Personalised music as a treatment for epilepsy.

In this paper we look at non-pharmaceutical treatments for intractable epilepsy based on neurophysiological methods especially with EEG analysis. In summary, there are a number of limbic and thalamo-cortical related structures involved in the processing of musical emotion (exposure), including the amygdala (arousal, expression of mood, fear), hippocampus (memory, regulation of HPA axis, stress), parahippocampal gyrus (recognition, memory retrieval), insula (valence), temporal poles (connectivity), ventral striatum (expectation and experience of reward), orbitofrontal cortex (valence) and cingulate cortex (autonomic regulation). One method is to audify (a form of sonification) EEG activity to find music by feedback to entrain abnormal EEG activity. We discuss various methods and our use of X-System (https://www.x-system.co.uk/) which is a computational model of the musical brain capable of predicting the neurophysiological effects of music. It models structures and pathways related to responses to music, including the cochlea, brain stem, auditory and motor cortex, as well as basal ganglia, cerebellum and limbic structures. It can predict autonomic and endocrine activity as well as the substrates of electrical activity to select music which can regularise EEG abnormalities to decrease epileptic activity and seizures, especially in those unresponsive to antiepileptic medication or invasive treatments.

Ethics in acute medicine.

Clinical ethics is a core part of the decision-making process. Whilst often reduced to the four principles approach, the situation is more complex. Teaching of ethics frequently focuses on quandary issues, such as assisted-suicide, but there is an ethical component to every clinical encounter. Where differences of opinion arise it is important to understand one's own perspective and that of others. Compassion is an important starting point.

Society for Acute Medicine undergraduate syllabus for Acute Internal Medicine.

This syllabus is intended to act as a guide for students and their instructors in medical schools. It describes the range of clinical presentations that they should be able to recognize and the underlying conditions that they should know how to treat. It also includes knowledge of the practice of Acute Internal Medicine and systems of care. The appropriate level of knowledge is that which would be expected of a non-specialist Foundation level doctor.

Controlling the configuration space topology of mechanical structures.

Linkages are mechanical devices constructed from rigid bars and freely rotating joints studied both for their utility in engineering and as mathematical idealizations in a number of physical systems. Recently, there has been a resurgence of interest in designing linkages in the physics community due to the concurrent developments of mechanical metamaterials, topological mechanics, and the discovery of anomalous rigidity in fiber networks and vertex models. These developments raise a natural question: to what extent can the motion of a linkage or mechanical structure be designed? Here, we describe a method to design the topology of the configuration space of a linkage by first identifying the manifold of critical points, then perturbing around such critical configurations. Unlike other methods, our methods are tractable and provide a simple visual toolkit for mechanism design. We demonstrate our procedure by designing a mechanism to gate the propagation of a soliton in a Kane-Lubensky chain of interconnected rotors.

Robust folding of elastic origami.

Self-folding origami, structures that are engineered flat to fold into targeted, three-dimensional shapes, have many potential engineering applications. Though significant effort in recent years has been devoted to designing fold patterns that can achieve a variety of target shapes, recent work has also made clear that many origami structures exhibit multiple folding pathways, with a proliferation of geometric folding pathways as the origami structure becomes complex. The competition between these pathways can lead to structures that are programmed for one shape, yet fold incorrectly. To disentangle the features that lead to misfolding, we introduce a model of self-folding origami that accounts for the finite stretching rigidity of the origami faces and allows the computation of energy landscapes that lead to misfolding. We find that, in addition to the geometrical features of the origami, the finite elasticity of the nearly-flat origami configurations regulates the proliferation of potential misfolded states through a series of saddle-node bifurcations. We apply our model to one of the most common origami motifs, the symmetric "bird's foot," a single vertex with four folds. We show that though even a small error in programmed fold angles induces metastability in rigid origami, elasticity allows one to tune resilience to misfolding. In a more complex design, the "Randlett flapping bird," which has thousands of potential competing states, we further show that the number of actual observed minima is strongly determined by the structure's elasticity. In general, we show that elastic origami with both stiffer folds and less bendable faces self-folds better.

Clinical decision making in acute medicine.

Clinical decision-making is a core skill for the practice of medicine and yet during training there is often little formal analysis of the process of clinical reasoning or instruction about how to do it better. This paper reviews the process of clinical decision-making with a particular focus on diagnostic reasoning. Aspects of psychology and philosophy are applied to the process along with consideration of potential sources of error and the steps that can be taken to minimize this.

A rare, but life-threatening sore throat: A case of Lemierre's syndrome.

We present the case of a previously healthy, immunocompetent male with Lemierre's Syndrome. He presented with headache, sore throat and pyrexia. Initial blood tests revealed raised inflammatory markers and electrolyte abnormalities. Blood cultured Fusobacterium necrophorum. He developed respiratory distress and imaging confirmed lung abscess and empyema due to septic emboli. He required surgical drainage and a prolonged course of antibiotics. This case highlights the rare, but life-threatening condition of Lemierre's Syndrome. We discuss the importance of prompt recognition and early antibiotic therapy.

Topological transitions in the configuration space of non-Euclidean origami.

Origami structures have been proposed as a means of creating three-dimensional structures from the micro- to the macroscale and as a means of fabricating mechanical metamaterials. The design of such structures requires a deep understanding of the kinematics of origami fold patterns. Here we study the configurations of non-Euclidean origami, folding structures with Gaussian curvature concentrated on the vertices, for arbitrary origami fold patterns. The kinematics of such structures depends crucially on the sign of the Gaussian curvature. As an application of our general results, we show that the configuration space of nonintersecting, oriented vertices with positive Gaussian curvature decomposes into disconnected subspaces; there is no pathway between them without tearing the origami. In contrast, the configuration space of negative Gaussian curvature vertices remains connected. This provides a new, and only partially explored, mechanism by which the mechanics and folding of an origami structure could be controlled.

Use of a flumazenil infusion to treat chlordiazepoxide toxicity.

"Alcohol detox" is a common presentation to acute medical services and is usually managed via standardised guidelines and protocols. We present a case of chlordiazepoxide toxicity, requiring repeated bolus doses and subsequently 24 hours of an intravenous infusion of flumazenil in response to guideline directed management of an alcohol withdrawal state. The use of prolonged flumazenil infusions to treat benzodiazepine toxicity is infrequently described. Chlordiazepoxide is metabolised in the hepatic microsomal pathway and hepatic impairment can lead to accumulation of toxic metabolites, which may have been the explanation for toxicity in this case. In patients at risk of liver dysfunction we advise the use of benzodiazepines not requiring phase 1 oxidative metabolism, such as lorazepam or oxazepam.

A brief history of hysteria: From the ancient to the modern.

In this paper we discuss the history of hysteria from the Babylonian and Assyrian texts through to the situation as it appears to us at the end of the 19th century. We note the shifting emphasis on causation, earlier ideas being linked to uterine theories, later speculations moving to the brain, and then the mind. We note the persistence of the condition referred to as hysteria over the millennia and the fascination that the condition has held for physicians, neurologists, and psychiatrists since the origins of known medical texts.

Preclinical development of AMG 139, a human antibody specifically targeting IL-23.

BACKGROUND AND PURPOSE: AMG 139 is a human anti-IL-23 antibody currently in a phase II trial for treating Crohn's disease. To support its clinical development in humans, in vitro assays and in vivo studies were conducted in cynomolgus monkeys to determine the pharmacology, preclinical characteristics and safety of this monoclonal antibody. EXPERIMENTAL APPROACH: The in vitro pharmacology, pharmacokinetics (PK), pharmacodynamics and toxicology of AMG 139, after single or weekly i.v. or s.c. administration for up to 26 weeks, were evaluated in cynomolgus monkeys. KEY RESULTS: AMG 139 bound with high affinity to both human and cynomolgus monkey IL-23 and specifically neutralized the biological activity of IL-23 without binding or blocking IL-12. After a single dose, linear PK with s.c. bioavailability of 81% and mean half-life of 8.4-13 days were observed. After weekly s.c. dosing for 3 or 6 months, AMG 139 exposure increased approximately dose-proportionally from 30 to 300 mg·kg(-1) and mean accumulation between the first and last dose ranged from 2- to 3.5-fold. Peripheral blood immunophenotyping, T-cell-dependent antigen responses and bone formation markers were not different between AMG 139 and vehicle treatment. No adverse clinical signs, effects on body weight, vital signs, ophthalmic parameters, clinical pathology, ECG, organ weights or histopathology were observed in the monkeys with the highest dose of AMG 139 tested (300 mg·kg(-1) s.c. or i.v.). CONCLUSIONS AND IMPLICATIONS: The in vitro pharmacology, PK, immunogenicity and safety characteristics of AMG 139 in cynomolgus monkeys support its continued clinical development for the treatment of various inflammatory diseases.

The prognosis of fixed dystonia: a follow-up study.

BACKGROUND: The syndrome of fixed dystonia includes both CRPS-dystonia and psychogenic dystonia. The underlying mechanisms are unclear, but a high prevalence of neuropsychiatric illness has previously been reported. METHODS: Clinical and neuropsychiatric follow-up study by telephone and self-administered instruments (HADS, SDQ-20, DES II, EQ-5D), on 41 patients with fixed dystonia after a mean of 7.6 (+/-3.6) years. RESULTS: We obtained information on clinical outcome in 35 (85.4%) patients and neuropsychiatric questionnaire data in 22 (53.7%). Eighty-three percent were women. Thirty-one percent had worsened, 46% were the same and 23% had improved, of whom 6% had major remissions. At follow-up, mean duration of illness was 11.8 (+/-4.9) years and mean age 43.2 (+/-14.8) years. Except for 1 patient who was re-diagnosed with corticobasal degeneration, the diagnosis remained unchanged in others. Forty-one percent had scores indicating anxiety and 18% indicating depression; 18% scored within the range of dissociative/somatoform disorders on DES II and 19% on SDQ-20. The mean EQ-5D index and VAS scores were 0.34 and 56.1%. Comparison between the 3 outcome groups revealed significant difference only in the EQ-5D (p=0.003). Only baseline CRPS predicted a worse outcome (chi(2)=0.006). CONCLUSIONS: Our findings revealed that the prognosis of this syndrome is poor, with improvement in less than 25% of patients, major remission in only 6% and continued worsening in a third. A high rate of neuropsychiatric findings was noted and new neuropsychiatric features had occurred in some. Average health status was poor. Of the baseline parameters, only CRPS predicted poorer outcome.

Prevalence, patterns, service needs, and assessment of neuropsychiatric disorders among people with epilepsy in residential care: validation of the Neuropsychiatric Inventory as a caregiver-rated measure of neuropsychiatric functioning in epilepsy.

We assessed 228 people with epilepsy (PWE) in the residential care setting using the Neuropsychiatric Inventory (NPI) and Brief Psychiatric Rating Scale (BPRS) as caregiver- and observer-rated instruments. There was a significant burden of psychopathology, about half of all subjects surveyed scoring positive on either or both instruments. Psychopathology as measured by the NPI and BPRS was significantly greater in cognitively impaired subjects than in those with intact cognitive function. The NPI was found to be a valid caregiver-rated measure of psychopathology in PWE, with a principal components analysis yielding a reliable and interpretable four-factor solution, psychosis, interictal dysphoric disorder, depression, and anxiety being identified. Mental health service needs were found to be considerable in this population, with a significant hidden burden of psychiatric comorbidity. As this population has ongoing service needs through the life span, further research is necessary.

Measuring left ventricular mechanical dyssynchrony from ECG-gated SPECT myocardial perfusion imaging.

Cardiac resynchronization therapy (CRT) has shown benefits in patients with severe heart failure. The traditional criteria to select patients for CRT (New York Heart Association [NYHA] class III or IV, depressed left ventricular [LV] ejection fraction, and prolonged QRS duration) result in at least 30% of the selected patients with no response to CRT. Recent studies with echocardiography have shown that the presence of LV dyssynchrony is an important predictor for response to CRT. However, the recent report from the predictors of response to cardiac resynchronization therapy (PROSPECT) trial suggested that under ''real-world'' conditions the current available echocardiographic techniques including tissue Doppler imaging (TDI) and myocardial strain-rate imaging are not ready for routine clinical practice to assess LV dyssynchrony. Phase analysis is a recently developed technique that allows measuring LV dyssynchrony from electrocardiogram (ECG)-gated single photon emission computed tomography (GSPECT) myocardial perfusion imaging (MPI). This technique uses Fourier harmonic functions to approximate regional wall thickening over the cardiac cycle and to calculate regional onset of mechanical contraction (OMC) phases. These OMC phases are obtained three-dimensionally over the entire left ventricle to quantitatively assess the degree of LV dyssynchrony. This technique has been compared to TDI and shown promising results in clinical validations. The advantages of this technique over echocardiography in measuring LV dyssynchrony are its automation, its high repeatability and reproducibility. It can be applied to any conventional GSPECT MPI study with no additional procedure. In this review the phase analysis methodology is described and its up-to-date clinical validations are summarized.

Vagus nerve stimulation for depression: efficacy and safety in a European study.

BACKGROUND: Vagus nerve stimulation (VNS) therapy is associated with a decrease in seizure frequency in partial-onset seizure patients. Initial trials suggest that it may be an effective treatment, with few side-effects, for intractable depression. METHOD: An open, uncontrolled European multi-centre study (D03) of VNS therapy was conducted, in addition to stable pharmacotherapy, in 74 patients with treatment-resistant depression (TRD). Treatment remained unchanged for the first 3 months; in the subsequent 9 months, medications and VNS dosing parameters were altered as indicated clinically. RESULTS: The baseline 28-item Hamilton Depression Rating Scale (HAMD-28) score averaged 34. After 3 months of VNS, response rates (> or = 50% reduction in baseline scores) reached 37% and remission rates (HAMD-28 score <10) 17%. Response rates increased to 53% after 1 year of VNS, and remission rates reached 33%. Response was defined as sustained if no relapse occurred during the first year of VNS after response onset; 44% of patients met these criteria. Median time to response was 9 months. Most frequent side-effects were voice alteration (63% at 3 months of stimulation) and coughing (23%). CONCLUSIONS: VNS therapy was effective in reducing severity of depression; efficacy increased over time. Efficacy ratings were in the same range as those previously reported from a USA study using a similar protocol; at 12 months, reduction of symptom severity was significantly higher in the European sample. This might be explained by a small but significant difference in the baseline HAMD-28 score and the lower number of treatments in the current episode in the European study.

Are patients with somatization disorder highly suggestible?

OBJECTIVE: High suggestibility is widely regarded as an important feature of patients with medically unexplained symptoms (MUS), particularly those with multiple MUS [i.e. somatization disorder (SD)], although there are few empirical data attesting to this assumption. A study was therefore conducted to compare levels of non-hypnotic suggestibility in patients with SD and medical controls. METHOD: A modified version of the Barber Suggestibility Scale was administered to 19 patients with SD and 17 controls with an established organic dystonia. RESULTS: Patients with SD were no more suggestible than control patients. Dystonia controls were more likely to deliberately comply with suggestions than the SD patients. CONCLUSION: Contrary to popular belief, high suggestibility is not necessarily a feature of SD.

The classification of neuropsychiatric disorders in epilepsy: a proposal by the ILAE Commission on Psychobiology of Epilepsy.

The classification of psychiatric disorders in epilepsy has evolved considerably from the first attempts in the 19th century. A dedicated subcommission of the ILAE Commission on Psychobiology of Epilepsy (now the Commission on Neuropsychiatric Aspects) has developed this classification proposal. The aim of this proposal is to separate disorders comorbid with epilepsy and those that reflect ongoing epileptiform activity from epilepsy-specific disorders, and to attempt to subclassify the epilepsy-specific disorders alone. Further, the classification of epilepsy-specific psychiatric disorders has largely followed their relationship to the ictus, with factors such as relationship to antiepileptic drug (AED) change being coded as additional information. Finally, this proposal presents a clinical and descriptive system of classification rather than an etiological classification on the grounds that there is currently inadequate information for the latter approach to be employed globally.

Friedrich Nietzsche's mental illness--general paralysis of the insane vs. frontotemporal dementia.

OBJECTIVE: For a long time it was thought that Nietzsche suffered from general paralysis of the insane (GPI). However, this diagnosis has been questioned recently, and alternative diagnoses have been proposed. METHOD: We have charted Friedrich Nietzsche's final fatal illness, and viewed the differential diagnosis in the light of recent neurological understandings of dementia syndromes. RESULTS: It is unclear that Nietzsche ever had syphilis. He lacked progressive motor and other neurological features of a progressive syphilitic central nervous system (CNS) infection and lived at least 12 years following the onset of his CNS signs, which would be extremely rare for patients with untreated GPI. Finally, his flourish of productivity in 1888 would be quite uncharacteristic of GPI, but in keeping with reports of burgeoning creativity at some point in the progression of frontotemporal dementia (FTD). CONCLUSION: We suggest that Nietzsche did not have GPI, but died from a chronic dementia, namely FTD.