Sven Lindberg

The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans

Primary ciliary dyskinesia (PCD) is characterized by dysfunction of respiratory cilia and sperm flagella and random determination of visceral asymmetry. Here, we identify the DRC1 subunit of the nexin-dynein regulatory complex (N-DRC), an axonemal structure critical for the regulation of dynein motors, and show that mutations in the gene encoding DRC1, CCDC164, are involved in PCD pathogenesis. Loss-of-function mutations disrupting DRC1 result in severe defects in assembly of the N-DRC structure and defective ciliary movement in Chlamydomonas reinhardtii and humans. Our results highlight a role for N-DRC integrity in regulating ciliary beating and provide the first direct evidence that mutations in DRC genes cause human disease.

Outcome of treatment with valacyclovir and prednisone in patients with Bell's palsy.

Idiopathic facial paralysis, or Bells palsy, shows a nonepidemic pattern that might indicate reactivation of a latent microorganism such as herpes simplex type I as a causative agent. Thirty percent of patients with Bells palsy given no treatment will not recover completely, and 5% will have severe sequelae. The aim of this study was to find out whether treatment with an antiviral drug in combination with corticosteroids is more effective than no medical treatment at all in patients with Bells palsy. Fifty-six consecutive adult patients attending the otorhinolaryngology department of the University Hospital of Lund from 1997 to 1999 were treated with 1 g of valacyclovir hydrochloride 3 times per day for 7 days and 50 mg of prednisone daily for 5 days, with the dose being reduced by 10 mg daily for the next 5 days. Fifty-six adult patients with Bells palsy attending the same department between 1995 and 1996 who were given no medical treatment were studied retrospectively and used as the control group. Forty-nine patients (87.5%) in the treatment group recovered completely, as compared with 38 patients (68%) in the control group (p <.05). One patient (1.8%) in the treatment group displayed severe sequelae, defined as a House-Brackmann score of IV or worse, as compared with 10 of 56 patients (18%) in the control group (p <.01). Among patients over 60 years old, 10 of 10 in the treatment group had complete recovery, as compared with 5 of 12 patients in the control group (p <.01). The present study showed a significantly better outcome in patients with Bells palsy treated with valacyclovir and prednisone as compared with patients given no medical treatment. This difference in outcome was especially pronounced among elderly patients.

The Paranasal Sinuses as Reservoirs for Nitric Oxide

OBJECTIVEnNitric oxide (NO) is an important mediator and inflammatory marker in human upper airways. Enzymes responsible for NO production have been demonstrated both in the nose and in the paranasal sinuses, but NO levels in the sinuses are reported to be several times higher than those in the nose. It has been postulated that the paranasal sinuses may be the primary sites for NO production in the upper respiratory tract. The present study was designed to compare the NO levels sampled from the nose with those found in the paranasal sinuses.nnnMATERIAL AND METHODSnNO levels in the maxillary sinus and nose were determined using a continuous chemiluminescence measuring technique in seven healthy volunteers.nnnRESULTSnWhen NO was sampled, via a drainage tube inserted into the maxillary sinus, a transient peak in NO level was recorded. The maximal NO level (5,761 +/- 1,513 ppb; n = 7) was reached within 10 s and was followed by the establishment of a lower steady-state level (304 +/- 51 ppb). When NO was continuously sampled from the nose a steady-state level, similar to that found in the sinus, was immediately established (313 +/- 52 ppb).nnnCONCLUSIONnThe data presented confirm previous findings of extremely high NO levels in the paranasal sinuses and suggest that these cavities may also function as reservoirs for NO.

Vestibular PREHAB and gentamicin before schwannoma surgery may improve long-term postural function

Background: Unilateral vestibular deafferentation (uVD), as performed in vestibular schwannoma surgery, results in a chronic vestibular deficit, though most of the insufficiency can be compensated by other sensory input. By vestibular training (prehabituation) performed before surgery, motor adaptation processes can be instigated before the actual lesion. The adaptation processes of the altered sensory input could be affected if the vestibular ablation and surgery were separated in time, by pretreating patients who have remaining vestibular function with gentamicin. Objective: To determine whether presurgical deafferentation would affect postsurgery postural control also in a long-term perspective (6 months). Method: 41 patients subjected to trans-labyrinthine schwannoma surgery were divided into four groups depending on the vestibular activity before surgery (with no clinical significant remaining function nu200a=u200a17; with remaining function nu200a=u200a8), whether signs of central lesions were present (nu200a=u200a10), and if patients with remaining vestibular activity were treated with gentamicin with the aim to produce uVD before surgery (nu200a=u200a6). The vibratory posturography recordings before surgery and at the follow-up 6 months after surgery were compared. Results: The subjects pretreated with gentamicin had significantly less postural sway at the follow-up, both compared with the preoperative recordings and compared with the other groups. Conclusion: The results indicate that by both careful sensory training and separating the surgical trauma and the effects of uVD in time, adaptive processes can develop more efficiently to resolve sensory conflicts, resulting in a reduction of symptoms not only directly after surgery but also perhaps up to 6 months afterwards.

Preoperative vestibular ablation with gentamicin and vestibular 'prehab' enhance postoperative recovery after surgery for pontine angle tumours - first report

Conclusions. Preoperative gentamicin in combination with vestibular ‘prehab’ offers a possibility to reduce postoperative malaise and speed up recovery and may be used for patients undergoing such surgery when there is remaining vestibular function. Objectives. Removal of pontine angle tumours in a patient with remaining vestibular function causes symptoms of acute vestibular loss. A simultaneous cerebellar lesion can cause a combined vestibule-cerebellar lesion. Patients and methods. Twelve patients with pontine angle tumours but with near normal vestibular function were treated with intratympanic gentamicin in combination with vestibular ‘prehab’ to achieve preoperative vestibular ablation and compensation. After work-up patients started with a home-based vestibular training programme for 14 days. They then received a total of 1.2 ml of 30 mg/ml buffered gentamicin in four intratympanic installations over 2 days. They continued training and returned 6–16 weeks later. All patients were tested with calorics, vestibular video-impulse testing of all six canals, VEMP, subjective visual vertical and horizontal, posturography and pure tone and speech audiometry. Results. There was a loss of caloric reactions and loss of impulses. In two patients the hearing deteriorated and in one hearing improved. All subjects were vestibulary compensated before surgery and no patient complained of dizziness or vertigo after surgery.

Method for Studying Gas Composition in the Human Mastoid Cavity by Use of Laser Spectroscopy

Objectives: We evaluated a method for gas monitoring in the mastoid cavity using tunable diode laser spectroscopy by comparing it to simultaneously obtained computed tomographic (CT) scans. Methods: The presented optical technique measures free gases, oxygen (O2), and water vapor (H2O) within human tissue by use of low-power diode lasers. Laser light was sent into the tip of the mastoid process, and the emerging light at the level of the antrum was captured with a detector placed on the skin. The absorption of H2O was used to monitor the probed gas volume of the mastoid cavity, and it was compared to the CT scan–measured volume. The ratio between O2 absorption and H2O absorption estimated the O2 content in the mastoid cavity and thus the ventilation. The parameters were compared to the grading of mastoid cavities based on the CT scans (n = 31). The reproducibility of the technique was investigated by measuring each mastoid cavity 4 times. Results: Both O2 and H2O were detected with good reproducibility. The H2O absorption and the CT volume correlated (r = 0.69). The average ratio between the normalized O2 absorption and the H2O absorption signals was 0.7, indicating a lower O2 content than in surrounding air (expected ratio, 1.0), which is consistent with previous findings made by invasive techniques. All mastoid cavities with radiologic signs of disease were detected. Conclusions: Laser spectroscopy monitoring appears to be a usable tool for noninvasive investigations of gas composition in the mastoid cavity, providing important clinical information regarding size and ventilation.

Expression of insulin signalling components in the sensory epithelium of the human saccule.

Several studies have demonstrated a link between diabetes and the dysfunction of the inner ear. Few studies, however, have reported the signalling mechanisms involved in metabolic control in human inner ear cells. Knowledge of the expression and role of the insulin receptor and downstream signalling components in the inner ear is sparce. Our immunohistochemistry approach has shown that the insulin receptor, insulin receptor substrate 1 (IRS1), protein kinase B (PKB) and insulin-sensitive glucose transporter (GLUT4) are expressed in the sensory epithelium of the human saccule, which also exhibits expression of a calcium-sensitive cAMP/cGMP phosphodiesterase 1C (PDE1C) and the vasopressin type 2 receptor. IRS1 and PDE1C are selectively expressed in sensory epithelial hair cells, whereas the other components are expressed in sensory epithelial supporting cells or in both cell types, as judged from co-expression or non-co-expression with glial fibrillary acidic protein, a marker for supporting cells. Furthermore, IRS1 appears to be localized in association with sensory nerves, whereas GLUT4 is expressed in the peri-nuclear area of stromal cells, as is the case for aquaporin 2. Thus, the insulin receptor, insulin signalling components and selected cAMP signalling components are expressed in the human saccule. In addition to well-known mechanisms of diabetes complications, such as neuropathy and vascular lesions, the expression of these proteins in the saccule could have a role in the observed link between diabetes and balance/hearing disorders.

Identification of New Signaling Components in the Sensory Epithelium of Human Saccule

Objective: To locate components and target proteins of relevance for the cAMP and cGMP signaling networks including cAMP and cGMP phosphodiesterases (PDEs), salt-inducible kinases (SIKs), subunits of Na+, K+-ATPases, and aquaporins (AQPs) in the human saccule. Methods: The human saccule was dissected out during the removal of vestibular schwannoma via the translabyrinthine approach and immediately fixed. Immunohistochemistry was performed using PDE, SIK, Na+, K+-ATPase, and AQP antibodies. Results: PDEs selective for cAMP (PDE4A, PDE4D, and PDE8A) and cGMP (PDE9A) as well a dual specificity PDE (PDE10A) were detected in the sensory epithelium of the saccule. Furthermore, AQP2, 4, and 9, SIK1 and the α-1 subunit of the Na+, K+-ATPase were detected. Conclusion: cAMP and cGMP are important regulators of ion and water homeostasis in the inner ear. The identification of PDEs and SIK1 in the vestibular system offers new treatment targets for endolymphatic hydrops. Exactly how the PDEs are connected to SIK1 and the SIK1 substrate Na+, K+-ATPase and to AQPs 2, 4, 9 remains to be elucidated. The dissection of the signaling networks utilizing these components and evaluating their roles will add new basic knowledge regarding inner ear physiology.

Recordings of Mucociliary Activity in Vivo: Benefit of Fast Fourier Transformation of the Photoelectric Signal

Investigations of mucociliary activity in vivo are based on photoelectric recordings of light reflections from the mucosa. The alterations in light intensity produced by the beating cilia are picked up by a photodetector and converted to photoelectric signals. The optimal processing of these signals is not known, but in vitro recordings have been reported to benefit from fast Fourier transformation (FFT) of the signal. The aim of the investigation was to study the effect of FFT for frequency analysis of photoelectric signals originating from an artificial light source simulating mucociliary activity or from sinus or nasal mucosa in vivo, as compared to a conventional method of calculating mucociliary wave frequency, in which each peak in the signal is interpreted as a beat (old method). In the experiments with the artificial light source, the FFT system was superior to the conventional method by a factor of 50 in detecting weak signals. By using FFT signal processing, frequency could be correctly calculated in experiments with a compound signal. In experiments in the rabbit maxillary sinus, the spontaneous variations were greater when signals were processed by FFT. The correlation between the two methods was excellent: r = .92. The increase in mucociliary activity in response to the ciliary stimulant methacholine at a dosage of 0.5 μg/kg was greater measured with the FFT than with the old method (55.3% ± 8.3% versus 43.0% ± 8.2%, p < .05, N = 8), and only with the FFT system could a significant effect of a threshold dose (0.05 μg/kg) of methacholine be detected. In the human nose, recordings from aluminum foil placed on the nasal dorsum and from the nasal septa mucosa displayed some similarities in the lower frequency spectrum (<5 Hz) attributable to artifacts. The predominant cause of these artifacts was the pulse beat, whereas in the frequency spectrum above 5 Hz, results differed for the two sources of reflected light, the mean frequency in seven healthy volunteers being 7.8 ± 1.6 Hz for the human nasal mucosa. It is concluded that the FFT system has greater sensitivity in detecting photoelectric signals derived from the mucociliary system, and that it is also a useful tool for analyzing the contributions of artifacts to the signal.

Cyclic Adenosine Monophosphate Stimulation of Mucociliary Activity in the Upper Airways in Vivo

Xanthine derivatives are known to accelerate mucociliary transport in the lower airways, probably by preventing degradation of cyclic adenosine monophosphate (cAMP) and thereby increasing its intracellular concentration. The purpose of this study was to investigate the effects of cAMP on mucociliary activity in the upper airways. The effect on the mucociliary activity in the rabbit maxillary sinus of the xanthine derivatives theophylline and enprophylline was compared to that of the cAMP analog dibutyryl cAMP. The compounds were administered into the maxillary artery, and the response was recorded with a photoelectric technique. Infusions of theophylline (1.0 and 10 mg/kg) increased mucociliary activity (22.8% ± 5.9%, n = 6, and 21.6% ± 4.9%, n = 7, p < .05, respectively). Infusions of enprophylline (1.0 and 10.0 mg/kg) accelerated mucociliary activity (at the highest dosage tested, 24.3% ± 4.1%). Infusions of dibutyryl cAMP (0.1 and 1.0 mg/kg) stimulated mucociliary activity, with the maximum increase (20.1% ± 3.0%, n = 13, p < .05) being observed at a dosage of 0.1 mg/kg. The infused substances increased mucociliary activity within 1 minute after the start of the infusion, the duration of the response being approximately 20 minutes for theophylline, 22 minutes for enprophylline, and 12 minutes for dibutyryl cAMP. The present results support the view that cAMP is involved in regulating mucociliary activity in the upper airways. It remains to be elucidated whether xanthines such as theophylline and enprophylline are beneficial in upper airway disease in which mucociliary function is impaired (eg, chronic sinusitis).