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.

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.

[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 immotile cilia syndrome: phase contrast light microscopy, scanning and transmission electron microscopy.

In the immotile cilia syndrome, transmission electron microscopy of the cilia shows abnormalities in the arrangement of the central pairs of tubules and in the dynein arms of the peripheral tubules, or in the radial spokes, We studied four nonrelated children, 9/12, 5, 6, and 6 years old, with situs inversus and a history of chronic sinusitis and bronchitis (Kartagener's syndrome) and four children in the same age group and with the same history, but without situs inversus. Under the phase contrast microscope no motile cilia were seen in the four patients with Kartagener's syndrome and in two of the four other children. Transmission electron microscopy showed aberrations in the cilia (absence of dyneim arms, random orientation of central tubules) in the patients with Kartagener's syndrome. Scanning electron microscopy revealed differences in morphology and arrangement of cilia between patients and controls. In the patients much more mucus was present on the mucosal surface. Furthermore, the cilia were in a state of disorder, with a multidirectional orientation instead of the parallel orientation seen in controls.

Experimental tracheal allograft revascularization and transplantation.

The feasibility of tracheal allotransplantation with a fascial vascular carrier was examined in three groups with varied dose sequences of immunosuppression. A control group (group 1) received no medication. The three experimental groups were given daily cyclosporine intramuscular doses of 5 mg/kg (group 2), 5 mg/kg plus 3 mg/kg methylprednisolone (Solu-Medrol) (group 3), and 10 mg/kg (group 4) for 6 weeks or until death. Grafts were assessed by silicone dye infusion of the artery of the fascial flap to examine their microcirculation and by quantitative histologic study. Group 1 evidenced complete rejection after a heterotopic revascularization period of 14 days. The allografts of the experimental groups remained viable after 14 days of revascularization and could be transplanted orthotopically after this period. After transplantation, the viability of group 2 tracheas was unpredictable with changes ranging from mild to complete rejection. Group 3 evidenced well-preserved transplant viability with infection-induced necrosis at the anastomoses caused by the corticosteroid component. All group 4 animals survived the follow-up period with normal allograft viability. Cyclosporine in a dosage of 10 mg/kg per day can effectively suppress the immune response after transplantation of vascularized tracheal allografts. This experimental model will allow future studies to examine airway wall immunogenicity.

Comparison of cardiac pacing modes in patients with chronic obstructive pulmonary disease.

STUDY OBJECTIVE: This study compares the relative benefits of dual chamber adaptive rate pacing (DDDR) with ventricular adaptive rate pacing (VVIR) in patients with chronic obstructive pulmonary disease (COPD). STUDY DESIGN: Cardiac hemodynamics were evaluated with serial exercise tests. A minimum of 2 h was allowed between studies. Pulmonary gas exchange was measured and cardiac output (CO) was determined at rest and immediately after maximum exercise by Doppler echocardiography. PATIENTS: Sixteen patients with DDDR pacemakers were studied. Eight patients had COPD and eight patients had normal lung function (NLF). Baseline lung function was documented with spirometry. INTERVENTIONS: The patients with NLF functioned as a control group. Prior to entry into the study, the rate-modulated parameters of the pacemaker were programmed to a clinically determined optimal set of parameters for each individual patient. These were not changed for the duration of the study. RESULTS: Both groups showed a statistically significant improvement in exercise duration, CO at maximum exercise, and cardiac output difference (CODiff) with the dual chamber adaptive rate pacing mode (DDDR). (COdiff is the change in CO from rest to maximum exercise.) Patients with NLF also showed a significant improvement in anaerobic threshold (AT) and VCO2 max with DDDR. Patients with lung disease showed a statistically significant improvement at all levels of exercise in the ventilatory equivalent for oxygen. CONCLUSION: In this study, those patients with chronic lung disease who required cardiac pacing performed significantly better in the DDDR mode as compared with the VVIR mode. Therefore, the DDDR pacing mode should provide an improved quality of life for the patient with COPD who also requires cardiac pacing.

Temporal bone resections for carcinoma of the middle ear and the external ear canal.

Petrosectomy has been used in the management of carcinoma of the external ear canal and the middle ear for the last 45 years. In recent years, there have been conflicting reports; some authors advocate a conservative approach, whereas others support an ultraradical approach. Most retrospective studies report patients who have been treated with radiotherapy or surgery as having undergone the primary modality depending on where the patient first presented. No selection criteria seem to have been employed. Although radiotherapy was used postoperatively, the problems of wound healing were not addressed. This study presents our experience with temporal bone resection as described by Lewis and shows that, in combination with patient selection and proper choice of incision, reconstruction and timely postoperative radiotherapy can achieve better results, and the patient's quality of life can be preserved.

Experimental revascularization of airway segments.

A series of experiments was conducted to assess the possibility of revascularizing tracheal autografts with the rabbit lateral thoracic fascial flap. Injection studies and histological evaluation displayed optimal revascularization and reepithelialization of the graft after 2 weeks.

Surgical management of brain tissue herniation into the middle ear and mastoid.

In the well pneumatized temporal bone, the temporal lobe of the brain is separated from the middle ear and mastoid process by a thin layer of bone known as the tegmen. Congenital defects, infection, and trauma can alter this structure in such a way that cerebral tissue herniates into the ear. This unusual condition may precipitate numerous otologic problems such as hearing loss, trapped squamous epithelium, and the potential for meningitis or encephalitis. The purpose of this paper is to define the problem as well as discuss the diagnosis and surgical management. The authors feel this should be a team effort, in many cases employing the assistance of a neurosurgeon, as the repair must often be intradural. Case histories and an extensive review of the literature are to be included.

Mucociliary clearance following segmental tracheal reversal.

Ciliated tracheal epithelium is arranged in a polarized pattern oriented according to the inferior-superior axis of the trachea and is responsible for the transport of mucus toward the larynx. In this study, ciliary beat orientation and the influence of external factors on mucociliary clearance direction were studied in rabbit inverted cervical tracheas. The animals displayed normal respiration postoperatively. After 16 weeks, airway clearance was studied by observation of the movement of silicone particles placed in the inverted segment and in normal parts of the ciliated epithelium. Cilia exhibited unidirectional and coordinated movement within inverted tracheal segments. As shown by the direction of effective flow produced by beating cilia and by scanning electron microscopy, the cilia in the inverted segment beat in the opposite direction from the cilia in the remainder of the trachea. This study demonstrated that ciliary orientation is irreversibly determined, but the reversal of ciliary beating within the cervical trachea had no adverse effects on the survival of the animals.

Tracheal autograft revascularization and transplantation.

OBJECTIVE: No vascular pedicle can be obtained reasonably to provide revascularization of a tracheal graft by direct microvascular suture. This study is a morphometric analysis of epithelial regeneration, submucosal revascularization, and mucosal thickness of isolated, tracheal segments revascularized by a lateral thoracic fascial flap. The purpose of the first part of the study is to determine the optimal period of tracheal viability after isolation and revascularization. The second part consisted of a reimplantation of the revascularized autograft into its original tracheal location. DESIGN: A tracheal segment was excised in 30 animals, and the segment was wrapped in the lateral thoracic fascia. The segments were reviewed histologically and morphometrically 2 to 28 days after graft isolation and after injection of the lateral thoracic artery with a blue silicone dye. Twelve grafts were reimplanted. Six segments were reinserted in the original direction and six segments were reinserted in the opposite direction. Tracheal airway clearance was studied by observation of the movement of carbon particles placed at different locations on the native and transplanted tracheal mucosa. MEAN OUTCOME MEASURES: Tracheal autograft revascularization and reepithelialization. RESULTS: Histologic evaluation of the revascularized grafts revealed an optimal viability of the autograft 16 to 20 days after isolation. The autografts could be reimplanted successfully after this period. This demonstrated the viability of the isolated grafts after a revascularization period of 16 days. The original direction of the mucosal clearance was preserved after reimplantation. The clearance in the opposite direction, with the 180 degrees rotated segments, however, had no influence on survival.

Mollaret's meningitis responding to phenylbutazonum. A case report.

A patient with Mollaret's meningitis is presented, with some unusual features. Criteria for the diagnosis are discussed. Many therapies for this recurrent aseptic meningitis have been suggested. In our patient there was a good response to phenylbutazonum, which to our knowledge has not been reported before.

Chronic middle ear disease and gastroesophageal reflux disease: a causal relation?

OBJECTIVE: To describe one patient with a puzzling therapy-resistant unilateral chronic otitis media, analyze his diagnosis, and describe three similar patients with the same symptoms and signs, i.e., a chronic ear problem together with gastroesophageal reflux disease (GERD). STUDY DESIGN: Thorough analysis of one patient with a chronic ear problem and GERD, both of which responded favorably after antireflux therapy consisting of omeprazole and conservative antireflux measures (raising the head of the bed by 20 to 25 cm, avoiding meals and drinks 3 hours before retiring, and other dietary and lifestyle modifications), and a search for more patients with similar coexisting conditions. SETTING: Tertiary referral center. METHODS: Patients with chronic ear problems and GERD were thoroughly analyzed by the otorhinolaryngologist and the gastroenterologist. The latter used endoscopy and Savary-Miller's classification of esophagitis, a 24-hour ambulatory dual esophageal pH monitoring, and esophageal manometry. RESULTS: Four patients were identified who had a chronic ear problem and simultaneous GERD. It is reasoned that the GERD leads to nasopharyngitis and this to a chronic ear problem. All the patients responded favorably to anti-GERD therapy. CONCLUSIONS: GERD may manifest itself as an extraesophageal manifestation, such as nasopharyngitis, leading to ear disease. Therapy-resistant chronic middle ear disease may be caused by GERD.

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.

Vascularized fascia as a transferable bed for experimental laryngeal reconstruction.

Laryngeal defects were reconstructed with a combined vascular flap consisting of lateral thoracic fascia used as a transferable vascular bed. A buccal mucosal graft was fixed on this bed as an internal lining. An autogenous cartilage graft, circumferentially wrapped in vascular connective tissue, was used as external support. The first focus of interest of this experimental study was to investigate the necessity of epithelial lining in the repair of a full-thickness laryngeal wall defect. The second focus of interest was to study reconstruction of the posterior glottis by introducing additional supporting material.

Experimental tracheal tube created with vascularized fascia.

An experimental fascial transferable bed was developed in the rabbit model. This tissue is reliable in bringing a viable mucosal graft inside the larynx. A vascular connective tissue sheet with full-thickness mucosa and autogenous cartilage for external support are needed. In this study a tracheal tube was preformed to study the use of autogenous cartilage as support for a circumferential lumen.

Primary ciliary dyskinesia: quantitative investigation of the ciliary ultrastructure with statistical analysis.

In this study the ultrastructure of cilia in patients with primary ciliary dyskinesia was compared to that in patients with other respiratory infections and with that in healthy individuals. After statistical analysis of the findings, the prevalence and the specificity of morphological changes in primary ciliary dyskinesia were established. Guidelines were developed by which the existence of primary ciliary dyskinesia can be ascertained in biopsies of nasal mucosa via transmission electron microscopy.

Experimental transferable vascular bed for laryngotracheal reconstruction: further observations.

Free fascia flaps have proven most reliable in providing a vascular bed for an epithelial free graft without adding bulk. They may be a useful tool for laryngotracheal reconstruction. A free flap consisting of a vascular network running in connective tissue can be developed on the rabbit external ear. The vascular characteristics of this flap were examined to test the reliability of the transferable vascular bed in laryngotracheal repair. The perichondrial free flap is useful for bringing an internal lining inside the lumen and for circumferential protection of supporting tissue. However, the natural tendency for surface contraction of perichondrium is a major disadvantage.

Use of a composite fascial carrier for laryngotracheal reconstruction.

A vascularized fascia flap may be used as a vascular carrier for free mucosal and cartilage grafts. This composite reconstruction technique has been performed in clinical situations with complex laryngeal or tracheal defects. This paper describes the technique and the rationale for applying this concept to some particular laryngotracheal defects. Morphologic and histologic aspects of this composite reconstruction technique using a transferable recipient bed are discussed.