3D printing technology is set to revolutionise medicine from prosthetics and tissue engineering, to customised medicines that are manufactured on demand

3D printing technology is set to revolutionise medicine from prosthetics and tissue engineering, to customised medicines that are manufactured on demand

Introduction: This study arose in the context of having to estimate risk to the musical abilities of a trained singer (patient A.M.) recommended for right anterior temporal lobectomy (RATL) to ameliorate medically intractable seizures. To date there has been no systematic investigation of reorganisation of musical functions in the presence of epileptogenic lesions, although it is well established that RATL can impair pitch processing in nonmusicians.Methods: Using fMRI, we compared the network activated by covert singing with lyrics in A.M. before and after surgery, while taking language activation and singing expertise into consideration. Before surgery, A.M. showed lower pitch accuracy of singing relative to individuals of similar experience (experts), thus we compared her to 12 healthy controls matched for singing pitch accuracy.Results: We found atypical organisation of A.M.'s singing network before surgery in the presence of a malformation of cortical development, including partial activation of the singing network of pitch-matched controls, and diffuse activation along the midline spreading laterally into association cortex, typical of generalised cortical hyperexcitability in intractable epilepsy. After tailored RATL, A.M. showed striking behavioural and neuroimaging changes, including significant improvement in pitch accuracy of singing relative to controls (p =.026) and the subjective experience of being a more technically proficient singer. This was accompanied by a significant reduction in cortical activation (p <.05, corrected), with a more focal, expert-like pattern of singing activation emerging, including decreased involvement of frontal language regions. These changes were largely specific to singing, with A.M. showing language activation and performance similar to controls.Conclusions: This case provides evidence for selective disruption of the singing network that reorganised after successful resection of an epileptogenic lesion and likely occurred through decoupling of the singing and language networks.

Objective: Retinal microvascular signs are markers of cardiovascular disease risk. There are limited data, on relationships between retinal microvascular signs and retinal microvascular endothelial function. We sought to determine the relationship of retinal vascular signs with retinal microvascular endothelial function in patients with or at high risk of coronary artery disease.Methods: Participants with atherosclerosis risk factors and coronary disease (n = 258; mean age 57 +/- 11 years) were recruited to have static and dynamic retinal vascular assessment. Retinal arteriolar dilatation in response to flicker light (FI-RAD) was measured using the Digital Vessel Analyser and expressed as percentage increase over baseline diameter. Static retinal photographs were acquired utilising a digital fundus camera for measurement of central retinal artery and vein equivalent (CRAE and CRVE), arteriovenous nicking (AVN) and focal arteriolar narrowing (FAN).Results: Intra-class correlation coefficient was 0.82 for flicker-light induced retinal arteriolar dilatation. There were modest associations in retinal vascular measurements between eyes. For each 10 mm decrease in retinal arteriolar diameter, the absolute increase in FI-RAD was 0.28% (95% CI 0.11, 0.45; p = 0.002) independent of age, gender and atherosclerosis risk factors. AVN and FAN were associated with attenuated FI-RAD (beta = -0.67%; 95% CI -1.20, -0.15; p = 0.012) and (beta = -0.83%; 95% CI -1.44, -0.23; p = 0.007) respectively after adjustment for age and gender.Conclusion: Assessment of retinal microvascular endothelial function is reproducible and correlated with retinal microvascular structure and signs, independent of atherosclerosis risk factors. Assessment of retinal vascular structure and function may provide insights into atherosclerotic disease.

Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in 10% of our cohort. Six of the 46 candidate genes had 1 or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathies to undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders.

ObjectiveStudies of focal epilepsy have revealed abnormalities of language organization; however, little attention has been paid to disorders of reading in this group. We hypothesized that language functional magnetic resonance imaging (fMRI) would reveal differences in language organization between focal epilepsy patients with and without reading difficulties.MethodsWe conducted language fMRI studies of 10 focal epilepsy patients with reading difficulties, 34 focal epilepsy patients without reading difficulties, and 42 healthy controls.ResultsWe defined regions of interests on the basis of activation patterns on an orthographic lexical retrieval task. Comparison of activations within these ROIs on a second Noun-Verb task revealed epilepsy-related effects (relative to healthy controls: reduced activation in left inferior frontal cortex), as well as greater activation in the right temporooccipital cortex specific to the reading difficulty group.SignificanceThese findings identify a focal epilepsy effect in the left frontal region (present in patients with and without reading difficulties), and a functional abnormality specific to the reading difficulty group localized to right temporooccipital cortexa region implicated in lexicosemantic processing. Our observations suggest a failure of left hemisphere specialization among focal epilepsy patients with reading difficulties. A PowerPoint slide summarizing this article is available for download in the Supporting Information section .

ObjectiveA Na-V beta 1(C121W) mouse model of human genetic epilepsy has enhanced neuronal excitability and temperature sensitivity attributed to a decreased threshold for action potential firing in the axon initial segment. To investigate the network consequences of this neuronal dysfunction and to establish a genetic disease state model we developed an in vitro assay to investigate CA1 network properties and antiepileptic drug sensitivity.MethodsCA1 network oscillations were induced by tetanic stimulation and average number of spikes, interspike interval (ISI), duration, and latency were measured in slices from control and Na-V beta 1(C121W) heterozygous mice in the presence and absence of retigabine or carbamazepine. Retigabine was also tested in a thermogenic seizure model.ResultsOscillations were reliably induced by tetanic stimulation and were maintained after severing connections between CA3 and CA1, suggesting a local recurrent circuit. Blocking alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), gamma-aminobutyric acid receptor A (GABA(A)), I-h, and T-type Ca2+ channels/receptors reduced the number of spikes. Slices from Na-V beta 1(C121W) heterozygous mice displayed several hallmarks of increased network excitability including increases in duration of the oscillation, the number and frequency of spikes and a decrease in their onset latency. The effect of genotype on network excitability was temperature sensitive, as it was seen only at elevated temperatures. Carbamazepine and retigabine were more effective in reducing network excitability in slices from Na-V beta 1(C121W) heterozygous mice. Retigabine appeared to be more effective in suppressing time to thermogenic seizures in Na-V beta 1(C121W) heterozygous mice compared to wild-type (WT) controls.SignificanceHippocampal networks of the Na-V beta 1(C121W) heterozygous mouse model of genetic epilepsy show enhanced excitability consistent with earlier single neuron studies bridging important scales of brain complexity relevant to seizure genesis. Altered pharmacosensitivity further suggests that genetic epilepsy models may be useful in the development of novel antiepileptic drugs that target disease state pathology.A PowerPoint slide summarizing this article is available for download in the Supporting Information section .

Transcranial magnetic stimulation was used to study the effect of recurrent seizures on cortical excitability over time in epilepsy. 77 patients with firm diagnoses of idiopathic generalized epilepsy (IGE) or focal epilepsy were repeatedly evaluated over three years. At onset, all groups had increased cortical excitability. At the end of follow-up the refractory group was associated with a broad increase in cortical excitability. Conversely, cortical excitability decreased in all seizure free groups after introduction of an effective medication.

Our objective was to evaluate the effectiveness of implementing standardized guidelines to mitigate metabolic and bone side effects of androgen deprivation therapy (ADT) in men with non-metastatic prostate cancer. We conducted a 2-year prospective cohort study at a tertiary referral teaching hospital. Overall, 236 men (mean age 69.8 +/- 7.1) commencing ADT for non-metastatic prostate cancer attended a baseline clinic visit between 2007 and 2011, and 153 men were eligible for follow-up after 2years of continuous ADT. Of these, 113 men had data available for analysis at 2years. At baseline, 87% of the men were overweight or obese, 61% had hypertension, 56% had hypercholesterolaemia, 27% prior cardiovascular disease, 11% osteoporosis and 40% osteopaenia. After 2years of ADT, there was an increase in waist circumference (+2.8 +/- 6.3cm, p=0.002), and, in men without diabetes, in HbA1c (+0.13 +/- 0.34%, p=0.019). Despite this, due to treatment, there were significant reductions in total cholesterol (-0.35 +/- 1.00mmol/L, p<0.001), and blood pressure (systolic -7.6 +/- 19.3mmHg; diastolic -4.7 +/- 11.6mmHg, p<0.001). After 2years, men not receiving anti-resorptive therapy experienced a significant decline in lumbar spine (-0.042 +/- 0.134g/cm2, p=0.012) and total hip bone mineral density (BMD) (-0.026 +/- 0.036g/cm2, p<0.001), whereas bisphosphonate treatment maintained stable BMD. Prevalence of anaemia increased from 13.8 to 32.5%. Older age independently predicted a greater drop in haemoglobin (p=0.005). We conclude that a structured approach to assess and treat men undergoing ADT effectively improves cardiovascular risk factors and prevents bone decay. Larger studies are needed to determine effects on cardiovascular outcomes, fracture prevention and survival.