Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in spinocerebellar ataxia type 1.

Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 co-repressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, disrupting the association between ATXN1 and Cic rescued the levels of these ion channel transcripts, and lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1.

A consultant-led anticoagulation review of all patients in one clinical commissioning group to prevent atrial fibrillation related stroke.

OBJECTIVE: Ensuring patients with Atrial fibrillation (AF) are appropriately anticoagulated across NHS Bedfordshire Clinical Commissioning Group (BCCG) with the primary goal of reducing AF-related strokes. METHODS: With Inspira Health, BCCG adopted the Primary Care Atrial Fibrillation (PCAF) Service which is led by Consultant Cardiologists. PCAF uses retrospective clinical audit to identify patients who require prospective face-to-face review on the need for anticoagulation. RESULTS: 34 GP practices participated covering a 376 311 population (80% of BCCG). 12 573 patients' medical records were audited. The initial AF register was 7301 patients (AF prevalence 1.9%) and an additional 265 patients were identified through AF casefinder resulting in an AF prevalence of 2.0%. From 7566 patients with AF, 5831 were already on anticoagulants (77.1%), with 50.5% (n = 2947) on VKA medications and 49.5% (n = 2884) on direct oral anticoagulants (DOACs). Of the DOAC patients, 595 (20.6%) required dosage review or up to date blood tests. Case notes were reviewed for 1735 patients not on anticoagulation, with 901 (51.9%) patients deemed not eligible for anticoagulation. This left 834 (48.1%) patients who were eligible for, but not on, anticoagulation. A further 407 (13.8%) patients currently taking VKA medications were deemed sup-optimal with regards to INR control with TTR < 65%. In total 1241 patients were invited for review by a Consultant Cardiologist at their local GP practice, with an attendance rate of 90%. From all face to face and virtual consultations, 908 patients had anticoagulants prescribed, changed, management of INRs improved or were in the process of being anticoagulated at the time of follow-up. From this we would expect 36.3 AF related strokes prevented and a cost saving to the NHS of £470 200 per year. CONCLUSION: Through comprehensive audit, BCCG have been able to ensure that patients with AF are appropriately anticoagulated in 80% of their catchment population. This has improved anticoagulation to prevent AF-related stroke.

Coarse fibrillatory waves in atrial fibrillation predict success of electrical cardioversion.

BACKGROUND: To determine whether the presence of "coarse" fibrillatory waves (Fw) seen on surface ECGs of patients with persistent atrial fibrillation (AF) predict maintenance of sinus rhythm (SR) at 6 weeks after electrical cardioversion (ECV). METHODS: Preprocedure ECGs from 94 consecutive patients with persistent AF scheduled to undergo ECV at a single centre were classified as having coarse Fw (≥0.1 mV) or fine Fw (<0.1 mV) in leads II or V1 . The primary outcome was ECG rhythm at 6-week clinical follow-up. Demographic and echocardiographic data were also collected. RESULTS: Thirty-two patient ECGs (34%) had coarse Fw on baseline ECG in either or both leads II or V1 with no significant differences in baseline demographics compared to those patients with fine Fw. At 6 weeks post-ECV, in the coarse Fw group 72% of patients maintained SR vs. 42% in the fine Fw group (χ2 , p = .006) with the odds ratio (OR) of maintaining SR at 6 weeks in the presence of coarse Fw being 3.5 (95% CI: 1.4-8.9, p = .007). Across the overall study population, there were no other significant univariate predictors of SR at 6 weeks post-ECV. CONCLUSION: Classifying persistent AF using the maximal Fw amplitude on a surface ECG is a simple and reproducible method of predicting medium-term success of ECV, independent of traditional risk factors.

Warfarin-induced purple toe syndrome successfully treated with apixaban.

Purple toe syndrome is a recognised adverse effect of warfarin therapy. The literature has described resolution of the ischaemic symptoms on withdrawal of the warfarin and switching to a low molecular weight heparin alternative. We present a case of an 82-year-old man with bilateral blanching vivacious toes and a livedo-reticularis type rash developing 2 weeks after being loaded with warfarin for first detected atrial fibrillation. Vascular surgical review and haematology thrombotic screen did not yield any other pathology and a diagnosis of purple toe syndrome due to warfarin was carried out. The warfarin was stopped and oral anticoagulation started with an oral factor Xa inhibitor, apixaban with resolution of his symptoms. This is the first case report of one of the novel oral anticoagulants being used to treat purple toe syndrome.

Loeys-Dietz syndrome: life threatening aortic dissection diagnosed on routine family screening.

A 52-year-old man was found to have a severely dilated aortic root and a Stanford type A dissection on familial screening echocardiography, following diagnosis of a dilated aorta in his son. The dissection required urgent surgical repair. Clinical examination suggested features of Loeys-Dietz syndrome type II, and subsequent demonstration of a mutation in the TGFBR1 gene in the patient and his son confirmed the diagnosis. This article highlights the high prevalence of inherited conditions in dilated aortic root presentations and the importance of family screening and surveillance to allow early surgical intervention.

A patient with tricho-rhino-phalangeal syndrome and mitral valve disease.

We describe the case of a 33 year old man with Tricho-Rhino-Phalangeal Syndrome (TRPS) and mitral valve disease. Tricho-Rhino-Phalangeal Syndrome is a rare multisystem disorder. The English literature has no record of any association with mitral valve disease which was a feature of our patient and his father both of whom were suffering from the syndrome. Doctors looking after patients with that condition should be alert to this possible association.