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.

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.

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.

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.

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.

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.

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.

Expression of VAMP-2-like protein in kidney collecting duct intracellular vesicles. Colocalization with Aquaporin-2 water channels.

Body water balance is controlled by vasopressin, which regulates Aquaporin-2 (AQP2) water channels in kidney collecting duct cells by vesicular trafficking between intracellular vesicles and the plasma membrane. To examine the molecular apparatus involved in vesicle trafficking and vasopressin regulation of AQP2 in collecting duct cells, we tested if targeting proteins expressed in the synaptic vesicles, namely vesicle-associated membrane proteins 1 and 2 (VAMP1 and 2), are expressed in kidney collecting duct. Immunoblotting revealed specific labeling of VAMP2 (18-kD band) but not VAMP1 in membrane fractions prepared from kidney inner medulla. Controls using preadsorbed antibody or preimmune serum were negative. Bands of identical molecular size were detected in immunoblots of brain membrane vesicles and purified synaptic vesicles. VAMP2 in kidney membranes was cleaved by tetanus toxin, revealing a tetanus toxin-sensitive VAMP homologue. Similarly, tetanus toxin cleaved VAMP2 in synaptic vesicles. In kidney inner medulla, VAMP2 was predominantly expressed in the membrane fraction enriched for intracellular vesicles, with little or no VAMP2 in the plasma membrane enriched fraction. This was confirmed by immunocytochemistry using semithin cryosections, which showed mainly vesicular labeling in collecting duct principal cells, with no labeling of intercalated cells. VAMP2 immunolabeling colocalized with AQP2 labeling in intracellular vesicles, as determined by immunoelectron microscopy after double immunolabeling of isolated vesicles. Quantitative analysis of 1,310 vesicles revealed a highly significant association of both AQP2 and VAMP2 in the same vesicles (P < 0.0001). Furthermore, the presence of AQP2 in vesicles immunoisolated with anti-VAMP2 antibodies was confirmed by immunoblotting. In conclusion, VAMP2, a component of the neuronal SNARE complex, is expressed in vesicles carrying AQP2, suggesting a role in vasopressin-regulated vesicle trafficking of AQP2 water channels.

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.

PEA3 is overexpressed in mouse metastatic mammary adenocarcinomas.

Transgenic mice bearing the rat neu proto-oncogene under the transcriptional control of the mouse mammary tumor virus (MMTV) promoter develop focal mammary adenocarcinomas after long latency that are metastatic to the lung in a high percentage of the tumor-bearing animals. Because expression of the neu gene in the mammary epithelium precedes the occurrence of tumors, it appears that another genetic event in addition to neu transgene expression is required for tumorigenesis. We have investigated the expression of PEA3, a new member of the ets oncogene family of transcriptional regulatory factors, in neu-induced mammary tumors to learn whether PEA3 plays a role in tumor progression in this organ. We observed high levels of PEA3 RNA in neu-induced tumors, but little, if any, PEA3 RNA in the surrounding mammary epithelium. Moreover, mammary tumors that had metastasized to the lung also overexpressed the PEA3 gene, whereas normal lung tissue did not. Similar results were obtained after analyses of other transgenic mouse lines bearing metastatic mammary tumors induced by polyomavirus middle T antigen. These findings suggest that enhanced expression of PEA3 may be required to facilitate mammary tumor progression and metastasis.

Functional connectivity of human premotor and motor cortex explored with repetitive transcranial magnetic stimulation.

Connections between the premotor cortex and the primary motor cortex are dense and are important in the visual guidance of arm movements. We have shown previously that it is possible to engage these connections in humans and to measure the net amount of inhibition/facilitation from premotor to motor cortex using single-pulse transcranial magnetic stimulation (TMS). The aim of this study was to test whether premotor activation can affect the excitability of circuits within the primary motor cortex (M1) itself. Repetitive TMS (rTMS), which is known to produce effects that outlast the train at the site of stimulation, was given for 20 min at 1 Hz over premotor, primary motor, and sensory areas of cortex at an intensity of 80% of the active motor threshold for the motor hand area. The excitability of some corticocortical connections in M1 was probed by using paired-pulse testing of intracortical inhibition (ICI) and intracortical facilitation (ICF) with a coil placed over the motor cortex hand area. rTMS over the premotor cortex, but not other areas, changed the time course of the ICI/ICF for up to 1 hr afterward without affecting motor thresholds or motor-evoked potential recruitment. The cortical silent period was also shortened. The implication is that rTMS at a site distant from the motor cortex can change the excitability of circuits intrinsic to the motor cortex.

A functional neuroanatomy of tics in Tourette syndrome.

BACKGROUND: Tics are involuntary, brief, stereotyped motor and vocal behaviors often associated with irresistible urges. They are a defining symptom of the classic neuropsychiatric disorder, Tourette syndrome (TS), and constitute an example of disordered human volition. The neural correlates of tics are not well understood and have not been imaged selectively. METHODS: Event-related [(15)O]H(2)O positron emission tomography techniques combined with time-synchronized audio and videotaping were used to determine the duration of, frequency of, and radiotracer input during tics in each of 72 scans from 6 patients with TS. This permitted a voxel-by-voxel correlational analysis within Statistical Parametric Mapping of patterns of neural activity associated with the tics. RESULTS: Brain regions in which activity was significantly correlated with tic occurrence in the group included medial and lateral premotor cortices, anterior cingulate cortex, dorsolateral-rostral prefrontal cortex, inferior parietal cortex, putamen, and caudate, as well as primary motor cortex, the Broca's area, superior temporal gyrus, insula, and claustrum. In an individual patient with prominent coprolalia, such vocal tics were associated with activity in prerolandic and postrolandic language regions, insula, caudate, thalamus, and cerebellum, while activity in sensorimotor cortex was noted with motor tics. CONCLUSIONS: Aberrant activity in the interrelated sensorimotor, language, executive, and paralimbic circuits identified in this study may account for the initiation and execution of diverse motor and vocal behaviors that characterize tics in TS, as well as for the urges that often accompany them. Arch Gen Psychiatry. 2000;57:741-748

Subthreshold rTMS over pre-motor cortex has no effect on tics in patients with Gilles de la Tourette syndrome.

OBJECTIVE: A previous study showed no effect of 1Hz repetitive transcranial magnetic stimulation (rTMS) on tics in Gilles de la Tourette Syndrome (GTS). We modified the rTMS protocol in order to investigate some of the possible methodological reasons for the negative outcome in that study. METHODS: In a single blinded placebo-controlled cross-over study in five GTS patients without obsessive compulsive disorder we probed whether longer trains (1800 stimuli) of 1 Hz pre-motor cortex rTMS at 80% of active motor threshold and application to both hemispheres can improve tics in GTS. This was measured with the Yale Global Tic severity rating scale, the MOVES self-rating scale and video analysis. RESULTS: We found no significant effect of either left pre-motor cortex stimulation alone, or left pre-motor followed by right pre-motor cortex stimulation. CONCLUSIONS: These results suggest that the rTMS protocol used in this study is not useful for the treatment of tics in GTS. SIGNIFICANCE: rTMS protocols need to be modified substantially in order to explore their potential for the treatment of tics in GTS.

Differences in lower extremity alignment between males and females. Potential predisposing factors for knee injury.

AIM: The goal of this study was to compare measures of lower extremity alignment between males and females, which may account for gender differences in anterior cruciate ligament injury rates. Static lower extremity alignment has been implicated as predisposing individuals to anterior cruciate ligament injury and may vary between males and females. An initial step in identifying relevant risk factors for injury is to determine those factors that vary between genders. METHODS: Thirty male and 27 female college aged individuals with no history of lower extremity injury participated. Three indices of lower extremity alignment were measured on each subject: quadriceps angle, thigh foot angle, and subtalar joint range of motion ratio. RESULTS: Q-angles in females exceeded values for males by 4.4 degrees (p<0.001). Thigh foot angle for females was 3.6 degrees greater than for males (p=0.020). Subtalar joint movement ratio did not vary between genders (p=0.573). CONCLUSION: Previous research suggests that abnormal alignment may predispose individuals to anterior cruciate ligament injury. The present findings may help to explain the difference in anterior cruciate ligament injury rates between males and females. Any tangible links between lower extremity alignment and anterior cruciate ligament injury rates must be confirmed with prospective studies.