F1000Research
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Background: X-linked spinal muscular atrophy (XL-SMA) results from mutations in the Ubiquitin-Like Modifier Activating Enzyme 1 ( UBA1). Previously, four novel closely clustered mutations have been shown to cause this fatal infantile disorder affecting only males. These mutations, three missense and one synonymous, all lie within Exon15 of the UBA1 gene, which contains the active adenylation domain (AAD). ⋯ Additionally, these missense variants retained Ubiquitin thioester bond formation and transthioesterification rates equal to that found in the wild type. Conclusions: Our results demonstrate a surprising shift from the likelihood of these XL-SMA mutations playing a damaging role in Uba1's enzymatic activity with Ubiquitin, to other roles such as altering UBA1 mRNA splicing via the disruption of splicing factor binding sites, similar to a mechanism in traditional SMA, or disrupting binding to other important in vivo binding partners. These findings help to narrow the search for the areas of possible dysfunction in the Ubiquitin-proteasome pathway that ultimately result in XL-SMA. Moreover, this investigation provides additional critical understanding of the mutations' biochemical mechanisms, vital for the development of future effective diagnostic assays and therapeutics.
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The classic view of sensorineural hearing loss has been that the primary damage targets are hair cells and that auditory nerve loss is typically secondary to hair cell degeneration. Recent work has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of the synaptic connections between hair cells and the auditory nerve. ⋯ Although not required for threshold detection when quiet, these high-threshold fibers are critical for hearing in noisy environments. Research suggests that primary neural degeneration is an important contributor to the perceptual handicap in sensorineural hearing loss, and it may be key to the generation of tinnitus and other associated perceptual anomalies. In cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from surviving auditory neurons and re-establishment of their peripheral synapses; thus, treatments may be on the horizon.
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Bronchial foreign body obstruction is common in all clinical settings. Obstruction of the airway due to foreign bodies and foreign body aspiration are major causes of childhood mortality and morbidity, which are a big challenge to manage. Occasionally, bronchial obstruction may be due to mucus plugs or other endogenous factors. ⋯ Chest CT scan was performed that suggested the presence of a right bronchial foreign body with right sided obstructive emphysema. The patient was stable with oxygenation and nebulization with ipratropium bromide, albuterol, normal saline and budesonide before the CT scan. Therefore, we conclude that symptoms resembling foreign body obstruction are not always aspirated or inhaled, and sometimes secreted sputum forms a plug, which mimics the symptoms of foreign body obstruction.
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The efficacy of the N-methyl-D-aspartate receptor antagonist ketamine as an analgesic agent is still under debate, especially for indications such as chronic pain. To understand the efficacy of ketamine for relief of pain, we performed a literature search for relevant narrative and systematic reviews and meta-analyses. ⋯ In contrast, for most other indications (that is, acute pain in the emergency department, prevention of persistent postoperative pain, cancer pain, and chronic non-cancer pain), the efficacy of ketamine is limited. Ketamine's lack of analgesic effect was associated with an increase in side effects, including schizotypical effects.
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Bronchopulmonary dysplasia, or BPD, is the most common chronic lung disease in infants. Genetic predisposition and developmental vulnerability secondary to antenatal and postnatal infections, compounded with exposure to hyperoxia and invasive mechanical ventilation to an immature lung, result in persistent inflammation, culminating in the characteristic pulmonary phenotype of BPD of impaired alveolarization and dysregulated vascularization. In this article, we highlight specific areas in current management, and speculate on therapeutic strategies that are on the horizon, that we believe will make an impact in decreasing the incidence of BPD in your neonatal intensive care units.