Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs covalently bound topoisomerase I-DNA complexes and is essential for preventing the formation of double-strand breaks that result when stalled topoisomerase I complexes interfere with DNA replication in yeast. Here we show that a deficiency of this DNA repair pathway in humans does not predispose to neoplasia or dysfunctions in rapidly replicating tissues, but instead causes spinocerebellar ataxia with axonal neuropathy (SCAN1) by affecting large, terminally differentiated, non-dividing neuronal cells. Using genome-wide linkage mapping and a positional candidate approach in a Saudi Arabian family affected with autosomal recessive SCAN1, we identified a homozygous mutation in TDP1 (A1478G) that results in the substitution of histidine 493 with an arginine residue. The His493 residue is conserved in TDP1 across species and is located in the active site of the enzyme. Protein modeling predicts that mutation of this amino acid to arginine will disrupt the symmetric structure of the active site. We propose that loss-of-function mutations in TDP1 may cause SCAN1 either by interfering with DNA transcription or by inducing apoptosis in postmitotic neurons.
Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.
C-MAC D-Blade® (Karl Storz, Tuttlingen, Germany) video laryngoscope (VL) has proved to be of immense utility in difficult intubation. But unfortunately, in an urgent situation, the predictable correct curvature of the endotracheal tube for effortless intubation is not met. We hypothesized that expertise is the most important variable in intubation and that novice students will be unable to intubate if the angle of curvature is incorrect. MethodsAn observational cross-sectional study was planned with 30 anesthesia residents, categorized into three groups based on their expertise in laryngoscopy. Students had to intubate an airway mannequin using the C-MAC D-Blade® VL with three different stylet angulations. The curvatures were 80, 100, and 120 degrees, which are commonly encountered in routine day-to-day practice. The time to get a stable glottic view, time to intubate, and ease of intubation were measured. ResultsThe mean time to intubate was the least with 100-degree angulation in group C (19.60 ± 0.97) while the maximum time was in group A with 80-degree angulation (61.49 ± 3.69). A significant difference was noted in time to get a stable glottic view when compared between the groups. There was no difference in time to intubate with different stylet angulations when compared between groups. ConclusionsNovices and experts could intubate even if the angle of curvature was incorrect taking more time. The time to laryngoscopy is significantly dependent on experience, but the time to intubate is influenced by the angle of curvature of the stylet.
Introduction. There is a growing focus on the need for an increased number of allied health professionals to reduce the pressure on acute hospitals through admission avoidance. There is little in the way of guidelines on how services should be delivered and a lack of evidence base demonstrating effectiveness. Methods. An audit has been carried out by the occupational therapy team in the Emergency Department to capture the total number of referrals to the occupational therapy service in the Emergency Department at Royal Berkshire Hospital and to capture discharge decisions made following occupational therapy input. Results. The occupational therapy team in the Emergency Department focuses particularly on admission avoidance using a home first approach to prevent patients from being admitted to acute wards. The results showed that the service was beneficial regarding both the number of referrals and the utilisation of various discharge destinations from the Emergency Department. Conclusion. The report has identified several areas for further research by the same team and implications for the wider literature base. The hope is that this report would highlight the role of occupational therapists working in the emergency department at Royal Berkshire Hospital and encourage the completion of further research in this area of practice.
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