Evaluation of PEG-L-asparaginase in asparagine suppression and anti-drug antibody development in healthy Beagle dogs: A multi-phase preclinical study.

L-asparaginase is a frequently used drug in the treatment of canine malignant lymphoma. Since production and availability of native E. coli-derived L-asparaginase are limited, PEG-L-asparaginase (PEG-ASP) is an alternative. However, recommended doses and dosing intervals are mainly empirically determined. A multi-phase clinical dose-finding study with seven healthy Beagle dogs was conducted to find the minimum effective dose and, potentially, a dosing interval for PEG-ASP in dogs. Plasma concentrations of amino acids and PEG-ASP activity were measured at various time points after administration of different doses of PEG-ASP. Anti-PEG and anti-asparaginase antibody titres were measured. Administration of 10 IU/kg PEG-ASP resulted in asparagine depletion in all dogs, albeit for various durations: for 9 days in all dogs, 15 days in five dogs, 21 days in three dogs and 29 days in one dog. Asparagine suppression occurred at PEG-ASP plasma concentrations < 25 IU/L. Subsequent administrations of a second and third dose of 20 IU/kg and 40 IU/kg PEG-ASP resulted in asparagine suppression at < 9 days in five dogs, accompanied by the development of antibodies against PEG and L-asparaginase. Two dogs with prolonged asparagine suppression after the second and third administration did not develop antibodies. Marked individual variation in the mechanism and duration of response to PEG-ASP was noted. Antibody formation against PEG-ASP was frequently observed and sometimes occurred after one injection. This study suggests that PEG-ASP doses as high as the currently used dose of 40 IU/kg might not be needed in treatment of canine malignant lymphoma.

Osteoradionecrosis of tympanic bone: reconstruction of outer ear canal with pedicled skin flap, combined with hyperbaric oxygen therapy, in five patients.

OBJECTIVE: To evaluate the results of one-stage surgical repair of the meatal skin defect in patients with long-lasting osteoradionecrosis of the outer ear canal, using a postauricular, inferiorly pedicled skin flap. All patients were also treated with hyperbaric oxygen both pre- and post-operatively. METHODS: A prospective study evaluating the results of a one-stage surgical procedure to repair the meatal skin defect in five patients with osteoradionecrosis of the outer ear canal. All patients were treated with hyperbaric oxygen both pre- and post-operatively. RESULTS: In four of the five patients, intact canal skin was achieved after surgery and hyperbaric oxygen therapy. One patient needed a second operation to cover a small remaining area of bare bone. In one patient, wound healing was unsatisfactory and an area of bare bone remained. CONCLUSION: In cases of osteoradionecrosis of the outer ear canal, the skin defect can be repaired with an inferiorly pedicled skin flap. Although not yet scientifically proven, the peri-operative application of hyperbaric oxygen may be of additional value to improve wound healing in areas of compromised tissue.

A review of the current literature on management of halitosis.

Halitosis is an unpleasant or offensive odour, emanating from the oral cavity. In approximately 80% of all cases, halitosis is caused by microbial degradation of oral organic substrates. Major degradation products are volatile sulphur-containing compounds. In this review, the available management methods of halitosis and their effectiveness and significance are presented and discussed. Undoubtedly, the basic management is mechanically reducing the amount of micro-organisms and substrates in the oral cavity. Masking products are not, and antimicrobial ingredients in oral healthcare products are only temporary effective in reducing micro-organisms or their substrates. Good short-term results were reported with chlorhexidine. Triclosan seems less effective, essential oils and cetylpyridinium chloride are only effective up to 2 or 3 h. Metal ions and oxidizing agents, such as hydrogen peroxide, chlorine dioxide and iminium are active in neutralizing volatile sulphur-containing compounds. Zinc seems to be an effective safe metal at concentrations of at least 1%. The effectiveness of active ingredients in oral healthcare products is dependent on their concentration and above a certain concentration the ingredients can have unpleasant side effects. Tonsillectomy might be indicated if (i) all other causes of halitosis are managed properly; (ii) halitosis still persists and (iii) crypts in tonsils are found to contain malodorous substrates.

Membrane properties and firing patterns of inferior colliculus neurons: an in vivo patch-clamp study in rodents.

The inferior colliculus (IC) is a large auditory nucleus in the midbrain, which is a nearly obligatory relay center for ascending auditory projections. We made in vivo whole cell patch-clamp recordings of IC cells in young-adult anesthetized C57/Bl6 mice and Wistar rats to characterize their membrane properties and spontaneous inputs. We observed spikelets in both rat (18%) and mouse (13%) IC neurons, suggesting that IC neurons may be connected by electrical synapses. In many cells, spontaneous postsynaptic potentials were sufficiently large to contribute to spike irregularity. Cells differed considerably in the number of simultaneous spontaneous postsynaptic potentials that would be needed to trigger an action potential. Depolarizing and hyperpolarizing current injections showed six different types of firing patterns: buildup, accelerating, burst-onset, burst-sustained, sustained, and accommodating. Their relative frequencies were similar in both species. In mice, about half of the cells showed a clear depolarizing sag, suggesting that they have the hyperpolarization-activated current I(h). This sag was observed more often in burst and in accommodating cells than in buildup, accelerating, or sustained neurons. Cells with I(h) had a significantly more depolarized resting membrane potential. They were more likely to fire rebound spikes and generally showed long-lasting afterhyperpolarizations following long depolarizations. We therefore suggest a separate functional role for I(h).

Nasal nitric oxide in cystic fibrosis with and without humming.

BACKGROUND: Nasal nitric oxide (nNO) values are reduced in patients with cystic fibrosis (CF). Humming during nNO measurement increases nNO values in healthy subjects. Nasal NO is reduced in patients with CF, sinus disease or nasal polyps. Humming nNO values have not been reported in CF patients yet. Our aim was to explore humming nNO values in CF patients and assess whether nNO during humming is a better discriminator than silent nNO measurements in this patient group. MATERIALS AND METHODS: In a cross sectional study we measured nNO concentrations in healthy controls (HC) and in CF patients (n = 23 and 31, respectively). The participants held their breath for 10 s while air was passively extracted from one nostril with 700 mL min(-1) for direct NO measurements (NIOX chemiluminescence analyser). Subsequently nNO was measured during humming with the mouth closed for 10 s. RESULTS: Mean nNO in parts per billion (p.p.b.) (SD) during breath hold was 499 (164) and 240 (139), respectively. The median nNO peak (p.p.b., minimum-maximum) during humming was 1500 (425-4100) for HC and 120 (23-500) for CF. There was a highly significant difference between nNO both with and without humming between CF and HC (P < 0.01). The sensitivity and specificity of nNO for detecting CF were better with humming. CONCLUSION: Nasal NO concentrations with and without humming are significantly decreased in CF. Humming nNO is an excellent discriminator between HC and CF and performs better than silent nNO.

Nasal nitric oxide and nasal allergy.

Measurements of nasal nitric oxide (nNO) are attractive because they are completely noninvasive and can easily be performed. The measurements may be useful in the early diagnosis of patients with chronic airway disorders such as Kartager's syndrome and cystic fibrosis. The possible use of nNO measurements in the diagnosis and treatment of allergic rhinitis still needs to be further evaluated because of the variable and also contradicting findings of nNO concentrations in this disease. In this review we will discuss the origin, production and measurement of nNO as well as the effect of allergic rhinitis, nasal allergen challenge and medication on nNO. Subsequently, we examine published data on allergic rhinitis and nNO, and summarize the effect of treatment of rhinitis on nNO. Finally, we discuss the potential future role for nNO in the diagnosis and management of allergic rhinitis.

Nasal NO measurement by direct sampling from the nose during breathhold: Aspiration flow, nasal resistance and reproducibility.

The objective of this study was assessment of the effect of aspiration flow, the nasal cycle, and time on nasal nitric oxide (nNO) concentrations in air sampled from one nostril during breathhold. nNO was measured in 45 healthy subjects (19 males, aged 18-45 years) from one nostril during breathholding. We compared nNO values and time to plateau in both nostrils with 3 aspiration flows (280, 700, 1,200 ml/min) and assessed the short-term and long-term reproducibility. Mean nNO values at flows of 280, 700 and 1,200 ml/min differed significantly (P < 0.01): 854, 474, 380 ppb, respectively. The (median) plateau was reached after 6, 4 and 3 s for the different flows. The within-subject coefficient of variability was always < 5%. We found no difference in nNO between left-, right-, largest or smallest nostril (P > 0.10). nNO values after 6, 24 h and 7 days were not significantly different from baseline (P > 0.10) and showed fair reproducibility. The highest aspiration flow was experienced as unpleasant. nNO can be measured in either nostril and shows no diurnal variation. The measurement is quick, reproducible, feasible and best accepted with an aspiration flow of 700 ml/min during breathhold for 10 s.

Physical and psychosocial correlates of head and neck cancer: an update of the literature and challenges for the future (1996-2003).

An update of the literature on physical and psychosocial aspects of head and neck cancer, with special emphasis on effects of treatment, patient-related factors and psychosocial intervention on quality of life (QoL). QoL deteriorates during and directly after treatment and returns only slowly to pre-treatment values. Organ preservation, gender and coping-strategies are factors related to QoL after treatment. As prognosis and survival were found to be comparable under different treatment regimes, we noticed a gradual shift in therapy towards organ preservation. Systematic care, using specific instruments is important for improving the QoL. We feel that more attention should be given to improving support, in order to optimize the QoL of patients during the palliative stage.

Nasal NO: normal values in children age 6 through to 17 years.

The present study is an assessment of normal values of nasal nitric oxide (nNO) in healthy children. Healthy children aged between 6-17 yrs were recruited from three schools in Rotterdam (The Netherlands). Breath was held for 10 s, while air was extracted from one nostril at 700 mL.min(-1). The mean nNO value at the response plateau after 7-10 s was recorded and the average of three measurements was used. In total, 340 children participated; the male:female ratio was 156:184. Three reliable measurements were available in 85% of the children. The nNO concentrations were distributed normally (mean 449 ppb, SD 115). They were not associated with sex, passive smoking or body mass index. In children aged <12 yrs nNO correlated positively with age, history of adenoidectomy and ambient NO. In children aged > or =12 yrs ambient NO was the only significant modifier. Prediction rules for nNO values in children were formulated. In conclusion, the current study presents normal values for nasal nitric oxide in children, which can be used to assess the value of nasal nitric oxide in respiratory illnesses.

Silent and humming nasal NO measurements in adults aged 18-70 years.

BACKGROUND: The concentration of nitric oxide (NO) measured from the nose is much higher than in the lower airways and increases during humming. We assessed nasal NO (nNO) normal values during breath hold and during humming in healthy adults. MATERIALS AND METHODS: Nasal NO concentrations were measured in healthy adults (ages 18-70). They held their breath for 10 s and thereafter hummed as loud as possible with their mouths closed also for 10 s. During breath hold, air was passively extracted from one nostril with 700 mL min(-1). The average NO concentration at the plateau after 7-10 s was recorded and the mean of three consecutive measurements was calculated. During humming, air was extracted with 1200 mL min(-1), the peak NO values were recorded. RESULTS: One hundred healthy adults participated (37 men). The nNO concentrations during breath hold were distributed normally (mean: 455 parts per billion (p.p.b.), SD 147). A random subgroup of 40 out of the 100 subjects (15 men) performed nNO measurement during humming. The median peak NO value was 1019 p.p.b. (SD 561) at the first, and 837 p.p.b. (SD 408) at the second measurement. There was a significant difference between the peak NO values of first and second humming. CONCLUSION: We present normal values for nNO in adults, which can be used to assess the value of nNO in respiratory illnesses. The peak nNO values during humming are variable, and their clinical relevance remains to be shown.

[Superior-canal dehiscence syndrome]. / Het 'superior-canal dehiscence'-syndroom.

Superior-canal dehiscence syndrome (SCDS) was first described in 1998; it manifests as symptoms of dizziness and oscillopsia when a sound or pressure stimulus is given to the ear concerned. SCDS is caused by dehiscence ofpetrosal bone overlying the superior, vertical semicircular canal, creating a 'third mobile window' to the labyrinth, in addition to the oval and round windows. Characteristic for this syndrome are eye movements with a vertical-torsion direction, evoked by sound stimuli, or pressure changes via the external ear canal and the Valsalva manoeuvre. The anomaly of the bony structure is visible on a CT scan. With its specific symptoms and characteristics, SCDS is an abnormality of the vestibular system that is relatively easy to diagnose. The syndrome may be treated with conservative or surgical means.

[Problems of the head and neck region in divers]. / Problemen in het hoofd-halsgebied bij duikers.

For understanding the problems in the head and neck region of divers, knowledge of some physical laws is needed. Primarily, problems of diving are related to barotrauma: tissue-damage by pressure. The most frequent problems encoutered with diving are problems in closed cavities, such as in ears, teeth, and sinuses. Other problems occuring are those of temporomandibular joints, facial nerves, and oral mucosal tissues.

The role of (duodeno)gastroesophagopharyngeal reflux in unexplained excessive throat phlegm.

Gastroesophageal reflux (GER), through the occurrence of gastroesophagopharyngeal reflux (GEPR), is an established cause of several otorhinolaryngological (ORL) manifestations. It has been suggested that unexplained excessive throat phlegm might also be a manifestation of GER, but formal evidence is lacking. The aim of the present study was to investigate the prevalence of GER as well as duodenogastroesophageal reflux (DGER) in consecutive patients with chronic complaints of excessive throat phlegm. Fifty-nine consecutive patients with chronic unexplained excessive throat phlegm, transparent in 33 patients (TTP) and yellow in 26 patients (YTP), underwent gastrointestinal endoscopy, 24-hr dual esophageal pH monitoring, and fiberoptic DGER monitoring. Proximal esophageal DGER monitoring was performed in seven YTP patients and analysis of bile acids in throat phlegm was performed on 16 samples. The effect of high-dose acid suppressive therapy was evaluated at 2-week intervals. Endoscopy and pH monitoring established a diagnosis of pathological GER in 75% of the patients. Pathological DGER was present in 56% of the patients and this was associated with YTP. Proximal DGER exposure was high in all investigated subjects and chemical analysis revealed a median bile acid concentration of 0.184 microM in nine YTP samples and no detectable bile acids in seven TTP samples. After a median of 4 weeks of acid suppressive therapy, most patients improved and 61% became asymptomatic. YTP patients were more likely to require maintenance acid suppressive therapy than TTP patients. Unexplained excessive throat phlegm is a sign suggestive of GER and GEPR, and unexplained yellow throat phlegm a sign suggestive of duodenogastroesophagopharyngeal reflux (DGEPR).

The cervico-ocular reflex is increased in whiplash injury patients.

Whiplash-associated disorders (WAD) are a major problem in the Western world, which put a formidable financial burden on modern society and which evoke an emerging debate on the true nature of their origin. To date there is no generally accepted test that allows us to diagnose WAD objectively. Because whiplash injury causes dysfunction of proprioception in the neck, we investigated the characteristics of the cervico-ocular reflex (COR) of presumptive WAD patients. These patients and age-matched healthy controls were rotated at different stimulus peak velocities in the dark while their head was fixed in space. The gain values of the COR were significantly increased in the patient population at a wide range of stimulus peak velocities with maximum difference at the lower frequencies (p = 0.037, ANOVA). Hence, although larger numbers of patients should be measured, the COR gain appears to be a parameter that may permit an objective diagnosis of WAD.

Development of the orohypopharyngeal cavity in normal infants and young children.

OBJECTIVE: To study the growth of the oropharynx and hypopharynx in infants and young children by measuring the lengths of the segments between nasopharyngeal valve and tongue base, tongue base and arytenoids, and arytenoids and upper esophageal sphincter. These measurements will be used as references for developing manofluoroscopy to study deglutition in infants and young children. PATIENTS AND METHODS: Twenty-three children (14 boys, 9 girls) between birth and 4 years of age were prospectively studied. All children had near normal growth parameters and were free of medical illnesses or other major medical conditions that are known to influence the pharyngeal cavity. Lateral videofluoroscopy was used to assess the pharyngeal structures during breathing. All images were digitally recorded and analyzed using a computer program designed specifically for this study. RESULTS AND CONCLUSIONS: Statistically significant correlations were found between the age or height of the patient and the distance from velopharyngeal valve to tongue base and the distance from tongue base to arytenoids, showing a linear increase of the length of the oro- and hypopharynx with age and patient height. There was no significant difference in the pharyngeal distances between boys and girls. On the basis of these results, a linear regression comparison could be established to define the length of each pharyngeal segment for any age until 4 years and for the 50th percentile of height.

Compensatory increase of the cervico-ocular reflex with age in healthy humans.

The cervico-ocular reflex (COR) is an ocular stabilization reflex that is elicited by rotation of the neck. It works in conjunction with the vestibulo-ocular reflex (VOR) and the optokinetic reflex (OKR) in order to prevent visual slip over the retina due to self-motion. The gains of the VOR and OKR are known to decrease with age. We have investigated whether the COR, a reflexive eye movement elicited by rotation of the neck, shows a compensatory increase and whether a synergy exists between the COR and the other ocular stabilization reflexes. In the present study 35 healthy subjects of varying age (20-86 years) were rotated in the dark in a trunk-to-head manner (the head fixed in spaced with the body passively rotated under it) at peak velocities between 2.1 and 12.6 deg s-1 as a COR stimulus. Another 15 were subjected to COR, VOR and OKR stimuli at frequencies between 0.04 and 0.1 Hz. Three subjects participated in both tests. The position of the eyes was recorded with an infrared recording technique. We found that the COR-gain increases with increasing age and that there is a significant covariation between the gains of the VOR and COR, meaning that when VOR increases, COR decreases and vice versa. A nearly constant phase lag between the COR and the VOR of about 25 deg existed at all stimulus frequencies.

[Causes of otalgia from outside the ear]. / Oorpijn door oorzaken buiten het oor.

Two patients, a man aged 50 and a woman aged 61 years, complained about otalgia without a hearing disorder. Both patients exhibited slight mucosal redness of the upper airway at examination of the ear, nose, and throat, but no other abnormalities. Subsequent CT investigations of the ear and paranasal sinuses revealed no pathology in either patient. The first patient's condition deteriorated; he was eventually found to have a bronchial carcinoma that might have involved the vagal nerve. The second patient, who had a diaphragmatic hernia, improved dramatically once her daily dose of omeprazole had been augmented. It seems that both patients suffered from otalgia referred by the vagal and/or glossopharyngeal nerve.

[Two patients with a perforation of the esophagus and hypopharynx, respectively, caused by a bone in their food]. / Twee patiënten met een perforatie van de slokdarm respectievelijk hypofarynx door een botje in het eten.

Two patients, men aged 58 and 28 years, developed pain in the throat while eating chicken and pork, respectively. In the emergency clinic and during a check-up on the following day, no foreign body could be found. On the third visit to the hospital, oesophagoscopy was performed. In one patient a chicken bone was found lying transversely in the oesophagus; after removal of this bone extraluminal pus was seen. In the other patient a pork bone was found in the right piriform recess, with a great deal of local pus. Both foreign bodies were removed during oesophagoscopy. The recovery of both patients was uneventful. A foreign body is found in the upper digestive tract in approximately one-third of the patients presenting to an emergency department with a history of foreign body ingestion. Serious complications occur in less than 1%; however, these complications can be life-threatening. If, based on the anamnesis, physical examination or radiological evaluation, there is suspicion of a foreign body in the oesophagus, or if the examination is incomplete, then oesophagoscopy should be performed.

Hereditary otovestibular dysfunction and Ménière's disease in a large Belgian family is caused by a missense mutation in the COCH gene.

OBJECTIVE: To report the clinical, auditory, and vestibular characteristics of a nonsyndromic otovestibular dysfunction in a large Belgian family caused by a missense mutation of the DFNA9 gene: COCH. STUDY DESIGN: Retrospective study of the clinical, audiologic, and vestibular data of 60 genetically affected cases. SETTING: Tertiary referral center. PATIENTS: All members of a Belgian kindred who carry the genetic (P51S) defect linked to the inherited hearing and vestibular impairment. INTERVENTIONS: Diagnostic otologic, audiometric, and vestibular analysis and imaging. MAIN OUTCOME MEASURES: Pure tone audiometry, supraliminary audiometry. and vestibular investigation. RESULTS: The autosomal dominant inherited impairment was characterized by peripheral degeneration of the inner ear, leading to total deafness and bilateral vestibular areflexia. CONCLUSIONS: The genetically affected persons of a Belgian family shared a progressive sensorineural hearing loss starting between the third and sixth decade. Vestibular symptoms started at about the same age as the hearing loss. The vestibular symptoms consisted of instability in darkness, a tendency to fall sideways, light-headiness, a drunken feeling, and attacks of vertigo. Most of the patients reported tinnitus, and half of them reported pressure in the ears. Clinically, 9 of the 60 patients met the criteria for definite Ménière's disease, and another 13 and 17 patients met the criteria for probable or possible Ménière's disease, respectively. All 9 were older than the age of 35, but only 1 was older than 55 years, so more than 30% of the patients were between 35 and 55 years old. A specific pattern could be recognized in the evolution of the otovestibular impairment. Under the age of 35 years, almost all the affected family members had normal hearing, whereas above the age of 55 years, the hearing loss was at least moderate, and vestibular hypofunction occurred. In between, there was a transition period of two to three decades, when deterioration of the cochleovestibular function occurred, with a temporary audiometric and vestibular asymmetry.