensory changes that may occur following a musculoskeletal injury without associated neural injury. Recommendations are made on clinical uses of quantitative sensory testing in orthopaedic physical therapy practice, and supporting clinical and laboratory evidence are presented. Examples related to joint injury are discussed, specifically, osteoarthritis of the knee and low back pain. Quantitative sensory testing may be a useful clinical tool to aid clinical decision making and for determination of prognosis.

A number of non-oral causes for oral malodor have been discussed. Several well documented etiologies for non-oral malodor include renal failure, cirrhosis of the liver, and diabetes mellitus. Each of these conditions has been examined using analytical instrumentation. In addition there appear to be several other metabolic conditions involving enzymatic and transport anomalies (such as trimethylaminuria) which lead to the systemic production of volatile malodors that manifest themselves as halitosis and/or altered chemoreception. Our studies include patients who have been referred to us after being examined by numerous clinical specialists with no identification or relief from their problem. This is due in part to the intermittent nature of many of these problems as well as an apparent lack of knowledge concerning many of these metabolic problems and their relation to oral symptoms.

• As part of the developmental process for the Head and Neck Intergroup trial of adjuvant chemotherapy for advanced resectable head and neck carcinoma, in 1981 the Radiation Therapy Oncology Group, Philadelphia, Pa, conducted two nonrandomized pilot studies using chemotherapy consisting of three courses of cisplatin and fluorouracil infusion. Chemotherapy was administered prior to surgery in 42 patients (induction) and after surgery in an additional 29 patients (sequential). The populations were roughly comparable with respect to tumor site and stage. Twelve of the 42 patients in the induction group and seven of the 29 in the sequential group are alive and with no evidence of disease at the last reported follow-up. The median survival was 31 months in the sequential group vs 20 months in the induction group. Only two of the 26 patients with less than a complete clinical response following induction chemotherapy are still alive. Twenty-seven of the 42 patients who received induction chemotherapy did not undergo surgery as initially planned. Despite the lack of surgery, at 5 years the survival between the two groups was not significantly different (27% for the induction group vs 23% for the sequential group). ( Arch Otolaryngol Head Neck Surg . 1991;117:288-291)

A case series of consecutive patients referred to physical therapy with patellofemoral pain syndrome (PFPS).Physical therapists often treat patients with PFPS, yet there is currently no consensus as to the most effective management strategies. The purpose of this case series is to describe the outcomes of patients referred to physical therapy with PFPS who were treated with a multimodal approach.Five patients were treated with a combination of thrust and nonthrust manipulation directed at the joints of the lower quarter, trunk and hip stabilization exercises, patellar taping, and foot orthotics. Outcome measures used to capture change in patient status included the Numeric Pain Rating Scale, the Kujala Anterior Knee Pain Scale, the Lower Extremity Functional Scale, and the Global Rating of Change.Five patients (median age, 15 years; range, 14-50 years) with a median duration of knee pain for 8 months (range, 3-24 months) were included in this prospective case series. Four (80%) of the 5 patients demonstrated decreased pain and a clinically significant improvement in function. These gains in function were maintained at a 6-month follow-up.Although a cause-and-effect relationship cannot be inferred from a case series, the outcomes achieved by the patients are consistent with studies incorporating manual physical therapy, exercise, patellar taping, and orthotic prescription to the management of conditions of the lower extremity. Further randomized controlled trials should be performed to determine the effectiveness of this multimodal approach for the management of individuals with PFPS.

Purpose: The University of Utah Comparative Genomic Hybridization Microarray Laboratory was one of the first US laboratories to offer comparative genomic hybridisation (CGH) microarray testing using a commercial platform in a clinical setting. Results for 1076 patients (1598 chips) are presented. Methods: The Spectral Genomics/PerkinElmer Constitutional Chip TM (targeted array), SpectralChip 2600 TM (whole genome array) and a “Combo” chip (both arrays run simultaneously) were the tests offered. Abnormal results were confirmed by an alternative method, most often fluorescence in situ hybridisation. Results: In 669 cases with known normal cytogenetics, an abnormal detection rate of 10.8% was observed, (5.3%, 12.2% and 14.1% for the Constitutional Chip TM , SpectralChip 2600 TM and Combo assay, respectively). Known copy number variants and single clone abnormalities are not included in these rates. Single clone abnormalities are reported separately. For 1076 total cases, we report an average abnormal rate of 16.9% (8.7%, 23.7% and 18.6% for the three assays). This rate includes characterisation of some abnormalities previously identified by cytogenetics. Conclusions: CGH microarray provides a likely aetiology for the clinical phenotype in many cytogenetically normal cases, and a whole genome array generally identifies copy number changes more effectively than a targeted chip alone.

The impact of smell and taste disorders on dietary habits and nutritional status has received limited research attention. This paper reports findings obtained from questionnaires and diet records completed by 40 healthy subjects and 118 patients with chemosensory dysfunction. Chemosensory disorders were frequently associated with decreases in food acceptability. Although dietary responses to these dysfunctions varied greatly, patients with distorted or phantom smell and/or taste sensations tended to report weight loss whereas those with simple sensory loss were more likely to report weight gain. Indices derived from diet records did not indicate that either group of patients was at substantial nutritional risk, but food frequency responses and estimates of body mass index were consistent with patient reports of changes in dietary patterns and weight. In addition, marked weight change and aberrant dietary practices were noted in individual patients. Thus, there were indications that chemosensory dysfunction may be associated with nutritionally important dietary alterations.

The authors examined the feasibility of using olfactory receptor neurons from living patients to test whether calcium signaling is altered in a neuronal cell population in bipolar disorder.Ratiometric fluorescence photomicroscopy was used to assess basal and stimulus-induced changes in intracellular calcium levels in biopsy-derived olfactory receptor neurons from seven euthymic patients with bipolar disorder who were medication-free, 10 euthymic patients with bipolar disorder who were treated with mood stabilizers, and 17 age- and sex-matched comparison subjects without bipolar disorder.Olfactory receptor neurons from the seven medication-free patients responded to stimuli predominantly with decreases in intracellular calcium, unlike those from the seven matched healthy subjects. Olfactory receptor neurons from patients treated with mood stabilizers were less likely to respond to stimulation than olfactory receptor neurons from medication-free patients.This study demonstrates the feasibility of using olfactory receptor neurons to examine alterations in intracellular signaling in neuronal cells from living patients. Our results, although based on a small number of subjects, suggest that altered intracellular calcium signaling in olfactory receptor neurons may be a trait of bipolar disorder.

Benign skeletal muscle neoplasms are rare, especially when compared with their malignant counterparts. Rhabdomyomas have been reported to account for only approximately 2% of all striated-muscle neop1asms.l Although it is difficult to know the true incidence of this rare tumor, up to 76% of reported noncardiac cases have been found to occur in the head and neck region.2 Rhabdomyomas can be subdivided into different groups, based on clinical and morphological differences. The purpose of this paper is to share a unique case presentation of a man who developed a recurrence of a parapharyngeal rhabdomyoma 25 years after primary surgical excision. This paper will review the literature and discuss presenting symptoms, differential diagnosis, histopathological findings, and treatment.

We present and discuss a case of lifelong tinnitus in an otolaryngologist (L.D.L.) followed by complete elimination of the tinnitus as a result of a cerebral vascular accident located in the left corona radiata. Pre- and post-CVA audiograms showed no change in hearing. A magnetic resonance imaging study of the brain documents the size and location of the lesion. Discussion looks at recent studies of the central nervous system showing evidence of increased activity related to tinnitus. Our assessment of the lesion and the resulting loss of tinnitus can be explained by the neurophysiological model of tinnitus, which includes plasticity of the central nervous system.

Summary: In the past, bilateral vocal fold immobility (BVFI) occurred most commonly after thyroidectomy. However, no large series documenting the etiology of adult BVFI has been published within the past fifteen years. This study reviews the etiologic patterns of BVFI at our institutions. We compare BVFI from before and after 1980. We also review combined studies of unilateral vocal fold immobility (UVFI) to compare and unilateral versus bilateral etiologic trends. In comparison with previously published series, fewer cases of BVFI present today as a complication of thyroid surgery and more as the result of malignancies and nonsurgical trauma. Unfortunately, BVFI caused by malignancy is not usually an initial sign of local disease, but an ominous sign of recurrence or metastases. In comparing UVFI and BVFI we found that thyroidectomy causes a higher percentage of BVFI than of UVFI. Over one-third of UVFI cases were caused by neoplasm which further underscores the potential seriousness of immobile vocal folds and the need for careful investigation.

Protein kinases A and C have been postulated to exert multiple effects on different elements of signal transduction pathways in olfactory receptor neurons. However, little is known about the modulation of olfactory responses by protein kinases in intact olfactory receptor neurons. To further elucidate the details of the modulation of odorant responsiveness by these protein kinases, we investigated the action of two protein kinase inhibitors: H89, an inhibitor of protein kinase A, and N-myristoylated EGF receptor, an inhibitor of protein kinase C, on odorant responsiveness in intact olfactory neurons. We isolated individual olfactory neurons from the adult human and rat olfactory epithelium and measured responses of the isolated cells to odorants or biochemical activators that have been shown to initiate cyclic AMP or inositol 1,4,5-trisphospate production in biochemical preparations. We employed calcium imaging techniques to measure odor-elicited changes in intracellular calcium that occur over several seconds. In human olfactory receptor neurons, the protein kinase A and C inhibitors affected the responses to different sets of odorants. In rats, however, the protein kinase C inhibitor affected responses to all odorants, while the protein kinase A inhibitor had no effect. In both species, the effect of inhibition of protein kinases was to enhance the elevation and block termination of intracellular calcium levels elicited by odorants. Our results show that protein kinases A and C may modulate odorant responses of olfactory neurons by regulating calcium fluxes that occur several seconds after odorant stimulation. The effects of protein kinase C inhibition are different in rat and human olfactory neurons, indicating that species differences are an important consideration when applying data from animal studies to apply to humans.

Women with a family history of breast cancer often over-estimate their personal risk for cancer and may view themselves as candidates for genetic testing even when the likelihood of an informative test result is low. We report here on genetic counseling of women with an intermediate family history of breast cancer, defined as women who have one or more biological relatives with breast cancer but whose pedigree suggests a low likelihood of autosomal dominant transmission. A genetic counseling protocol based on traditional genetic counseling strategies was developed with additional components added to address the needs of women with moderately increased breast cancer risk. These additional components included information about non-genetic risk factors, comparisons of high and moderate risk pedigrees, and evaluation of personal risk based on both genetic and nongenetic risk factors. Most participants liked the genetic counseling and found it useful. At baseline, participants over-estimated both their personal risk of breast cancer and that of the average woman. After counseling, estimates of personal and average risk of breast cancer were lower, although both remained higher than actual risk. Most participants reported that they felt less worried about breast cancer after receiving their personal-risk estimate. At baseline, most women judged themselves to be candidates for genetic testing and expressed interest in testing. The number who considered themselves candidates for testing was reduced after counseling (60% versus 82%) but still constituted a majority. Similarly, interest in testing was partially reduced by counseling (60% versus 91%). We conclude that genetic counseling can help women with an intermediate family history of breast cancer to develop more accurate views of their risk, reduce their breast cancer worry, and aid some of them in developing a more realistic view of genetic testing.

We present only the 12th reported case of a laryngeal leiomyosarcoma. This tumor was diagnosed with the aid of the newer immunohistochemical stains on archival paraffin-embedded tissue. The diagnosis and management of these tumors is based largely on the patterns seen in the small number of earlier reported cases of head and neck leiomyosarcomas and laryngeal sarcomas.

Human olfactory neuroepithelium (OE) is situated within the olfactory cleft of the nasal cavity and has the characteristic property of continually regenerating neurons during the lifetime of the individual. This regenerative ability of OE provides a unique model for neuronal differentiation, but little is known about the structure and biology of human olfactory mucosa. Thus, to better understand neurogenesis in human OE, we studied the expression of olfactory marker protein (OMP), TrkB and NeuroD in human nasal biopsies and autopsy specimens and compared these data with those obtained from normal and regenerating mouse OE. We show that NeuroD and TrkB are coordinately expressed in human OE. Thus, by using these markers we have been able to extend the known boundaries of the human OE to include the inferior middle turbinate. In normal mouse OE, TrkB and OMP expression overlap in cells closest to the superficial layer, but TrkB is expressed more strongly in the lower region of this layer. In contrast, NeuroD expression is more basally restricted in a region just above the globose basal cells. These characteristic expression patterns of OMP, TrkB and NeuroD were also observed in the regenerating mouse OE induced by axotomy. These results support a role of NeuroD and brain-derived neurotrophic actor (BDNF), the preferred ligand for TrkB, in the maintenance of the olfactory neuroepithelium in humans and mice.

Although fine-needle aspiration biopsy of salivary gland masses has been reported in the otolaryngology literature, the use of sonography to guide the biopsy of nonpalpable masses and masses seen on other cross-sectional imaging studies has not been described. Our goal was to evaluate sonographically guided biopsy of masses and lymph nodes related to the salivary glands. We analyzed the records of 18 patients who had undergone fine-needle aspiration biopsy of a salivary gland mass or lymph node with a 25-, 22-, or 20-gauge needle. A definitive cytologic diagnosis was made for 13 of the 18 patients (72%); cytology was suggestive but not definitive in three patients (17%) and insufficient in two (11%). Definitive diagnoses were made in three cases of reactive lymph node, in two cases each of lymph node metastasis and Warthin's tumor, and in one case each of pleomorphic adenoma, adenoid-cystic carcinoma, schwannoma-neurofibroma, parotid metastasis, parotid lymphoma, and Sjögren's-related lymphoid-epithelial lesion. Sonographically guided biopsy allows for confident needle placement in masses seen on computed tomography and magnetic resonance imaging. Sonography can usually distinguish a perisalivary lymph node from true intrasalivary masses, and it can help the surgeon avoid the pitfall of a nondiagnostic aspiration of the cystic component of masses. We conclude that sonographically guided biopsy of salivary gland masses can provide a tissue diagnosis that can have a direct impact on clinical decision making.

We have examined spontaneous and neostigmine-induced recovery after an initial dose of Org 9487 1.5 mg kg-1 followed by three repeat doses of Org 9487, a 30-min infusion of Org 9487 or two incremental doses of rocuronium. Mean clinical duration after incremental doses of Org 9487 0.5 mg kg-1 increased from 12.3 (SD 3.4) min to 14.0 (4.0) and 15.9 (5.9) min (P0.01), and after rocuronium from 14.4 (5.2) min to 19.2 (5.9) min (P0.01). Times for spontaneous recovery from a T1 of 25% to a TOF ratio of 0.8 after the last bolus dose of Org 9487 and after a 30-min infusion were 72.4 (16.5) and 66.1 (26.9) min compared with 36.7 (15.8) min in the group receiving reocuronium. These times were significantly reduced to 9.9 (4.5), 8.6 (6.1) and 5.7 (2.5) min, respectively, after neostigmine administration at a T1 of 25% (P0.05). We conclude that administration of Org 9487 by repeat bolus doses or infusion was associated with slow spontaneous recovery but neostigmine administration resulted in adequate recovery in less than 10 min.

The neuromuscular blocking effects and the reversibility of cisatracurium 0.1 or 0.15 mg.kg-1 were compared with those of atracurium 0.5 mg.kg-1 during anaesthesia with propofol, nitrous oxide and isoflurane. Neuromuscular block was monitored using train-of-four stimulation while recording the mechanomyographic response of the adductor pollicis muscle. The block was either allowed to recover spontaneously or was antagonised with neostigmine 50 micrograms.kg-1 at 10% or 25% recovery of the first twitch of the train-of-four. The median times to maximum block were 2.7, 2.2 and 1.5 min following cisatracurium 0.1 and 0.15 mg.kg-1 and atracurium 0.5 mg.kg-1, respectively. After cisatracurium 0.1 mg.kg-1 had been given, the median time to recovery of the train-of-four ratio to 0.8 ('adequate recovery') was 74 min during spontaneous recovery, 48 min after reversal with neostigmine when the first twitch of the train-of-four had returned to 10% of control and 50 min after reversal when the first twitch of the train-of-four had returned to 25% of control. These times for cisatracurium 0.15 mg.kg-1 and atracurium 0.5 mg.kg-1 were 90, 66 and 57 min and 75, 56 and 54 min, respectively. Administration of neostigmine significantly shortened the time to adequate recovery for both drugs but there were no significant differences in the case of either neuromuscular blocking drug between the groups of patients given neostigmine at 10 or 25% recovery of the first twitch of the train-of-four.

Renewed attention to chemosensory dysfunction has revealed that a substantial portion of the population are affected during their lives, many simply as a result of aging. The authors discuss terminology, assessment, etiology, and prognosis and compare current understanding with that presented by Mackenzie in 1884.

Rawson, N. E., G. Gomez, B. Cowart, J. G. Brand, L. D. Lowry, E. A. Pribitkin, and D. Restrepo. Selectivity and response characteristics of human olfactory neurons. J. Neurophysiol. 77: 1606–1613, 1997. Transduction mechanisms were investigated in human olfactory neurons by determining characteristics of odorant-induced changes in intracellular calcium concentration ([Ca2+]i). Olfactory neurons were freshly isolated from nasal biopsies, allowed to attach to coverslips, and loaded with the calcium-sensitive indicator fura-2. Changes in [Ca2+]i were studied in response to exposure to individual odors, or odorant mixtures composed to distinguish between transduction pathways mediated by adenosine 3′5′-monophosphate (cAMP; mix A) or inositol 1,4,5-trisphosphate (InsP3; mix B). Overall, 52% of biopsies produced one or more odorant-responsive olfactory neurons, whereas 24% of all olfactory neurons tested responded to odorant exposure with a change in [Ca2+]i. As in olfactory neurons from other species, the data suggest that odorant exposure elicited calcium influx via second-messenger pathways involving cAMP or InsP3. Unlike olfactory neurons from other species that have been tested, some human olfactory neurons responded to odorants with decreases in [Ca2+]i. Also in contrast with olfactory neurons from other species, human olfactory neurons were better able to discriminate between odorant mixtures in that no neuron responded to more than one type of odor or mixture. These results suggest the presence of a previously unreported type of olfactory transduction mechanism, and raise the possibility that coding of odor qualities in humans may be accomplished to some degree differently than in other vertebrates, with the olfactory neuron itself making a greater contribution to the discrimination process.

To determine whether elapsed radiation therapy treatment time relates to survival in patients with head and neck cancer treated sequentially with chemotherapy and radiation therapy.From 1981 to 1988, 76 adult patients with bulky stage II-IV head and neck cancer received induction chemotherapy (fluorouracil and cisplatin). Those with a complete or partial response (n = 46) received full-dose definitive radiation therapy (range, 64.0-77.5 Gy; median, 70 Gy). Those with less than a partial response (n = 21) underwent surgery and postoperative radiation therapy (n = 15), palliative radiation therapy (n = 4), or palliative chemotherapy (n = 2). Nine patients refused to undergo radiation therapy after induction chemotherapy.The 5-year overall survival rates were as follows: 32% in all patients, 38% in patients who underwent chemotherapy and radiation therapy, and 27% in patients who underwent chemotherapy, surgery, and radiation therapy. The number of days between radiation therapy treatments was highly predictive of overall survival. In the groups with treatments less than 55 days apart, 56-65 days apart, and more than 66 days apart, the 5-year survival rates were 56%, 46%, and 15%, respectively (P = .02).The time between radiation therapy treatments is strongly predictive of survival in patients undergoing sequential chemotherapy and radiation therapy. The use of induction chemotherapy does not negate the need to avoid treatment interruptions during definitive radiation therapy.

Olfactory neuroblastoma (ONB) is a rare neuronal malignancy of the olfactory mucosal. Markers used in the diagnosis of ONB do not distinguish ONB from other neuronal tumors or tumors with neuroendocrine features thus making the diagnosis of ONB difficult. Using a modified RT-PCR technique, we show that the human homologue of the Drosophila achaete-scute gene HASH1 is expressed in 6 primary and one metastatic ONB specimens, whereas Olfactory Marker Protein (OMP) is not. Previous studies have shown that HASH1 is expressed in immature olfactory neurons and is required for their development. OMP, whose function is unknown, is expressed exclusively in mature olfactory neurons. Together, these data suggest that ONB is derived from immature olfactory neurons of neuroectodermal origin. Analysis of RNA expression in primary tumor specimens and in an established cell line make this an ideal system to study olfactory growth and differentiation. Furthermore, these studies represent the first molecular genetic analysis of this rare and unusual neuronal tumor.

Chronic cutaneous small vessel (leukocytoclastic) vasculitis (LCV) is a process believed to be related to the presence of circulating immune complexes. The most frequent causes and associated disorders are medications, infections, collagen vascular disorders, paraproteinemias, and, rarely, neoplasia. Reports of food or food additives as a causative factor for LCV have appeared but are rare. We report a patient with chronic cutaneous LCV in whom the presumed cause was an excipient (a dye) used in the capsule form of lithium carbonate. Furthermore, ingestion of foods containing dyes results in a disease flare in our patient.

An unusual localization of intranasal angiomyolipoma is described in an adult male patient with no signs of tuberous sclerosis. The lesion was composed of mature fat cells, vascular spaces with lack of elastic tissue, and presence of bundles of mature smooth muscle cells. Antibodies to intermediate filaments revealed presence of vimentin and absence of desmin in both smooth muscle bundles and in vessel walls. A review of the literature has shown that this is only the third reported case of the angiomyolipoma of the nasal cavity, and some important differences between this entity and renal angiomyolipoma are described.

Introduction: Follow-up of individuals treated for a primary squamous carcinoma of the upper aerodigestive tract is critical because of the high risk of development of either recurrent disease or a new primary tumor. A mail survey of physicians actively practicing head and neck surgery was undertaken. Materials and Methods: A multiple-choice survey was distributed to 400 members of the American Society for Head and Neck Surgery. Respondents indicated approach to post-treatment follow up. Results : Surveys were returned from 290 members (73%). Routine monthly follow up is advocated by 73% of respondents during the first postoperative year. Patients are followed every 2 to 3 months in the second postoperative year by 90% of respondents. During postoperative years, 3 to 5 patients are seen every 4 to 6 months by 97% of respondents. All respondents see patients either semiannually or annually for the remainder of their lives. Sixty percent of respondents advocate annual screening chest radiographs, whereas 14% do not order routine chest radiographs. The overwhelming majority of respondents reserve barium swallow and computed tomographic (CT) scans for evaluation of symptomatic patients. Similarly, nuclear imaging is reserved for patients with specific symptoms or abnormal laboratory tests. Blood tests most frequently monitored include complete blood cell count (CBC) (43%), thyroid function test (22%), and liver function test (20%). Follow-up endoscopic evaluation under anesthesia is reserved for symptomatic patients by over 95% of respondents. Conclusion: These data demonstrate that head and neck surgeons rarely use supplemental studies other than chest radiography during routine follow up. The authors speculate that routine chest radiography may be valuable in screening for a second primary carcinoma. Techniques to screen for esophageal tumors remain contentious.

This is a report of a 10-year median follow-up of a randomized, prospective study investigating the optimal sequencing of radiation therapy (RT) in relation to surgery for operable advanced head and neck cancer. In May 1973, the Radiation Therapy Oncology Group (RTOG) began a Phase III study of preoperative radiation therapy (50.0 Gy) versus postoperative radiation therapy (60.0 Gy) for supraglottic larynx and hypopharynx primaries. Of 277 evaluable patients, duration of follow-up is 9-15 years, with 7.6% patients lost to follow-up before 7 years. Loco-regional control was significantly better for 141 postoperative radiation therapy patients than for 136 preoperative radiation therapy patients (p = 0.04), but absolute survival was not affected (p = 0.15). When the analysis was restricted to supraglottic larynx primaries (60 postoperative radiation therapy patients versus 58 preoperative radiation therapy patients), the difference for loco-regional control was highly significant (p = .007), but not for survival (p = 0.18). In considering only supraglottic larynx, 78% of loco-regional failures occurred in the first 2 years. Thirty-one percent (18/58) of preoperative patients failed locally within 2 years versus 18% (11/60) of postoperative patients. After 2 years, distant metastases and second primaries became the predominant failure pattern, especially in postoperative radiation therapy patients. This shift in the late failure pattern along with the increased number of unrelated deaths negated any advantage in absolute survival for postoperative radiation therapy patients. The rates of severe surgical and radiation therapy complications were similar between the two arms. Because of an increased incidence of late distant metastases and secondary primaries, additional therapeutic intervention is required beyond surgery and postoperative irradiation to impact significantly upon survival.

Injection of Teflon® paste is a commonly accepted procedure to improve the caliber of voice in unilateral vocal cord paralysis. There are several drawbacks to Teflon injection, among them respiratory obstruction (from overinjected Teflon) and unsatisfactory voice quality (Teflon causes stiffness of the vocal folds). This paper is a preliminary report on lipoinjection instead of Teflon injection into a paralyzed vocal fold. Fat appears to impart a soft bulkiness to the injected cord, while allowing it to retain its vibratory qualities. It is autologous material and can be retrieved if excessively overinjected. The fate of autologous fat injected into a paralyzed vocal cord remains unknown. Most of the literature on lipoinjection concerns repairs of depressed scars or breast augmentation. Our longest follow-up has been 12 months. Three patients have had this procedure, and the results appear to be very encouraging.

The authors present a case of a highly atypical, possibly malignant, hibernoma. It presented as a deep-seated tumor in the retropharynx of a 57-year-old male. A review of possible similar cases is presented. The patient is without recurrence 4 years after complete excision and radiation therapy. The tumor must be differentiated from liposarcoma. The clinical potential must await the accumulation and observation of additional cases.

— One hundred persons were selected from our audiology records who showed at least 20 dB bilateral sensorineural hearing loss. The number 100 was picked for an adequate statistical analysis. The patients were taken from the chart files which are filed in chronological order. Letters were mailed with instructions for fasting 14 hours prior to testing except for the consumption of water. On presentation, a history was taken for diabetes, height and weight, and the blood pressure was recorded. The blood samples were drawn in clot tubes and taken to a commercial laboratory for overnight refrigeration and testing of the serum. Testing included observation of serum for massive chylomicronemia, triglycerides, cholesterol and lipoprotein electrophoresis (by the cellulose acetate method). Lipoprotein testing results showed 12 patients with Type II A or II B and 8 patients with Type IV abnormalities. No Types I, III or V were found. These 20 patients represent a lower number of hyperlipoproteinemic patients than would be expected in the general population.

The presence or absence of distant metastases in squamous cell carcinoma of the head and neck is critical in making rational therapeutic decisions. Radionucleotide bone and liver scans are frequently utilized in the initial evaluation of these patients for possible distant metastases. The true value of routine bone and liver scans in the initial staging of primary squamous cell carcinoma of the head and neck is unknown. One hundred eighteen patients with primary squamous cell carcinoma of the head and neck, evaluated during a five-year period, were retrospectively reviewed. Eight percent were stage I, 18% stage II, 21% stage III, 53% stage IV. Because metastatic carcinoma of the head and neck is primarily regional or pulmonary, the low prevalence of liver and bone metastases limits the usefulness limits the usefulness of these radionucleotide scans. We conclude that routine bone and liver scanning is not a valuable diagnostic technique in the initial staging of head and neck carcinoma when clinical or biochemical evidence of distant metastases is not present.

One hundred and ten patients with supraglottic squamous cell carcinoma have been randomized for preoperative radiation therapy and surgery versus surgery and postoperative radiation therapy. Data have been analyzed on 94 patients in this preliminary report. The differences between the two groups with respect to local control and survival are not statistically significant at this time. Additional accrual and continued follow-up are necessary in order to make a more definite treatment comparison.

Two hundred and ninety-eight patients with squamous cell carcinoma of the oral cavity, oropharynx, supraglottic larynx, hypopharynx or maxillary sinus have been randomized for preoperative radiation therapy and surgery vs. surgery and postoperative radiation therapy plus, in the case of patients with lesions of the oral cavity and oropharynx, radical radiation therapy. Data have been analyzed on 243 patients in this interim report. The differences between the three groups with respect to local control and survival are not statistically significant at this time. Additional accrual and continued follow-up are necessary to make definite treatment comparisons.

Congenital vascular anomalies of the aortic arch are unusual etiologies of dysphagia in the adult. Swallowing abnormalities associated with compression of the esophagus primarily occur at birth or in the immediate neonatal period. However, as the result of arteriosclerotic vascular disease or aneurysm formation, anomalies which were asymptomatic postnatally may produce dysphagia in the adult. A retrospective analysis of 59 cases with aortic arch anomalies presenting initially in adulthood revealed characteristic clinical signs and symptoms. An aberrant right subclavian artery with left aortic arch was the most frequently encountered abnormality. The embryologic development of each vascular anomaly is described and the value of selective arteriography with contrast esophagography is stressed. Patients with minimal swallowing impairment are treated with dietary management alone. Surgical division of the anomalous artery is indicated only when severe dysphagia is associated with progressive life-threatening anorexia and weight loss.

Between March 1973 and June 1979, patients with advanced operable squamous cell carcinoma of the supraglottic larynx or hypopharynx were randomly allocated to receive either preoperative radiation therapy (5,000 rad) or postoperative radiation therapy (6.000 rad). Patients with oral cavity or oropharynx lesions were randomly assigned either preoperative radiation, postoperative radiation, or definitive radiatio therapy (6,500–7,000 rad), with surgery reserved for slavage if residual disease was present 6 weeks after completion of irradiation. Three hundred twenty patients were evaluable with a median follow-up of 60 months. Based on results in 277 patients across all four region combined, locoregional control was significantly better for patients assigned to receive psotoperative radiation therapy (65%) compared with those assigned to receive preoperative radiation therapy (48%, P=0.04). This was due to higher rate of both persistent and recurrent local and regional disease in the preoperative group. Survival also showed a trend to be better in the postoperative group (38%) compared with the preoperative group (38%) compared with the preoperative group (33%, P = 0.10). Rates of severe surgical and radiation therapy complications were similar overall. Forty-three patients were evalauble for each of the three treatment regimens assigned to patients with oral cavity or oropharynx lesions. Due to the small number of patients available for this portion of the trial, the observed differences for overall survival (4-year percentage 33% overall; 30% preoperative, 36% postoperative, 33% definitive radiation therapy) and for locoregional control (45% overall; 43% preoperative, 52% postoperative, 38% definitive radiation therapy) were not statistically significant. The use of definitive radiation therapy with surgical rescue as an ethically justified alternative treatment for these tumors remains a question for further research.

With the multi-faceted approach to head and neck cancer today, maintaining caloric intake by long-term enteral hyperalimentation is commonplace. Along with the tremendous advantages of this form of nutrition, the disadvantage of hyperosmolar nonketotic diabetic acidotic coma is present. Mortality rates are quoted from 40% to 70% according to the literature reviewed. Therefore, prevention is the best form of treatment. The cause, diagnosis, and treatment will be discussed.

The CT signs of aberrant course of the internal carotid artery are presented and are contrasted against those of anomalously high jugular bulb, glomus tympanicum and cholesterol granuloma.

Fibrous dysplasia (FD) of the paranasal sinuses is rare and often presents a diagnostic challenge. It is usually secondary to extension of disease from adjacent bones and is rarely limited to the sinuses. We have described three cases of FD involving the paranasal sinuses, including the first reported case of FD isolated to the sphenoid sinus. A brief update of the clinical aspects, radiographic appearance, diagnosis, and management of craniofacial FD is provided.

Mucoepidermoid carcinoma is most commonly found in the parotid gland. It rarely occurs in the larynx and hypopharynx. There are only 32 reported cases from these areas. A case of a mucoepidermoid carcinoma of the hypopharynx is presented. Although the initial impression was squamous cell carcinoma, glandular structures were found in metastatic lymph nodes in the neck specimen, and after mucicarmine stains were positive, the final diagnosis was changed to mucoepidermoid carcinoma. This case illustrates the difficulty in diagnosing mucoepidermoid carcinoma, especially in unexpected locations. Differentiating mucoepidermoid carcinoma from other neoplasms is important because treatment may differ depending on the diagnosis. The pathologic spectrum of mucoepidermoid carcinoma is presented, and the management of these tumors with respect to the histologic grade is discussed.