Management of vagus nerve stimulation therapy in the peri-operative period: Guidelines from the Association of Anaesthetists: Guidelines from the Association of Anaesthetists.

Vagus nerve stimulation is a well-established treatment option for patients with drug-resistant epilepsy and has an expanding range of other clinical indications. Side effects of vagus nerve stimulation therapy include: cough; voice changes; vocal cord adduction; rarely, obstructive sleep apnoea; and arrhythmia. Patients with implanted vagus nerve stimulation devices may present for unrelated surgery and critical care to clinicians who are unfamiliar with their function and safe management. These guidelines have been formulated by multidisciplinary consensus based on case reports, case series and expert opinion to support clinicians in the management of patients with these devices. The aim is to provide specific guidance on the management of vagus nerve stimulation devices in the following scenarios: the peri-operative period; peripartum period; during critical illness; and in the MRI suite. Patients should be aware of the importance of carrying their personal vagus nerve stimulation device magnet with them at all times to facilitate urgent device deactivation if necessary. We advise that it is generally safer to formally deactivate vagus nerve stimulation devices before general and spinal anaesthesia. During periods of critical illness associated with haemodynamic instability, we also advise cessation of vagus nerve stimulation and early consultation with neurology services.

Ribozyme-based therapeutic approaches for autosomal dominant retinitis pigmentosa.

PURPOSE: To design, generate, and compare in vitro a range of hammerhead ribozymes targeting retinal transcripts implicated in autosomal dominant retinitis pigmentosa (adRP) and thereby identify ribozymes that may be valuable as therapeutic agents for adRP. To address mutational heterogeneity in rhodopsin and peripherin-linked adRP using mutation-independent ribozyme-based therapeutic approaches. METHODS: Ribozyme and cDNAs constructs were cloned into pcDNA3 and expressed in vitro from the T7 promoter. Cleavage reactions were separated on polyacrylamide gels, visualized by autoradiography, and quantified using an instant imager. Ribozymes targeting rhodopsin and peripherin transcripts in a mutation-independent manner (Rz9, Rz10, and Rz40) and a multimeric ribozyme (RzMM) targeting rhodopsin transcripts were evaluated for in vitro activity. Parameters such as V:(max), K:(m), k(2) and k(-1) were established for each ribozyme. RESULTS: Four ribozymes targeting retinal transcripts were evaluated. Mutation-independent ribozymes targeting degenerate sites or untranslated regions in retinal transcripts resulted in cleavage products of predicted size, whereas transcripts from modified replacement genes remained intact. Detailed kinetic evaluation of ribozymes revealed substantial differences in cleavage rates between ribozymes. CONCLUSIONS: Mutation-independent hammerhead ribozymes targeting rhodopsin and peripherin have been screened in vitro, and a number of extremely efficient ribozymes identified subsequent to detailed kinetic analyses, suggesting that these ribozymes may provide mutation-independent methods of treating adRP. These are the first ribozymes reported that potentially will provide benefit for inherited retinopathies.

Transorally obtained oxygen tension as an indicator of arterial oxygen tension.

Transcutaneous oxygen electrodes have been used with success in neonates as indicators of arterial oxygenation, but with less success in adults because of differences in skin thickness and vascularity. In this study, a prototype transoral oxygen electrode was evaluated to determine if a heated mucous membrane would yield arterialized values of oxygen tension in adults. Using a miniaturized Clark electrode, we measured transoral oxygen tension (PtoO2) in 29 subjects at steady-state conditions. Simultaneously a sample was anaerobically obtained from a radial artery for measurement of arterial oxygen tension (PaO2). Data were analyzed using linear regression analysis, Student's t test, and analysis of variance. There was no statistically significant difference between nonwhite and white subjects or male and female subjects. There was a highly significant difference (P less than 0.001) between the pooled, matched values for PtoO2 versus PaO2, and the regression between the PtoO2 and the PaO2 was linear (slope 0.92, y-intercept -8.37, r = 0.62, P less than 0.003). The calculated ratio of PtoO2 to PaO2 was 0.83 +/- 0.03 (standard error). We concluded that the PtoO2 was linearly related to the PaO2, although its accuracy in reflecting PaO2 was low. This finding correlates with previously published data that suggested that the PtoO2 reflects tissue oxygen tension rather than arterialized oxygen tension. Gender and race appeared not to affect the function of the electrode in our study.

A clinical evaluation of the accuracy of the Nellcor N-100 and Ohmeda 3700 pulse oximeters.

Two pulse oximeters, the Nellcor N-100 and the Ohmeda 3700, were compared with arterial blood values and with each other in a clinical evaluation of performance. Three hundred twenty-nine simultaneously sampled blood/oximeter data pairs from use of both makes of pulse oximeters on each of 152 test subjects were included in the comparison analysis for each oximeter. Among the patients, disease type and severity and hospital location varied widely. Basic descriptive statistics and linear regression analysis were employed to facilitate comparison. Both oximeters displayed a statistically significant but clinically insignificant bias when compared with arterial blood oxyhemoglobin: -0.31 (P = 0.023) and 0.59 (P = 0.001) for the Ohmeda 3700 pulse oximeter and the Nellcor N-100 pulse oximeter, respectively. Relative to arterial blood oxyhemoglobin, the 95% tolerance intervals were +4.84 to -5.45 (10.3) for the Ohmeda 3700 and +6.94 to -5.76 (12.7) for the Nellcor N-100. Regressed against [oxyhemoglobin + carboxyhemoglobin + methemoglobin] as x, the Nellcor N-100 read y = 0.85(x) + 12.5, r = 0.83, P less than 0.0001, and the Ohmeda 3700 read y = 1.02(x) - 5.3, r = 0.86, P less than 0.0001.

Apoptotic photoreceptor death in the rhodopsin knockout mouse in the presence and absence of c-fos.

A combined total of approximately 100 mutations have been encountered within the rhodopsin gene in retinitis pigmentosa (RP) and congenital night blindness. Mice carrying a targeted disruption of the rhodopsin gene phenotypically mimic RP, losing their photoreceptors over a period of 3 months and having no recordable rod electroretinogram. These animals will serve as a model for both recessive and dominant disease (in the latter case, the presence of normal and mutant human rod opsin transgenes on the murine Rho(-/-)background). Precise knowledge of apoptotic photoreceptor cell death, together with factors which may influence apoptosis will be required for optimum utility of Rho(-/-)mice as a model for therapeutic genetic intervention. A peak phase of apoptosis of the photoreceptors of Rho(-/-)mice was shown to occur at 24 days post-birth. The extent of apoptosis appeared to be similar, irrespective of whether or not the rod opsin knockout was present on a c-fos(+/+)or c-fos(-/-)genetic background, the latter known to favor survival of photoreceptors following exposure of mouse retinas to excessive light. These data clearly support the existence in animals of distinct apoptotic pathways in light-induced, as opposed to mutation-induced apoptosis, and together with similar observations recently reported in studies of the naturally occurring rd mouse, may assist in focusing future research on precisely defining the distinct molecular pathways giving rise to such dichotomy.

Strategems in vitro for gene therapies directed to dominant mutations.

A major difficulty associated with the design of gene therapies for autosomal dominant diseases is the immense intragenic heterogeneity often encountered in such conditions. In order to overcome such difficulties we have designed, and evaluated in vitro, three strategies which avoid a requirement to target individual mutations for genetic suppression. In the first, normal and mutant alleles are suppressed by targeting sequences in transcribed but untranslated regions of transcript (UTRs), enabling introduction of a replacement gene with the correct coding sequencing but altered UTRs to prevent suppression. A second approach involves suppression in coding sequence and concurrent introduction of a replacement gene by exploiting the degeneracy of the genetic code. A third strategy utilises intragenic polymorphism to suppress the disease allele specifically, the advantage being that a proportion of patients with different disease mutations have the same polymorphism. These approaches provide a wider choice of target sequence than those directed to single disease mutations and are appropriate for many mutations within a given gene. General methods for suppression may be directed towards the primary defect or a secondary effect associated with the disease process, such as apoptosis. Three general methods targeting the primary defect which circumvent problems of allelic genetic heterogeneity are explored in vitro using hammerhead ribozymes designed to target transcripts from the rhodopsin, peripherin and collagen 1A1 and 1A2 genes, extensive genetic heterogeneity being a feature of associated disease pathologies.