Inflammation and behavior following irradiation-induced injury in the developing brain

Radiotherapy is used in the treatment of pediatric brain tumors and is often associated with debilitating late effects, such as intellectual impairment. Areas in the brain harboring stem cells are particularly sensitive to irradiation (IR) and loss of these cells may contribute to cognitive deficits. It has been demonstrated that IR-induced inflammation negatively affects neural progenitor differentiation. Therefore, it is necessary to investigate the inflammatory mechanism to be able to find potential treatment strategies. One moderate dose of IR to the young rodent brain caused injuries that were detectable after several months, including impaired growth. We have shown that IR to the developing brain induces an acute inflammatory response. An unexpected finding was that microglia died shortly after treatment. The consequences of IR-induced microglia loss can either be that the injury, due to pronounced inflammation, is decreased, or that injury is enhanced due to weakened repair mechanisms. Further investigations are needed to elucidate how the loss of microglia affects the response to IR and brain development. The third complement component (C3) is a key protein of the complement system which we found to be upregulated after IR. C3 has been shown to be important for neurogenesis, and therefore we wanted to investigate the role of complement activation after IR by using C3-deficient mice. Interestingly, the IR-induced injury, measured as tissue loss and decrease of proliferating cells, was not as pronounced in the dentate gyrus of C3-deficient mice as in wild type mice. This indicates that manipulation of the complement system could be a fruitful strategy to protect the neurogenic areas from IR-induced injuries. We have studied functional consequences of IR to the growing brain. We saw that one dose of IR to the young rodent brain caused behavioral changes that were detectable months and even one year after the treatment. Furthermore, non-irradiated animals performed better than irradiated ones in different learning tasks. Importantly, months after IR C3-deficient mice made fewer errors in place learning and reversal learning tests than WT mice. These results indicate that the complement system contributes to both morphological and functional IR-induced injury in the young brain

Eustachian tube function and tympanic membrane findings after chronic secretory otitis media

Objective: The etiology of secretory otitis media (SOM) is multifactorial. The main factors discussed are infection and tuba[ dysfunction. This study aimed to detect poor tuba[ function and tympanic membrane pathology in young adults after extremely long-standing SOM. Methods: Thirty-four patients, 16-25 years old, with previous chronic SOM persisting at least 6 years (mean 11.2 years, range 6.2-18.6 years), were retrospectively examined at a mean of 18 years after their first myringotomy or tube insertion and comparison was made with 15 controls. The medical records were scrutinized, otomicroscopic examination was performed and the Eustachian tube function was studied in a mini pressure chamber. Results: The mean age at SOM onset was 2.4 years (range 0.5-8.4 years) and the mean period from the last myringotomy or when the last tube had disappeared to follow-up was 6.7 years (range 1.3-12.8 years). Tympanic membrane pathology was found in 76% of the ears of SOM patients and in none (0%) of controls (P < 0.001). The youngest patients had more atrophy than the older patients (P < 0.05) and more myringosclerosis was observed in patients with shorter interval between SOM ending and examination. The patients were found to have significantly poorer active tuba[ function; i.e. higher inability to equilibrate negative or negative and positive middle ear pressure, compared with controls (P < 0.001). The majority of the patients (74%) still experienced some kind of discomfort in their ears at the time of examination. Conclusions: Still in adulthood patients with chronic SOM during childhood exhibit dysfunction of the tube and tympanic membrane pathology to a high extent. (C) 2003 Elsevier Ireland Ltd. AIL rights reserved

Course and long-term outcome of 'refractory' secretory otitis media

Objective: The course and the long-term outcome of 'refractory' secretory otitis media (SOM), defined as continuous SOM for more than 6 years, were studied in 52 young patients. They had during childhood been treated for bilateral SOM on average for 12 years (range 6 to 26 years). The mean interval between resolution of SOM and examination was 7 years. Methods: At follow up the patients' medical records were scrutinized with regards to transmyringeal ventilation tubes, adenoidectomy, sequelae and complications, and a questionnaire was filled in to document other diseases. Results: The onset of SOM showed two peaks, one at the age of one year and one at the age of 3.5 years. Patients whose onset of SOM was related to an episode of acute otitis media (AOM) were younger at SOM onset than those who had no such relation. Otorrhoea and AOM episodes were more frequent during the SOM periods, with blocked or expelled tubes, than during periods with patent tubes. Cholesteatoma were seen in 3 per cent and perforations in 5 per cent of patients. Conclusions: Extremely long-standing SOM does not necessarily result in myringeal perforation or cholesteatoma to a greater extent than that seen in patients with shorter durations of SOM. However, at follow up one-third of the patients reported hearing impairment and a majority felt discomfort when flying or diving

Auditory consequences of recurrent acute purulent otitis media

To investigate whether recurrent purulent otitis media results in permanent hearing loss, we studied 2 subgroups of children from a cohort, earlier prospectively followed from birth to the age of 3 years. One subgroup had recurrent acute otitis media (n = 12). and the other had no acute otitis media at all ("healthy" children; n = 21). At follow-up of these subgroups at the age of 10. no child had acute otitis media or secretory otitis media. There was no difference between the groups in hearing level thresholds at the frequencies 125 Hz to 8 kHz. However, in the children with recurrent acute otitis media, as compared with the controls, the hearing levels at high frequencies (8 to 16 kHz) and the acoustic middle ear reflex thresholds were elevated, the middle ear compliance was higher, and click-evoked otoacoustic emission response levels and middle ear pressures were lower. The results suggest that the middle car mechanics of children with recurrent acute otitis media are affected, and also that their cochlear function might be disturbed

Oral bacteria – The missing link to ambiguous findings of exhaled nitrogen oxides in cystic fibrosis

SummaryBackgroundNitrite in exhaled breath condensate (EBC) has been shown to be elevated in cystic fibrosis (CF), while exhaled nitric oxide (FENO) is paradoxically low. This has been argued to reflect increased metabolism of NO while its diffusion is obstructed by mucus. However, we wanted to study the possible influence of salivary nitrite and bacterial nitrate reduction on these parameters in CF patients by the intervention of an anti-bacterial mouthwash.MethodsEBC and saliva were collected from 15 CF patients (10–43 years) and 15 controls (9–44 years) before and 5min after a 30s chlorhexidine mouthwash, in parallel with measurements of FENO. Nitrite and nitrate concentrations were measured fluorometrically.ResultsEBC nitrite, but not nitrate, was significantly higher in the CF patients (median 3.6 vs 1.3μM in controls, p<0.05) and decreased after mouthwash in both groups (3.6–1.4μM, p<0.01; 1.3–0.5μM, p<0.01). Salivary nitrite correlated significantly to EBC nitrite (r=0.60, p<0.001) and decreased correspondingly after chlorhexidine, whereas salivary nitrate increased. FENO was lower in CF and the difference between patients and controls was accentuated after mouthwash (5.4 vs 8.4ppb in controls, p<0.05).ConclusionEBC nitrite mainly originates in the pharyngo-oral tract and its increase in CF is possibly explained by a regional change in bacterial activity. The limited lower airway contribution supports the view of a genuinely impaired formation and metabolism of NO in CF, rather than poor diffusion of the molecule

Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3.

Previous work implicated the complement system in adult neurogenesis as well as elimination of synapses in the developing and injured CNS. In the present study, we used mice lacking the third complement component (C3) to elucidate the role the complement system plays in hippocampus-dependent learning and synaptic function. We found that the constitutive absence of C3 is associated with enhanced place and reversal learning in adult mice. Our findings of lower release probability at CA3-CA1 glutamatergic synapses in combination with unaltered overall efficacy of these synapses in C3 deficient mice implicate C3 as a negative regulator of the number of functional glutamatergic synapses in the hippocampus. The C3 deficient mice showed no signs of spontaneous epileptiform activity in the hippocampus. We conclude that C3 plays a role in the regulation of the number and function of glutamatergic synapses in the hippocampus and exerts negative effects on hippocampus-dependent cognitive performance