Aetiology of cerebrospinal fluid rhinorrhoea in a Dutch retrospective cohort from two tertiary referral centres.

BACKGROUND: Cerebrospinal fluid (CSF) rhinorrhoea has different aetiologies, with spontaneous leaks related to female gender and obesity. Limited data is available on patient characteristics and surgical outcomes across different aetiologies of CSF leaks in relatively non-obese populations. METHODS: Retrospective cohort study from two tertiary referral centres including adult patients that underwent surgical closure of a CSF leak, divided into four aetiologies: traumatic, iatrogenic, secondary to structural intracranial pathology (SIP), and spontaneous. Data included patient characteristics, presenting symptoms, preoperative radiologic findings, intracranial pressure (ICP) and surgical outcomes. RESULTS: 72 patients were included: 9 traumatic, 15 iatrogenic, 4 SIP and 44 spontaneous leaks. Primary surgical success was 79%, rising to 93% with reinterventions. Spontaneous leak cases displayed highest female proportion and BMI. A meningo(-encephalo)cele was present in 33 patients and was associated with surgical failure and previous meningitis. No significant differences were observed between different aetiologies regarding patient characteristics, presenting symptoms, or surgical success rates. CONCLUSIONS: Even in a relatively non-obese population, the majority of CSF leaks is spontaneous and associated with female gender and obesity. Otherwise, no differences exist across aetiologies regarding patient characteristics, presenting symptoms or surgical success.

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

A novel QTL underlying early-onset, low-frequency hearing loss in BXD recombinant inbred strains.

The DBA/2J inbred strain of mice has been used extensively in hearing research as it suffers from early-onset, progressive hearing loss. Initially, it mostly affects high frequencies, but already at 2-3 months hearing loss becomes broad. In search for hearing loss genes other than Cadherin 23 (otocadherin) and fascin-2, which make a large contribution to the high-frequency deficits, we used a large set of the genetic reference population of BXD recombinant inbred strains. For frequencies 4, 8, 16 and 32 kHz, auditory brainstem response hearing thresholds were longitudinally determined from 2-3 up to 12 weeks of age. Apart from a significant, broad quantitative trait locus (QTL) for high-frequency hearing loss on chromosome 11 containing the fascin-2 gene, we found a novel, small QTL for low-frequency hearing loss on chromosome 18, from hereon called ahl9. Real-time quantitative polymerase chain reaction of organs of Corti, isolated from a subset of strains, showed that a limited number of genes at the QTL were expressed in the organ of Corti. Of those genes, several showed significant expression differences based on the parental line contributing to the allele. Our results may aid in the future identification of genes involved in low-frequency, early-onset hearing loss.

In vivo dynamic clamp study of I(h) in the mouse inferior colliculus.

Approximately half of the cells in the mouse inferior colliculus have the hyperpolarization-activated mixed cation current I(h), yet little is known about its functional relevance in vivo. We therefore studied its contribution to the processing of sound information in single cells by making in vivo whole cell recordings from the inferior colliculus (IC) of young-adult anesthetized C57Bl/6 mice. Following pharmacological block of the endogenous channels, a dynamic clamp approach allowed us to study the responses to current injections or auditory stimuli in the presence and absence of I(h) within the same neuron, thus avoiding network or developmental effects. The presence of I(h) changed basic cellular properties, including depolarizing the resting membrane potential and decreasing resting membrane resistance. Sound-evoked excitatory postsynaptic potentials were smaller but at the same time reached a more positive membrane potential when I(h) was present. With I(h), a subset of cells showed rebound spiking following hyperpolarizing current injection. Its presence also changed more complex cellular properties. It decreased temporal summation in response to both hyperpolarizing and depolarizing repetitive current stimuli, and resulted in small changes in the cycle-averaged membrane potential during sinusoidal amplitude modulated (SAM) tones. Furthermore, I(h) minimally decreased the response to a tone following a depolarization, an effect that may make a small contribution to forward masking. Our results thus suggest that previously observed differences in IC cells are a mixture of direct effects of I(h) and indirect effects due to the change in membrane potential or effects due to the co-expression with other channels.