Andersen-Tawil syndrome: deep phenotyping reveals significant cardiac and neuromuscular morbidity.

Andersen-Tawil syndrome is a neurological channelopathy caused by mutations in the KCNJ2 gene that encodes the ubiquitously expressed Kir2.1 potassium channel. The syndrome is characterized by episodic weakness, cardiac arrythmias and dysmorphic features. However, the full extent of the multisystem phenotype is not well described. In-depth, multisystem phenotyping is required to inform diagnosis and guide management. We report our findings following deep multimodal phenotyping across all systems in a large case series of 69 total patients, with comprehensive data for 52. As a national referral centre, we assessed point prevalence and showed it is higher than previously reported, at 0.105 per 100 000 population in England. While the classical phenotype of episodic weakness is recognized, we found that a quarter of our cohort have fixed myopathy and 13.5% required a wheelchair or gait aid. We identified frequent fat accumulation on MRI and tubular aggregates on muscle biopsy, emphasizing the active myopathic process underpinning the potential for severe neuromuscular disability. Long exercise testing was not reliable in predicting neuromuscular symptoms. A normal long exercise test was seen in five patients, of whom four had episodic weakness. Sixty-seven per cent of patients treated with acetazolamide reported a good neuromuscular response. Thirteen per cent of the cohort required cardiac defibrillator or pacemaker insertion. An additional 23% reported syncope. Baseline electrocardiograms were not helpful in stratifying cardiac risk, but Holter monitoring was. A subset of patients had no cardiac symptoms, but had abnormal Holter monitor recordings which prompted medication treatment. We describe the utility of loop recorders to guide management in two such asymptomatic patients. Micrognathia was the most commonly reported skeletal feature; however, 8% of patients did not have dysmorphic features and one-third of patients had only mild dysmorphic features. We describe novel phenotypic features including abnormal echocardiogram in nine patients, prominent pain, fatigue and fasciculations. Five patients exhibited executive dysfunction and slowed processing which may be linked to central expression of KCNJ2. We report eight new KCNJ2 variants with in vitro functional data. Our series illustrates that Andersen-Tawil syndrome is not benign. We report marked neuromuscular morbidity and cardiac risk with multisystem involvement. Our key recommendations include proactive genetic screening of all family members of a proband. This is required, given the risk of cardiac arrhythmias among asymptomatic individuals, and a significant subset of Andersen-Tawil syndrome patients have no (or few) dysmorphic features or negative long exercise test. We discuss recommendations for increased cardiac surveillance and neuropsychometry testing.

A Comparison of Quantum and Molecular Mechanical Methods to Estimate Strain Energy in Druglike Fragments.

Reducing internal strain energy in small molecules is critical for designing potent drugs. Quantum mechanical (QM) and molecular mechanical (MM) methods are often used to estimate these energies. In an effort to determine which methods offer an optimal balance in accuracy and performance, we have carried out torsion scan analyses on 62 fragments. We compared nine QM and four MM methods to reference energies calculated at a higher level of theory: CCSD(T)/CBS single point energies (coupled cluster with single, double, and perturbative triple excitations at the complete basis set limit) calculated on optimized geometries using MP2/6-311+G**. The results show that both the more recent MP2.X perturbation method as well as MP2/CBS perform quite well. In addition, combining a Hartree-Fock geometry optimization with a MP2/CBS single point energy calculation offers a fast and accurate compromise when dispersion is not a key energy component. Among MM methods, the OPLS3 force field accurately reproduces CCSD(T)/CBS torsion energies on more test cases than the MMFF94s or Amber12:EHT force fields, which struggle with aryl-amide and aryl-aryl torsions. Using experimental conformations from the Cambridge Structural Database, we highlight three example structures for which OPLS3 significantly overestimates the strain. The energies and conformations presented should enable scientists to estimate the expected error for the methods described and we hope will spur further research into QM and MM methods.

Axially Chiral Enamides: Substituent Effects, Rotation Barriers, and Implications for their Cyclization Reactions.

The barrier to rotation around the N-alkenyl bond of 38 N-alkenyl-N-alkylacetamide derivatives was measured (ΔG(⧧) rotation varied between <8.0 and 31.0 kcal mol(-1)). The most important factor in controlling the rate of rotation was the level of alkene substitution, followed by the size of the nitrogen substituent and, finally, the size of the acyl substituent. Tertiary enamides with four alkenyl substituents exhibited half-lives for rotation between 5.5 days and 99 years at 298 K, sufficient to isolate enantiomerically enriched atropisomers. The radical cyclizations of a subset of N-alkenyl-N-benzyl-α-haloacetamides exhibiting relatively high barriers to rotation round the N-alkenyl bond (ΔG(⧧) rotation >20 kcal mol(-1)) were studied to determine the regiochemistry of cyclization. Those with high barriers (>27 kcal mol(-1)) did not lead to cyclization, but those with lower values produced highly functionalized γ-lactams via a 5-endo-trig radical-polar crossover process that was terminated by reduction, an unusual cyclopropanation sequence, or trapping with H2O, depending upon the reaction conditions. Because elevated temperatures were necessary for cyclization, this precluded study of the asymmetric transfer in the reaction of individual atropisomers. However, enantiomerically enriched atropsiomeric enamides should be regarded as potential asymmetric building blocks for reactions that can be accomplished at room temperature.

Medium-Ring Effects on the Endo/Exo Selectivity of the Organocatalytic Intramolecular Diels-Alder Reaction.

The intramolecular Diels-Alder reaction has been used as a powerful method to access the tricyclic core of the eunicellin natural products from a number of 9-membered-ring precursors. The endo/exo selectivity of this reaction can be controlled through a remarkable organocatalytic approach, employing MacMillan's imidazolidinone catalysts, although the mechanistic origin of this selectivity remains unclear. We present a combined experimental and density functional theory investigation, providing insight into the effects of medium-ring constraints on the organocatalyzed intramolecular Diels-Alder reaction to form the isobenzofuran core of the eunicellins.

Myasthenia in pregnancy: best practice guidelines from a U.K. multispecialty working group.

A national U.K. workshop to discuss practical clinical management issues related to pregnancy in women with myasthenia gravis was held in May 2011. The purpose was to develop recommendations to guide general neurologists and obstetricians and facilitate best practice before, during and after pregnancy. The main conclusions were (1) planning should be instituted well in advance of any potential pregnancy to allow time for myasthenic status and drug optimisation; (2) multidisciplinary liaison through the involvement of relevant specialists should occur throughout pregnancy, during delivery and in the neonatal period; (3) provided that their myasthenia is under good control before pregnancy, the majority of women can be reassured that it will remain stable throughout pregnancy and the postpartum months; (4) spontaneous vaginal delivery should be the aim and actively encouraged; (5) those with severe myasthenic weakness need careful, multidisciplinary management with prompt access to specialist advice and facilities; (6) newborn babies born to myasthenic mothers are at risk of transient myasthenic weakness, even if the mother's myasthenia is well-controlled, and should have rapid access to neonatal high-dependency support.

Computational investigation of the competition between the concerted Diels-Alder reaction and formation of diradicals in reactions of acrylonitrile with nonpolar dienes.

The energetics of the Diels-Alder cycloaddition reactions of several 1,3-dienes with acrylonitrile, and the energetics of formation of diradicals, were investigated with density functional theory (B3LYP and M06-2X) and compared to experimental data (Hall et al., J. Org. Chem.1993, 58, 7049-7058). For the reaction of 2,3-dimethyl-1,3-butadiene with acrylonitrile, the concerted reaction is favored over the diradical pathway by 2.5 kcal/mol using B3LYP/6-31G(d); experimentally, this reaction gives both cycloadduct and copolymer. The concerted cycloaddition of cyclopentadiene with acrylonitrile is preferred computationally over the stepwise pathway by 5.9 kcal/mol; experimentally, only the Diels-Alder adduct is formed. For the reactions of (E)-1,3-pentadiene and acrylonitrile, both cycloaddition and copolymerization were observed experimentally; these trends were mimicked by the computational results, which showed only a 1.2 kcal/mol preference for the concerted pathway. For the reactions of (Z)-1,3-pentadiene and acrylonitrile, the stepwise pathway is preferred by 3.9 kcal/mol, in agreement with previous experimental findings that only polymerization occurs. M06-2X is known to give more accurate activation and reaction energetics (Pieniazek, et al., Angew. Chem. Int.2008, 47, 7746-7749), but the energies of diradicals are too high.

Atrial fibrillation.

My first placement as a nursing student was on a cardio-thoracic surgical ward, where patients frequently present with atrial fibrillation (AF). The learning zone article has helped to improve my knowledge and understanding of AF, including symptoms, risk factors, diagnosis and treatment.

Prevalence of genetically confirmed skeletal muscle channelopathies in the era of next generation sequencing.

We provide an up-to-date and accurate minimum point prevalence of genetically defined skeletal muscle channelopathies which is important for understanding the population impact, planning for treatment needs and future clinical trials. Skeletal muscle channelopathies include myotonia congenita (MC), sodium channel myotonia (SCM), paramyotonia congenita (PMC), hyperkalemic periodic paralysis (hyperPP), hypokalemic periodic paralysis (hypoPP) and Andersen- Tawil Syndrome (ATS). Patients referred to the UK national referral centre for skeletal muscle channelopathies and living in UK were included to calculate the minimum point prevalence using the latest data from the Office for National Statistics population estimate. We calculated a minimum point prevalence of all skeletal muscle channelopathies of 1.99/100 000 (95% CI 1.981-1.999). The minimum point prevalence of MC due to CLCN1 variants is 1.13/100 000 (95% CI 1.123-1.137), SCN4A variants which encode for PMC and SCM is 0.35/100 000 (95% CI 0.346 - 0.354) and for periodic paralysis (HyperPP and HypoPP) 0.41/100 000 (95% CI 0.406-0.414). The minimum point prevalence for ATS is 0.1/100 000 (95% CI 0.098-0.102). There has been an overall increase in point prevalence in skeletal muscle channelopathies compared to previous reports, with the biggest increase found to be in MC. This can be attributed to next generation sequencing and advances in clinical, electrophysiological and genetic characterisation of skeletal muscle channelopathies.

Safety evaluation of the Guardian device on the common carotid artery in sheep.

Background: Pulse pressure intensity in middle-aged adults is a risk factor for dementia. The Guardian device (The Brain Protection Company, Sydney, Australia) has been developed to reduce pulse pressure, as a potential therapy. Objectives: The aim of this study was to evaluate the safety of the Guardian, a novel pulse modulation device designed to reduce the intensity of the pulse pressure that penetrates into the cerebral small vessels. The Guardian is a helix that gently wraps around the common carotid artery (CCA) to slightly change its shape, to absorb pulsatility, without lowering flow. Methods: The Guardian was implanted bilaterally on the CCAs of 10 mature sheep for chronic implant periods of 3, 6 or 8 months. The ratio of internal device diameter to outer diameter of the CCA varied from 63% to 92% (n = 20). The implant position on the vessel was marked surgically at implant. Gross pathology and histopathology of the CCA were examined at 3- and 6-months post explant. Most devices were explanted using open surgery, however minimally invasive surgical explant techniques were examined in 2 animals to assess the potential of this approach for explant in humans if required. Results: The Guardian was successfully implanted with no adverse events, and minimally invasive explant appeared to be viable for removal. Following implant, the device was surrounded by a thin fibrous capsule, with similar pathology at 3- and 6-months. Minimal or no movement was observed. CCA sections appeared histologically normal, with no evidence of thrombosis, stenosis, fibrosis, chronic inflammatory response, or vessel degeneration. Conclusions: The feasibility of surgical implantation and biomaterial safety of the Guardian was confirmed over 8 months. Minimally invasive explant of the Guardian has the potential to be viable. Further work is required to demonstrate efficacy in vitro and/or in vivo before evaluation in humans.

Atom-transfer cyclization with CuSO4/KBH4: a formal "activators generated by electron transfer" process also applicable to atom-transfer polymerization.

The 4-exo and 5-exo-trig atom-transfer cyclizations of 1, 8a-e, 9, 12, and 13 can be mediated with as little as 0.05 mol % of Cu(TPMA)SO(4)·5H(2)O in the presence of 2.5 mol % of borohydride salts in 10 min at room temperature in air. This formal "activators generated by electron transfer" (AGET) procedure utilizes a cheap and oxidatively stable copper source (CuSO(4)·5H(2)O) and can be carried out in environmentally benign solvents (EtOH). It is possible to alter the product distribution in the 5-endo radical-polar crossover reactions of 10a,b and 11 by tailoring the amount of borohydride. Cyclization onto alkynes 14 and 15 is also possible in only 20 min. Controlled radical polymerization of styrene, with increased rates over conventional atom-transfer radical polymerization (ATRP), can be carried out in a controlled fashion (Mn, PDI) using either CuBr or CuSO(4)·5H(2)O and Bu(4)NBH(4).

Patterns of admissions in an acute medical unit: priorities for service development and education.

An Acute Medical Unit has recently been established at York Hospital. The present study sought to characterise the case mix of acutely unwell medical patients to allow identification of priorities for ongoing service development and to assess educational opportunities for trainees in the region. Data were collected for 16001 admission episodes between January 2010 and April 2011 inclusive. These allowed characterisation of the case mix, and identified key priorities where clinical pathway do not yet exist, namely heart failure, urinary tract infection, and acute diarrhoea. Good educational opportunities exist for most aspects of the Acute Medicine curriculum; several weaknesses were identified, and trainees might address these by undertaking a specific period of specialty training in endocrinology and neurology.

Bond rotation dynamics of enamides: the effect of the acyl group and potential for chirality transfer during 5-endo trig radical cyclizations.

Barriers to rotation of the N-alkenyl bond in a series of N-cycloalkenyl-N-benzyl acetamide derivatives have been measured in different solvents by variable-temperature NMR experiments. The barriers range from 9.7 to 14.2 kcal/mol, depending on substituents on the acetamide acyl group. Polar solvents such as chloroform and methanol increase the barrier to rotation compared to nonpolar solvents such as toluene. The barrier to rotation of "mimics" for acetamide-based radicals are estimated. The relative order of the values of k(rot) for different acyl groups parallels their reported Taft E(s) paramaters. For successful chirality transfer in 5-endo trig radical cyclization, it is evident that rotations would need to be significantly slower than those reported here.

Andersen-Tawil Syndrome Presenting with Complete Heart Block.

Andersen-Tawil syndrome (ATS) is a rare autosomal dominant neuromuscular disorder due to mutations in the KCNJ2 gene. The classical phenotype of ATS consists of a triad of periodic paralysis, cardiac conduction abnormalities and dysmorphic features. Episodes of either muscle weakness or cardiac arrhythmia may predominate however, and dysmorphic features may be subtle, masking the true breadth of the clinical presentation, and posing a diagnostic challenge. The severity of cardiac involvement varies but includes reports of life-threatening events or sudden cardiac death, usually attributed to ventricular tachyarrhythmias. We report the first case of advanced atrioventricular (AV) block in ATS and highlight clinical factors that may delay diagnosis.

Implantation and long-term assessment of the stability and biocompatibility of a novel 98 channel suprachoroidal visual prosthesis in sheep.

Severe visual impairment can result from retinal degenerative diseases such as retinitis pigmentosa, which lead to photoreceptor cell death. These pathologies result in extensive neural and glial remodelling, with survival of excitable retinal neurons that can be electrically stimulated to elicit visual percepts and restore a form of useful vision. The Phoenix99 Bionic Eye is a fully implantable visual prosthesis, designed to stimulate the retina from the suprachoroidal space. In the current study, nine passive devices were implanted in an ovine model from two days to three months. The impact of the intervention and implant stability were assessed using indirect ophthalmoscopy, infrared imaging, and optical coherence tomography to establish the safety profile of the surgery and the device. The biocompatibility of the device was evaluated using histopathological analysis of the tissue surrounding the electrode array, with a focus on the health of the retinal cells required to convey signals to the brain. Appropriate stability of the electrode array was demonstrated, and histological analysis shows that the fibrotic and inflammatory response to the array was mild. Promising evidence of the safety and potential of the Phoenix99 Bionic Eye to restore a sense of vision to the severely visually impaired was obtained.

Safety and biocompatibility of a bionic eye: Imaging, intraocular pressure, and histology data.

The data presented here are related and supplementary data to the research article "Implantation and long-term assessment of the stability and biocompatibility of a novel 98 channel suprachoroidal visual prosthesis in sheep" [1]. In Eggenberger et al., nine sheep of the Suffolk (N=2) and Dorper (N=7) breeds were implanted in the left eye with an electrically inactive, suprachoroidal retinal stimulator (Bionic Eye) for durations of up to 100 days. The surgical safety, implant stability and device biocompatibility were assessed. Intraocular pressure measurements, indirect and infrared ophthalmoscopy and optical coherence tomography were performed at fixed time points to evaluate the clinical effects of the surgery and device implantation. Post-mortem eye tissue collection and histology was performed to measure the effects of the intervention at the cellular level. The data, including a comprehensive collection of fundus, infrared, optical coherence tomography and histology images can be used as a reference for comparison with other research, for example, active retinal stimulators. Furthermore, these data can be used to evaluate the suitability of the sheep model, in particular Dorper sheep, for future research.

Paediatric nurses' understanding of the process and procedure of double-checking medications.

AIMS AND OBJECTIVES: To understand paediatric nurses' understanding and practice regarding double-checking medication and identify facilitators and barriers to the process of independent double-checking (IDC). BACKGROUND: A system of double-checking medications has been proposed as a way of minimising medication error particularly in situations involving high-risk medications, complex processes such as calculating doses, or high-risk patient populations such as infants and children. While recommendations have been made in support of IDC in paediatric settings little is known about nursing practice and the facilitators and barriers to this process. DESIGN: A descriptive qualitative design was used. METHODS: Data were collected via three focus group interviews. Six to seven paediatric nurses participated in homogenous groups based on level of practice. Data were analysed using thematic analysis. CONCLUSIONS: This study demonstrates that, while IDC is accepted and promoted as best practice in a paediatric setting, there is a lack of clarity as to what this means. This study supports other studies in relation to the influence of workload, distraction and environmental factors on the administration process but highlights the need for more research in relation to the impact of the power dynamic between junior and senior nurses. The issue of automaticity has been unexplored in relation to nursing practice but this study indicates that this may have an important influence on how care is delivered to patients. RELEVANCE TO CLINICAL PRACTICE: While the focus of this study was in the paediatric setting, the findings have relevance to other settings and population groups. The adoption of IDC in health care settings must have in place: policy and guidelines that clearly define the process of checking, educational support, an environment that supports peer critique and review, well-designed medication areas and accessible resources to support drug administration.