Exacerbations and Pseudomonas aeruginosa colonization are associated with altered lung structure and function in primary ciliary dyskinesia.

BACKGROUND: Recurrent bacterial infections of the respiratory tract are one of the major clinical features of the primary ciliary dyskinesia (PCD), a rare genetic disease due to malfunctioning of motile cilia. Chronic infections and persistent inflammation of the respiratory system result in progressive lung disease. Aim of the study was to highlight the main factors associated with clinical, functional and anatomical deterioration in PCD patients. METHODS: We retrospectively analyzed data from 58 patients with PCD, 37 adults and 21 children. The demographic and clinical data, forced expiratory volume at 1 s (FEV1) and forced vital capacity (FVC), sputum microbiology and imaging results (chest CT scores-modified Bhalla) were recorded. Patients were stratified according to the number of exacerbations (< 2/year vs ≥ 2/year) and chronic Pseudomonas aeruginosa (PA) colonization. The possible correlations between lung function and chest CT scores were assessed; we also evaluated the correlation between these parameters and the severity scores for bronchiectasis (BSI, FACED and e-FACED). RESULTS: Chest CT scores showed a significant correlation with FEV1 (p = 0.0002), age (p <  0.0001), BMI (p = 0.0002) and number of lung lobes involved (p <  0.0001). PA colonization had an overall prevalence of 32.6%: no significant difference in FEV1 between PA colonized and non-colonized patients was found (p = 0.70), while chest CT score was significantly worse in chronic PA colonized patients (p = 0.009). Patients with a high number of exacerbation (≥ 2/year) were older (p = 0.01), had lower FEV1 (p = 0.03), greater number of lobes involved (p < 0.001) and worse CT score than patients with low number of exacerbations (p = 0.001); they also had higher prevalence of PA chronic bronchial infection (33.3% versus 13.6%, p = 0.10). Multivariable linear regression analyses adjusted for gender, age and BMI showed positive associations between PA colonization and number of exacerbations with severity of disease (number of lobes involved, CT score, BSI, FACED, and e-FACED). CONCLUSIONS: In our PCD population the number of exacerbations (≥ 2/year) and PA colonization were the two most relevant factors associated with severity of disease.

Emerging ciliopathies: are respiratory cilia compromised in Usher syndrome?

PURPOSE: Usher syndrome is a ciliopathy involving photoreceptors and cochlear hair cells (sensory cilia): since sensory and motor ciliopathies can overlap, we analysed the respiratory cilia (motile) in 17 patients affected by Usher syndrome and 18 healthy control subject. PATIENTS AND METHODS: We studied the mucociliary transport time with the saccharine test, ciliary motility and ultrastructure of respiratory cilia obtained by nasal brushing; we also recorded the classical respiratory function values by spirometry. RESULTS: All enrolled subjects showed normal respiratory function values. The mean mucociliary transport time with saccharine was 22.33 ± 17.96 min, which is in the range of normal values. The mean ciliary beat frequency of all subjects was 8.81 ± 2.18 Hz, which is a value approaching the lower physiological limit. None of the classical ciliary alterations characterizing the "ciliary primary dyskinesia" was detected, although two patients showed alterations in number and arrangement of peripheral microtubules and one patient had abnormal ciliary roots. CONCLUSIONS: Respiratory cilia in Usher patients don't seem to have evident ultrastructural alterations, as expected, but the fact that the ciliary motility appeared slightly reduced could emphasize that a rigid distinction between sensory and motor ciliopathies may not reflect what really occurs.

Tinnitus sound therapy with open ear canal hearing aids.

OBJECTIVE: The aims of this study were to evaluate the efficacy of open ear canal hearing aids in tinnitus treatment and to investigate the influence of gender, age, medication usage, tinnitus cause, tinnitus perception side, tinnitus pitch, pure tone audiometry, distortion product otoacoustic emissions, and minimal masking level on outcome. METHODOLOGY: One hundred tinnitus patients were evaluated by the tinnitus handicap inventory (THI) at the beginning of the study and after nine months of treatment. All subjects were submitted to counselling and sound enrichment from the simple sound amplification provided by the open ear canal hearing aids. RESULTS: Initial mean THI score was 54.22 (+/- 20.37) and final mean score was 28.32 (+/- 16.50), p < 0.0001. No statistically significant correlations were found between THI value reduction and the studied parameters. CONCLUSION: Open ear canal hearing aids were useful in all tinnitus patients with mild hearing loss.

Are results of tinnitus retraining therapy maintained over time? 18-month follow-up after completion of therapy.

Tinnitus retraining therapy (TRT) is a useful treatment for tinnitus. The aim of this study was to evaluate the results obtained after 18 months of TRT as well as 18 months after completion of therapy, i.e. 36 months after initiation of TRT. Forty-five subjects suffering from an idiopathic tinnitus with or without hyperacusis for at least 6 months were recruited. There were significant improvements during therapy (p < 0.001) and the mean Tinnitus Handicap Inventory (THI) was lowered by more than 20 points. These improvements persisted 18 months after treatment completion. Furthermore, the percentage of patients reporting the disappearance of their difficulties in various activities (relaxation, concentration, sleep, social relations and work) increased continuously after treatment completion. TRT improved self-perceived disability induced by chronic tinnitus for a long time after the end of therapy.

Hearing aids for the treatment of tinnitus.

Clinical evidence shows that the use of hearing aids in tinnitus patients provides two benefits: it makes the patient less aware of the tinnitus and it improves communication by reducing the annoying sensation that sounds and voices are masked by the tinnitus. Hearing loss reduces stimulation from external sounds resulting in increased awareness of tinnitus and deprivation of input may change the function of structures of the auditory pathways. Tinnitus is often caused by expression of neural plasticity evoked by deprivation of auditory input. With hearing aid amplification, external sounds can provide sufficient activation of the auditory nervous system to reduce the tinnitus perception and it may elicit expression of neural plasticity that can reprogram the auditory nervous system and thereby have a long-term beneficial effect on tinnitus by restoring neural function. To obtain the best results, hearing aids should be fitted to both ears, use an open ear aid with the widest amplification band, and disabled noise reducing controls. In some cases a combination device would be preferable. The conditions required in order to obtain good results include not only the use of devices, but above all, their adaptation to the needs of the single patient, by counseling and customization. Wearing the hearing aid must become second nature to the patient even though it is only one element of the therapy.

[Sensorineural hearing loss in childhood: evaluation of economic impact in view of vaccine prevention of cases due to congenital cytomegalovirus infection]. / Sordità neurosensoriale infantile: valutazione dell'impatto economico nella prospettiva della prevenzione vaccinale dei casi da infezione congenita da Cytomegalovirus.

Sensorineural hearing loss (SNHL) is a serious public health problem which affects 1-3% per hundred live born babies in developed countries. The congenital cytomegalovirus (CMV) infection is its most important non-genetic cause. The evaluation of the effectiveness of future programs of anti-CMV vaccination requires an assessment of the present costs of SNHL. Direct costs for the Italian public system were calculated per prosthesis child until his full age and turned out to add up to 260,000 euro. Private costs are difficult to be assessed and anyhow are highly dependent from the socio-economic level. This preliminary assessment suggests that the vaccination would be cost-saving if SNHL cases due to congenital CMV were more than 21 per year, corresponding to a congenital infection prevalence higher than 0.21%o.

Usher syndrome: an effective sequencing approach to establish a genetic and clinical diagnosis.

Usher syndrome is an autosomal recessive disorder characterized by retinitis pigmentosa, sensorineural hearing loss and, in some cases, vestibular dysfunction. The disorder is clinically and genetically heterogeneous and, to date, mutations in 11 genes have been described. This finding makes difficult to get a precise molecular diagnosis and offer patients accurate genetic counselling. To overcome this problem and to increase our knowledge of the molecular basis of Usher syndrome, we designed a targeted resequencing custom panel. In a first validation step a series of 16 Italian patients with known molecular diagnosis were analysed and 31 out of 32 alleles were detected (97% of accuracy). After this step, 31 patients without a molecular diagnosis were enrolled in the study. Three out of them with an uncertain Usher diagnosis were excluded. One causative allele was detected in 24 out 28 patients (86%) while the presence of both causative alleles characterized 19 patients out 28 (68%). Sixteen novel and 27 known alleles were found in the following genes: USH2A (50%), MYO7A (7%), CDH23 (11%), PCDH15 (7%) and USH1G (2%). Overall, on the 44 patients the protocol was able to characterize 74 alleles out of 88 (84%). These results suggest that our panel is an effective approach for the genetic diagnosis of Usher syndrome leading to: 1) an accurate molecular diagnosis, 2) better genetic counselling, 3) more precise molecular epidemiology data fundamental for future interventional plans.

Some observations concerning 200 stapedectomies: fifteen years postoperatively.

In this study, a statistical evaluation of the hearing improvement, the incidence of postoperative tinnitus and vertigo, and the permanency of the surgically restored hearing of 120 women and 80 men operated on for otosclerosis between 1970 and 1971 was undertaken. The standardized operating procedure in all of these cases involved the use of a Gelfoam and wire prosthesis (Schuknecht 3). All patients underwent normal audiological examinations, including determination of bone and air conduction values. Pure tone thresholds were determined by averaging the values for 500, 1,000, 2,000 and 4,000 Hz. The incidence (10%) of severe sensorineural loss in regard to age, preoperative bone conduction, and oval window pathology was examined. Severe sensorineural losses had occurred immediately postoperatively in 14 of the ears. In the remaining ears, losses were gradual in the course of 15 years. Hearing thresholds in ears not subjected to operation were also determined.

Nasal ciliary function and ultrastructure in Down syndrome.

OBJECTIVES/HYPOTHESIS: To investigate the in vivo nasal ciliary beat and the ciliary ultrastructure in Down syndrome because, although in this condition an increased susceptibility to respiratory tract infections has been reported by several authors, the nature of this phenomenon is not fully understood. STUDY DESIGN: Experimental study of 18 subjects with Down syndrome and 18 healthy control subjects. METHODS: Ciliary beat frequency (CBF) was measured on samples of ciliated epithelium obtained from the inferior nasal turbinate; a further brushing for ultrastructural analysis was performed only in subjects showing a CBF reduction or a ciliary movement alteration. RESULTS: The mean CBF in the group with Down syndrome was 7 +/- 2.82 Hz, and in the control subjects it was 10.94 +/- 0.65 Hz. In the same 66.6% of subjects with Down syndrome, we observed a fibrillatory movement of cilia and no metachronicity was present. Moreover, in 14 subjects with Down syndrome as hyperproduction of mucus was present. Ultrastructural evaluation at transmission election microscopy instead revealed a normal architecture of cilia. CONCLUSION: We attribute the nature of the mucociliary defect in Down syndrome to recurrent respiratory tract infections causing changes in mucus properties as in rheological parameters and not to a primitive defect of cilia.

Nasal ciliary beat after insertion of septo-valvular splints.

OBJECTIVE: At present, endonasal paraseptal splints are devices frequently employed in rhinosurgery. We evaluated the local tolerance of a newly shaped device, the Guastella/Mantovani splint (G/M-SVS), with respect to the physiological mechanism of mucociliary clearance. STUDY DESIGN AND SETTING: The study involved 20 patients who underwent septoplasty and/or turbinoplasty or other nasal surgical procedures. A sample of ciliated cells was obtained by nasal brushing and was examined ex vivo to determine the ciliary beat frequency (CBF) and morphology, before and 15 days after surgery. RESULTS: Before surgery the mean CBF was 10.87 Hz +/- 0.56 Hz and when splints were removed it was 10.25 Hz +/- 1.9 Hz. Morphological evaluation of the ciliary motion after surgery demonstrated a normal, coordinated beat. CONCLUSIONS: The G/M-SVS does not appear to interfere with the physiological mechanism of mucociliary clearance since CBF remain within a normal range. SIGNIFICANCE: This is the first study that demonstrates an optimal tolerability and safety of the septo-valvular splints on nasal mucosa.

Effects of salmeterol on cilia and mucus in COPD and pneumonia patients.

The present study was performed to evaluate the effects of salmeterol xynaphoate on ciliary beat frequency (CBF) of nasal epithelium and on rheological parameters of tracheobronchial mucus. We studied 10 steady-state COPD patients, eight patients with community-acquired pneumonia and eight healthy subjects as controls. They underwent a nasal brushing of the inferior turbinate to study the CBF in basal conditions and following application of salmeterol at 10(-5), 10(-6), 10(-7) and 10(-8) M concentrations directly to the epithelial samples. We also collected sputum samples, in COPD patients only, by the technique for "protected expectoration" for the rheological assessment in basal conditions and following addition of salmeterol at 10(-5), 10(-6), 10(-7) and 10(-8) M concentrations. Only samples with basal viscosity values higher than 2000 mPa/s were admitted. Our results confirmed previous studies that demonstrate a ciliostimulating effect induced by salmeterol. The mean basal CBF was 11.18 +/- 0.75 Hz in control subjects, while the pathological subjects showed a markedly lower basal values: 8.64 +/- 0.88 Hz (p = 0.000) and 8.83 +/- 0.68 Hz (p = 0.000), in COPD and pneumonia patients, respectively. Salmeterol induced ciliostimulation in both patients groups as well as the healthy controls. The maximum increase in CBF, highly significant, was obtained at 10(-6) M concentrations of salmeterol, while this effect decreased at lower concentrations. Regarding the action of salmeterol on rheological parameters, a direct effect of salmeterol on mucus cannot been demonstrated and the described beneficial clinical effects on mucociliary clearance occurring in vivo are probably related to an indirect effect of stimulation of ciliary beat. This preliminary study suggests that, in addition to COPD, salmeterol could be a useful therapeutic agent in pneumonia also, for its positive effect on ciliary movement other than bronchodilation, but this finding needs further investigations.

Sudden hearing loss and MTHFR 677C>T/1298A>C gene polymorphisms.

PURPOSE: Sudden hearing loss (SHL) can be caused by vascular disorders favoring impaired cochlear perfusion. A number of inherited prothrombotic risk factors have been considered in the pathogenesis of vascular impairment and the possible role of genetic alterations has recently been suggested. We aimed to investigate the relationship between SHL and MTHFR 677 and 1298 gene polymorphisms. METHODS: DNA genotyping was performed on peripheral blood leukocytes in 45 SHL patients and 135 controls. RESULTS: Wild-type MTHFR (677CC/1298AA) was significantly more frequent in the controls (P=0.01), and gene polymorphisms (677CT, 677TT, 1298AC, 1298CC, compound 677CT/1298AC) were significantly more frequent in the patients (P=0.005; Ptrend=0.001). CONCLUSION: These data suggest that MTHFR gene polymorphisms may be considered as risk factors for SHL and participate on vascular impairment related to this disorder. Further studies, based on large series of patients, are needed to definitely assess the role of this prothrombotic factor in the etiopathogenesis of SHL.

Audiological evaluation in adult beta-thalassemia major patients under regular chelation treatment.

With the improved life expectation of beta -thalassemia major patients, new clinical problems, such as hearing damage, must be evaluated. Fifty-seven patients (32 F, 25 M; age range 17-32 years) have been studied to define risk factors for development of sensorineural hearing loss. All patients with beta -thalassemia major received daily chelation therapy with subcutaneous injection of desferrioxamine (30-50 mgkg(-1)per day). We performed an otological visit and pure tone audiometry as well as impedance; patients were followed for 3 years. Four patients with a conductive hearing loss were excluded; 66.6% had a normal audiogram; 22.8% had a slight sensorineural deficit (

Effects of zafirlukast on bronchial asthma and allergic rhinitis.

Asthma and allergic rhinitis are common conditions, occurring with increasing prevalence and frequently coexist. In both conditions histamine and cysteinil leukotrienes are important pathogenic inflammatory mediators. We evaluated the effects of the leukotriene receptor antagonist zafirlukast, 20mg administered twice daily for 2 weeks, in patients with allergic rhinitis and bronchial asthma during the grass pollen season. Patients underwent skin prick testing, spirometry, rhinomanometry, mucus transport test with saccharine, nasal epithelial brushing to study ciliary beat and, finally, nasal lavage.Thirty-five subjects completed the study. At the end of the study period, zafirlukast significantly reduced asthma and rhinitis symptoms (P< or =0.05); FEV(1) values were unchanged (P=0.10), whereas nasal resistances showed a decrease following treatment (P=0.01). Ciliary beat frequency (CBF) also improved (P=0.00), although mucociliary transport showed no improvement (P=0.87). The number of eosinophils in nasal lavage fluid decreased (P=0.00) while that of neutrophils was unchanged (P=0.09). These positive effects suggest that zafirlukast may be usefully employed in the treatment of both bronchial asthma, as previously demonstrated, and allergic rhinitis.

A novel dominant missense mutation--D179N--in the GJB2 gene (Connexin 26) associated with non-syndromic hearing loss.

Mutations of the GJB2 gene, encoding Connexin 26, are the most common cause of hereditary congenital hearing loss in many countries, and account for up to 50% of cases of autosomal-recessive non-syndromic deafness. By contrast, only a few GJB2 mutations have been reported to cause an autosomal-dominant form of non-syndromic deafness. We report on a family from southern Italy in whom dominant, non-syndromic, post-lingual hearing loss is associated with a novel missense mutation in the GJB2 gene. Direct sequencing of the gene showed a heterozygous G-->A transition at nucleotide 535, resulting in an aspartic acid to asparagine amino acid substitution at codon 179 (D179N). This mutation occurred in the second extracellular domain (EC2), which would seem to be very important for connexon-connexon interaction.

Beta-thalassemia and pulmonary function.

BACKGROUND AND OBJECTIVE: The survival of patients with beta-thalassemia major and intermedia has improved considerably. This has focused attention on the long-term sequelae of the disease itself and its treatment. The effect of hemosiderosis in major organs (heart, liver, etc) are well-recognized, but the pathophysiology of any lung damage is less clearly understood. We studied lung function changes in 32 patients with beta-thalassemia. DESIGN AND METHODS: Respiratory function tests, CO diffusion and arterial blood gas analysis were performed on 19 patients with beta-thalassemia major (9 F, 10 M) and 13 with beta-thalassemia intermedia (6 M, 7 F). All investigations were performed 24 hours before the patients received a blood transfusion or when they were in a stable state hematologic condition. Echocardiography was performed in all patients and the ejection fraction was employed as a measure of cardiac function. RESULTS: No patient had clinical signs of pulmonary dysfunction. Pulmonary function tests, however, showed a reduction of all main parameters (TLC, FVC, FEV1 and RV) in most patients with beta-thalassemia major, indicating a restrictive type of dysfunction. The pulmonary function of patients with beta-thalassemia intermedia seemed to be preserved. Arterial blood gas values were within the normal range, while in some subjects CO diffusion approached the lower limits of normality. There was no evidence that the observed abnormalities in pulmonary function were secondary to congestive heart failure. INTERPRETATION AND CONCLUSIONS: Iron deposition due to repeated blood transfusions may play a central role in determining lung alterations although the majority of patients are well chelated, suggesting that more than one causal mechanisms could be involved.