Daniel Birchall

Analysis of haemodynamic disturbance in the atherosclerotic carotid artery using computational fluid dynamics.

Computational fluid dynamics (CFD) provides a means for the quantitative analysis of haemodynamic disturbances in vivo, but most work has used phantoms or idealised geometry. Our purpose was to use CFD to analyse flow in carotid atherosclerosis using patient-specific geometry and flow data. Eight atherosclerotic carotid arteries and one healthy control artery were imaged with magnetic resonance angiography (MRA) and duplex ultrasound, and the data used to construct patient-specific computational models used for CFD and wall shear stress (WSS) analysis. There is a progressive change in three-dimensional (3-D) velocity profile and WSS profile with increasing severity of stenosis, characterised by increasing restriction of areas of low WSS, change in oscillation patterns, and progressive rise in WSS within stenoses and downstream jets. Areas of turbulent, retrograde flow and of low WSS are demonstrated in the lee of the stenoses. This study presents the largest CFD analysis of abnormal haemodynamics at the atheromatous carotid bifurcation using patient-specific data and provides the basis for further investigation of causal links between haemodynamic variables and atherogenesis and formation of unstable plaque. We propose that this provides a means for the prospective assessment of relative stroke risk in patients with carotid atherosclerosis.

EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia

The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here we show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease.

Proton magnetic resonance spectroscopy in frontotemporal dementia

This study of frontotemporal dementia (FTD) was carried out to determine whether MR spectroscopy can provide an in vivo marker for the neuronal loss and gliosis that occur in this condition. We compared spectra in frontal and temporal regions known to be affected early in the course of the disease with spectra in the parietal lobe that is spared until late stages of FTD. We were interested in the relative concentrations of two compounds, NAA (a marker of neuronal integrity) and mI (a marker of gliosis), expressed as ratios to creatine (a relatively stable brain constituent). MR spectroscopy was performed on the temporal, parietal, and anterior cingulate cortices of five patients with the established semantic dementia form of FTD, two patients with the frontal form of FTD and 13 age matched controls. Structural MRI and neuropsychometry were also performed. Patients with FTD had reduced NAA/Cr in frontal and temporal, but not parietal lobes. The two patients with the frontal form of FTD had increased mI/Cr in their cingulate cortices. These data show for the first time that MR spectroscopy can reveal regionally selective abnormalities in patients with FTD. This opens up the possibility of using MR spectroscopy as a clinical tool to identify earlier presentations of the condition.

Acquired Chiari 1 malformation and syringomyelia following lumboperitoneal shunting for pseudotumour cerebri

An important but not widely recognised complication of lumboperitoneal shunting is the development of a Chiari 1 deformity and syringomyelia. We present a case of a patient who developed symptomatic cerebellar tonsillar descent and syrinx formation following treatment of pseudotumour cerebri with lumboperitoneal shunting. A 31 year old woman was diagnosed with pseudotumour cerebri following development of headaches, loss of vision, and papilloedema, in association with a cerebrospinal fluid (CSF) opening pressure of 36 cm H2O. Cranial imaging showed an attenuated ventricular system and no other abnormality. In particular, the posterior fossa was …

Increased expression of fatty acid binding protein 4 and leptin in resident macrophages characterises atherosclerotic plaque rupture

Objective Resident macrophages play an important role in atheromatous plaque rupture. The macrophage gene expression signature associated with plaque rupture is incompletely defined due to the complex cellular heterogeneity in the plaque. We aimed to characterise differential gene expression in resident plaque macrophages from ruptured and stable human atheromatous lesions. Methods and results We performed genome-wide expression analyses of isolated macrophage-rich regions of stable and ruptured human atherosclerotic plaques. Plaques present in carotid endarterectomy specimens were designated as stable or ruptured using clinical, radiological and histopathological criteria. Macrophage-rich regions were excised from 5 ruptured and 6 stable plaques by laser micro-dissection. Transcriptional profiling was performed using Affymetrix microarrays. The profiles were characteristic of activated macrophages. At a false discovery rate of 10%, 914 genes were differentially expressed between stable and ruptured plaques. The findings were confirmed in fourteen further stable and ruptured samples for a subset of eleven genes with the highest expression differences (p < 0.05). Pathway analysis revealed that components of the PPAR/Adipocytokine signaling pathway were the most significantly upregulated in ruptured compared to stable plaques (p = 5.4 × 10−7). Two key components of the pathway, fatty-acid binding-protein 4 (FABP4) and leptin, showed nine-fold (p = 0.0086) and five-fold (p = 0.0012) greater expression respectively in macrophages from ruptured plaques. Conclusions We found differences in gene expression signatures between macrophages isolated from stable and ruptured human atheromatous plaques. Our findings indicate the involvement of FABP4 and leptin in the progression of atherosclerosis and plaque rupture, and suggest that down-regulation of PPAR/adipocytokine signaling within plaques may have therapeutic potential.

Analysis of haemodynamic factors involved in carotid atherosclerosis using computational fluid dynamics.

Atherosclerosis presents a massive healthcare burden in both the developing and developed world. There is mounting evidence relating to the involvement of haemodynamic factors in the pathogenesis of this process. This article aims to review the current understandings that have developed in this area, and to present a demonstrative case study obtained using state of the art computational fluid dynamics (CFD) methodology to model and analyse haemodynamic factors within the atheromatous carotid artery bifurcation.

Prevalence of active epilepsy in rural Tanzania: A large community-based survey in an adult population

PURPOSE To estimate the prevalence of active epilepsy in adults in an established demographic surveillance site in rural Tanzania. To describe the clinical characteristics of epilepsy and to estimate the treatment gap in this population. METHODS A pilot study established that a previously validated screening questionnaire was sensitive for detecting cases of epilepsy in a Kiswahili-speaking Tanzanian population. A door-to-door census of the adult population (total 103,026) used the screening questionnaire to identify possible cases of epilepsy, who were then assessed by a research doctor to establish a diagnosis of epilepsy or otherwise. The prevalence of active epilepsy in this population was estimated with age-standardisation to the WHO standard population. Seizure types and epilepsies were classified according to current recommendations of the International League Against Epilepsy. The treatment gap for epilepsy was estimated based on antiepileptic drug use as reported by cases. RESULTS Two hundred and ninety-one cases of active epilepsy, all with convulsive seizures, were identified. The age-standardised prevalence was 2.91/1000 adults (95% CI 2.58-3.24); the crude prevalence adjusted for non-response was 3.84/1000 adults (95% CI 3.45-4.20). Focal-onset seizures accounted for 71.5% of all cases identified. The treatment gap was 68.4% (95% CI 63.0-73.7). CONCLUSIONS This is one of the largest community-based studies of the prevalence of epilepsy in adults conducted in sub-Saharan Africa to date. We identified a lower prevalence than has previously been described in this region. The high proportion of focal onset seizures points to a large burden of acquired, and possibly preventable, epilepsy in this population. A treatment gap of 68.4% confirms that interventions to raise awareness of the treatable nature of epilepsy are warranted in this and similar populations.

Subclinical semitendinosus and obturator externus involvement defines an autosomal dominant myopathy with early respiratory failure

We recently described a dominant limb myopathy characterised by early respiratory failure whilst affected individuals were still ambulant (autosomal dominant myopathy with early respiratory failure). Early diagnosis and exclusion of this disorder is difficult because of the insidious onset in late adult life and the highly selective muscle involvement, both clinically and pathologically. We performed muscle magnetic resonance imaging on seven cases of autosomal dominant myopathy with early respiratory failure (age range 37-66 years, 4 male) and show selective early involvement of semitendinosus and obturator externus on magnetic resonance imaging that cannot be detected clinically, with different rates of progression in closely related muscles. These findings are specific to autosomal dominant myopathy with early respiratory failure and enable early non-invasive diagnosis for individuals at risk.

Henoch-Schönlein Purpura With Posterior Reversible Encephalopathy Syndrome

We describe atypical Henoch-Schönlein purpura with posterior reversible encephalopathy syndrome in a normotensive 11-year-old girl. Her Henoch-Schönlein purpura was atypical because she initially presented with abdominal pain and vomiting and neurologic complications, rather than with the classic rash of Henoch-Schönlein Purpura. This previously healthy child was also unusual because she manifested the radiologic and clinical features of posterior reversible encephalopathy syndrome in the absence of hypertension induced by Henoch-Schönlein purpura. Her abnormal findings resolved with supportive therapy. We discuss the association of posterior reversible encephalopathy syndrome with Henoch-Schönlein purpura in three previously reported cases.

Disease activity and cognition in rheumatoid arthritis: an open label pilot study

IntroductionWe hypothesised that fatigue in rheumatoid arthritis (RA) is related to TNF-alpha induced dysregulation of cerebral blood flow. Our objectives were to assess fatigue, cognitive function and cerebral blood flow before and after initiation of anti-TNF treatment.MethodsIn a pilot study, 15 patients initiating treatment with adalimumab were assessed for fatigue using a visual analogue scale (FACIT-F), cognitive function using a panel of psychometric tests and regional cerebral blood flow using MR perfusion imaging.ResultsPatients improved clinically after anti-TNF therapy in terms of DAS28 and FACIT-F. Furthermore significant improvements were documented in full scale, verbal and performance IQ following therapy. There was a non-significant trend towards reduced cerebral perfusion in both grey and white matter, and fatigue at 3 months correlated with cerebral blood flow in white (p = 0.014) and grey (p = 0.005) matter.ConclusionsWe demonstrate for the first time a significant improvement in cognitive function following effective treatment of RA. Although we observed minor reductions in cerebral blood flow, and a correlation between cerebral blood flow and fatigue, a larger, controlled study would be required to affirm a causal relationship.