HES1 promoter activation dynamics reveal the plasticity, stemness and heterogeneity in neuroblastoma cancer stem cells.

Notch signaling and its downstream gene target HES1 play a critical role in regulating and maintaining cancer stem cells (CSCs), similar to as they do during embryonic development. Here, we report a unique subclass of Notch-independent Hes-1 (NIHes-1)-expressing CSCs in neuroblastoma. These CSCs maintain sustained HES1 expression by activation of HES1 promoter region upstream of classical CBF-1 binding sites, thereby completely bypassing Notch receptor-mediated activation. These stem cells have self-renewal ability and potential to generate tumors. Interestingly, we observed that NIHes-1 CSCs could transition to Notch-dependent Hes-1-expressing (NDHes-1) CSCs where HES1 is expressed by Notch receptor-mediated promoter activation. We observed that NDHes-1-expressing CSCs also had the potential to transition to NIHes-1 CSCs and during this coordinated bidirectional transition, both CSCs gave rise to the majority of the bulk cancer cells, which had an inactive HES1 promoter (PIHes-1). A few of these PIHes-1 cells were capable of reverting into a CSC state. These findings explain the existence of a heterogenic mode of HES1 promoter activation within the IMR-32 neuroblastoma cell line and the potential to switch between them. This article has an associated First Person interview with the first authors of the paper.

Cardiovascular autonomic function and baroreflex sensitivity in drug-resistant temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) is often associated with autonomic manifestations. Sudden unexpected death in epilepsy (SUDEP) is a leading cause of mortality in epilepsy. Cardiac disturbances and autonomic dysfunction are the potential mechanisms behind SUDEP. Though heart rate variability (HRV) and autonomic function tests are well studied in drug-resistant temporal lobe epilepsy, there is a paucity of data on baroreflex sensitivity (BRS), a better marker of cardiac mortality in this population. We aimed to study the interictal cardiac autonomic function and BRS in people living with drug-resistant temporal lobe epilepsy compared to healthy controls. MATERIALS AND METHODS: Thirty drug-resistant temporal lobe epilepsy (TLE) individuals and thirty healthy volunteers were recruited. Heart rate variability at rest, heart rate and blood pressure (BP) at rest, during deep breathing, postural change, BP response to isometric handgrip exercise, and baroreflex sensitivity were recorded in all study participants. The results were analyzed and compared between the two groups. RESULTS: Compared to controls, the resting heart rate, HRV, parasympathetic reactivity test, and BRS significantly differed in people living with drug-resistant TLE. Time-domain indices including SDNN (p < 0.001), RMSSD (p < 0.001), NN50 (p < 0.001), and pNN50 (p < 0.001) were significantly reduced in the patients compared to controls. In frequency-domain indices, the total power was reduced (p < 0.001) in drug-resistant TLE. The parasympathetic reactivity such as changes in heart rate during deep breathing (E: I) (p < 0.02) and postural change (30:15) (p < 0.005) were significantly reduced in the patients. Baroreflex sensitivity was also significantly reduced in the drug-resistant TLE group (p < 0.001). CONCLUSION: The present study findings are suggestive of parasympathetic dysfunction in drug-resistant TLE. Reduced HRV and BRS may increase the risk of SUDEP in people living with epilepsy.

Increased vascular risk factors, atherosclerosis, and psychological distress among Indian adults with refractory epilepsy in comparison to well-controlled epilepsy.

OBJECTIVE: Comparison of cardiovascular risk factors, atherosclerosis, and psychological distress among adults with refractory versus well-controlled epilepsy. METHODS: The cross-sectional study consisted of two groups of 40 people each: Group I - People with well-controlled epilepsy, Group II - People with refractory epilepsy. Age- and gender-matched people of 20-50 years were recruited. People who were diabetic, smokers, hypertensive, alcoholic, pregnant, with infections, and lactating women were excluded from the study. Biochemical parameters, fasting glucose, lipid profile, fasting insulin, leptin, adiponectin, Lp[a], hsCRP, TyG INDEX, HOMA1-%S, HOMA1-IR, HOMA1-%B, QUICKI, FIRI, AIP, AC, CLTI, MLTI, CRI-I, CRI-II, and CIMT were estimated. Stress levels [PSS-10, GAD-7 & PHQ-9] were assessed based on the scoring system from the questionnaires. RESULTS: The existence of metabolic syndrome, levels of triglycerides, TyG index, MDA, OSI, CIMT, AIP, and stress scores [PSS-10, GAD-7 & PHQ-9] were significantly higher in the refractory-epilepsy group in comparison to the well-controlled group. There were associations between LDL -C and CIMT as well as between GAD-7 and CIMT among all the study subjects. There were no significant differences in the levels of glucose homeostasis parameters, hsCRP, leptin, adiponectin, and Lp[a] between the two groups. Based on the ROC analysis, MDA [AUC = 0.853] and GAD-7 [AUC = 0.900] are useful in the differential diagnosis of the study groups. CONCLUSION: People with refractory epilepsy had increased levels of vascular risk factors, atherosclerosis, and stress levels compared to people with well-controlled epilepsy. Suitable disease management and therapeutic approaches to address cardiovascular and psychological distress could be planned out among people with refractory epilepsy to improve their quality of life.

Liquid Drug Delivery Approaches for the Treatment of Occlusive Arterial Disease: A Systematic Review.

OBJECTIVE: Local Liquid drug (LLD) delivery devices have recently emerged as a novel approach to treat peripheral arterial disease. This systemic review aims to identify and evaluate the clinical utility of the most commonly used delivery devices. METHODS: A systemic review was performed using the Medical Subjects Heading terms of "drug delivery," "liquid," "local," and "cardiovascular disease" in PubMed, Google Scholar, and Scopus. RESULTS: Four commonly used delivery devices were identified, including (1) the Bullfrog Micro-Infusion Device, (2) the ClearWay RX Catheter, (3) the Occlusion Perfusion Catheter, and (4) the Targeted Adjustable Pharmaceutical Administration. All have shown to successfully deliver liquid therapeutic into the target lesion and have exhibited favorable safety and efficacy profiles in preclinical and clinical trials. The LLD devices have the ability to treat very long or multiple lesions with a single device, providing a more economical option. The safety profile in LLD clinical studies is also favorable in view of recent concerns regarding adverse events with crystalline-paclitaxel-coated devices. CONCLUSION: There is clear clinical evidence to support the concept of local liquid delivery to treat occlusive arterial disease. CLINICAL IMPACT: The 'leave nothing behind' strategy has been at the forefront of the most recent innovations in the field of interventional cardiology and vascular interventions. Although drug coated balloons have overcome limitations associated with plain old balloon angioplasty and peripheral stents, recent safety concerns and cost considerations have impacted their usage. In this review, various liquid drug delivery devices are presented, showcasing their capabilities and success in both preclinical and clinical settings. These innovative liquid delivery devices, capable of targeted delivery and their ability to be re-used for multiple treatment sites, may provide solutions for current unmet clinical needs.

Risk factors of intracranial haemorrhage in preeclampsia: a case-control study.

Intracranial haemorrhage (ICH) is an uncommon but one of the most devastating and potentially fatal complications of preeclampsia. Most ICHs in pregnancy are reported in the absence of a vascular lesion, and severe systolic hypertension is thought to be an important risk factor even though many reports suggest that ICH can complicate preeclampsia even at lower blood pressure levels. In this case-control study of preeclamptic women, risk factors associated with ICH were compared in women who did and did not develop ICH. During the study period, ICH occurred in 1.8% (42/2167) pregnancies with preeclampsia, with 45.2% (n = 19/42) resulting in maternal mortality. HELLP syndrome (OR = 11.5; 95% CI 3.8-34.8), multiparity (OR 3.2; 95% CI 1.4-7.7), nausea/vomiting (OR = 3.6; 95% CI 1.4-9.3), and lower educational attainment (OR = 38.2; 95% CI 3.5-423.6) were associated with the increased probability of ICH. The incidence of caesarean birth (n = 29, 74.4% vs. n = 161, 34.5%) and neonatal mortality (n = 4, 13.3% vs. n = 17, 4.0%) were higher among preeclamptic who have ICH compared to those who did not have it. Improving awareness as well as early identification of those at risk of preeclampsia and complications can limit the impact of ICH among pregnant women with preeclampsia, especially in low- to middle-income countries.

Risk factors for posterior reversible encephalopathy syndrome in hypertensive pregnant women presenting with seizures.

Pregnant women developing generalised tonic-clonic seizures in the absence of a prior neurological disorder are often diagnosed as eclamptic. Posterior reversible encephalopathy syndrome (PRES) is a distinct neuroimaging condition associated with long-term sequelae, which may occur in pregnancy. Some reports suggested PRES to be the pathophysiological process leading to eclampsia, whereas others observed PRES and eclampsia to have varying clinical severity and risk factors. In this case-control study, risk factors associated with PRES were compared to those for eclampsia in women with hypertension presenting with seizures who had undergone neuroimaging. PRES was noted to occur in 22.5% (51/227) hypertensive pregnant women presenting with seizures that otherwise would have been classified as eclampsia. An additional 51 women with eclampsia underwent neuroimaging. Women who had PRES had higher systolic (155.3 vs 144.5, p = 0.04), diastolic (99.2 vs 93.4, p = 0.006) and mean (117.9 vs 110.4, p = 0.001) blood pressure at admission compared to those with eclampsia. Eclampsia and PRES may occur through a similar pathophysiological mechanism, resulting in the same spectrum of neurological complications of preeclampsia, with PRES being the severest form of the disease process. PRES is difficult to differentiate from eclampsia based on clinical and laboratory investigation, except for high blood pressures, without adjunctive MRI/CT neuroimaging. Future studies should assess the role of biomarkers as well as long-term neurological sequelae in pregnant women with a diagnosis of PRES.

Managing pregnancy in women with Sturge-Weber syndrome: case report and review of the literature.

Sturge-Weber syndrome (SWS) is a sporadic congenital neuro-cutaneous anomaly with capillary-venous malformation involving the brain, eye, and the ophthalmic division of the trigeminal nerve. In these cases, physiological changes in pregnancy, including hormonal and hemodynamic changes, may predispose to increased seizure frequency and even a life-threatening intracranial haemorrhage. There are only few case reports available about the management of women with pregnancy and SWS. We report two patients with SWS diagnosed in childhood and managed during pregnancy and reviewed the outcomes and complications during pregnancy in women with this disorder.

Neuroimaging Profile of drug-resistant Epilepsy from a Tertiary Care Center in South India.

BACKGROUND AND AIMS: Drug-resistant epilepsy (DRE) is a common and important neurological problem to identify with scope for curative surgical treatment if underlying cause is delineated. There are very few prospective structured studies in our population. This study aimed to look at the neuroimaging profile of DRE presenting in a tertiary care center in South India. MATERIALS AND METHODS: All patients diagnosed clinically as DRE as per International League Against Epilepsy (ILAE) criteria and who underwent magnetic resonance imaging (MRI) over a period of 24 months were included in the study. Their clinical and MRI features were documented and analyzed. RESULTS: A total of 150 patients diagnosed with DRE were included in the study. Clinically, 96 of them presented with generalized tonic-clonic seizures (GTCS), 36 with complex partial seizures (CPS), 14 with simple focal seizures, and two each with atonic seizures and focal seizures with secondary generalization. Magnetic resonance imaging (done in 1.5 T) was normal in 32%. In those with abnormal MRI, mesial temporal sclerosis (MTS) was the commonest pathology seen in 41.3%, followed by cortical malformations (6.7%), tumors (2.6%), vascular malformations (2.7%), and other nonspecific lesions (12%). CONCLUSION: The clinical and neuroimaging profile of DRE showed that DRE is more common in younger age (of less than 30 years); presents mainly with GTCS or CPS; mesial temporal sclerosis is the commonest underlying pathology which was bilateral in 8.6%; temporal lobe lesions predominate (49.3% of all DRE); and cortical malformation, low-grade tumors, and vascular lesions are other important causes.

Video teleconsultation services for persons with epilepsy during COVID-19 pandemic: An exploratory study from public tertiary care hospital in Southern India on feasibility, satisfaction, and effectiveness.

PURPOSE: During the COVID-19 pandemic, there is a large unmet need for follow-up services, particularly for chronic diseases such as epilepsy. Alternative methods to reach these people have become necessary. We assessed the feasibility, satisfaction, and effectiveness of video teleconsultation using mobile phones for managing persons with epilepsy (PWEs) on follow-up at a tertiary care center in the southern part of India. PATIENTS AND METHODS: We included PWEs aged 18 years and over who have been evaluated in person within the past six months, with details available in electronic health records (EHRs), and advised regular follow-up after getting telephonic consent. We excluded those requiring emergency care and those seeking teleconsultation for new symptoms. Participants were sent a message in English and in the local language about the possibility of a video teleconsultation. If willing, they were informed about the date, time, and technical requirements such as smartphones, browsing facilities, etc. Feasibility and effectiveness were assessed. Satisfaction/acceptability was assessed using Telemedicine Satisfaction Questionnaire. RESULTS: From June 2020 to October 2020, we selected 336 PWEs after screening 1100 records, and we tried video teleconsultation in 141 (41.8%) PWEs. We achieved successful video connections in 95 (28.2%) and audio consultations in 46 (13.6%). The median duration for calling the participants, making successful connections, and consultation was 8 (5-14) min. The majority required two (47.4%) or three (32.6%) attempts. Sixty-five PWEs (68.4%) used caretaker's mobile phones. We gave prescriptions to all, and 18 received new drugs. Out of 95 PWEs, 90% either 'agreed' or 'strongly agreed' on 12 out of 14 telemedicine satisfaction questions. CONCLUSION: Although we need to make video teleconsultation more feasible, our synchronous mobile video teleconsultation model is an effective and acceptable method to follow up PWEs. This real-time model has the advantage that it does not require any mobile application to be downloaded and installed. Further studies are needed to evaluate methods to improve the reach of these services particularly to vulnerable groups of the population.

Evaluation of auditory spectral resolution abilities in children with benign epilepsy with centrotemporal spikes using spectral temporally modulated ripple test.

PURPOSE: Spectral resolution is imperative for complex listening tasks such as understanding speech in the presence of background noise and has a significant role in children, particularly classroom learning. The present study evaluated the auditory spectral resolution abilities of children with Benign epilepsy with centrotemporal spikes (BECTS). METHOD: This cross-sectional study conducted from August 2017 to March 2020 recruited 23 children with clinical and electrographic features consistent with BECTS as cases. Fifteen age and sex matched typically developing children (TDC) were taken as controls. Spectral resolution abilities were evaluated using the recently developed Spectral temporally modulated Ripple test (SMRT). RESULTS: The mean age of the cases was 10.63 ±â€¯1.91 years with a slight male preponderance (69%). The mean (±SD) SMRT thresholds in the cases and controls were 5.90 (±1.91) and 7.21 (±1.03) respectively. The auditory spectral resolution threshold measured by SMRT in children with BECTS was observed to be significantly lower when compared to the controls (p of 0.021). CONCLUSION: Children with BECTS have a lower spectral resolution threshold by SMRT.

Interictal autonomic changes in persons with epilepsy (PWE) on carbamazepine (CBZ) versus other anti-seizure drug monotherapy: A cross-sectional study.

OBJECTIVE: Epilepsy is one of the most prevalent neurological conditions and carbamazepine is a commonly used anti-seizure drug (ASD), especially in developing nations. There are reports of carbamazepine causing atrioventricular conduction defects and autonomic dysfunctions and its implication in Sudden Unexpected Death in Epilepsy (SUDEP) is controversial. We planned this study to assess the effect of carbamazepine (CBZ) on autonomic function compared to other ASDs in persons with epilepsy. METHODS: In this cross-sectional study, we assessed the sympathetic and parasympathetic autonomic functions in persons with epilepsy (PWE) on CBZ versus other anti-seizure monotherapy using tests of heart rate variability including its time-, frequency- and non-linear domains, heart rate response to deep breathing, valsalva maneuver, and blood pressure response to isometric handgrip. RESULTS: Persons with epilepsy on CBZ monotherapy did not show a significant reduction in the time domain parameter SDRR compared to other ASDs used as monotherapy (mean ±â€¯SD, 38.04 ±â€¯18.75 ms vs 44.37 ±â€¯20.35 ms; p = 0.125). However, PWE on CBZ had significantly lower time-domain measurements including RMSSD (mean ±â€¯SD 31.95 ±â€¯17.29 ms vs 42.02 ±â€¯22.29 ms; p = 0.018), SDSD (mean ±â€¯SD 31.91 ±â€¯17.26 ms vs 41.96 ±â€¯22.27 ms; p 0.018), and pNN50 [median (IQR) 05.45(0.69-25.37) vs 16.38(2.32-36.83); p = 0.030]. Frequency domain measures of HRV, heart rate responses to deep breathing, valsalva maneuver and tilt-testing and BP responses to valsalva and tilt-testing were not significantly different between the groups. CONCLUSION: The findings of our study indicate reduced parasympathetic activity in persons on CBZ monotherapy compared to other ASDs, which may pose risk of SUDEP. Carbamazepine may thus be avoided in those at risk of autonomic dysfunction and SUDEP.

Deciphering the capacitance frequency technique for performance-limiting defect-state parameters in energy-harvesting perovskites.

With emerging thin-film PIN-based optoelectronics devices, a significant research thrust is focused on the passivation of trap states for performance enhancement. Among various methods, the capacitance frequency technique (CFT) is widely employed to quantify the trap-state parameters; however, the trapped charge-induced electrostatic effect on the same is not yet established for such devices. Herein, we present a theoretical methodology to incorporate such effects in the CF characteristics of well-established, but not limited to, carrier-selective perovskite-based PIN devices. We show that the electrostatic effect of trapped charges leads to non-linear energy bands in the perovskite layer, which results in the underestimation of the trap density from existing CFT models. Consequently, a parabolic band approximation with effective length (PBAEL) model is developed to accurately predict the trap density for shallow or deep states from CFT analysis. In addition, we demonstrate that the attempt-to-escape frequency, which dictates the trapping dynamics, can be well extracted by eliminating the electrostatic effect at a reduced perovskite thickness. We believe that our work provides a unified theoretical platform for CFT to extract trap-state parameters for a broad class of organic, inorganic, and hybrid semiconductor-based thin-film devices for energy-conversion applications such as solar cells, LEDs, artificial photosynthesis, etc.

A universal drug delivery catheter for the treatment of infrapopliteal arterial disease using liquid therapy.

OBJECTIVE: The objective of this study was to investigate the safety and feasibility of treating infrapopliteal lesions using a novel drug delivery catheter locally delivering liquid paclitaxel. BACKGROUND: Balloon angioplasty is currently the Gold Standard to treat below-the-knee disease; however, restenosis continues to be a great challenge following these percutaneous revascularization procedures. METHODS: The Occlusion Perfusion Catheter for Optimal Delivery of Paclitaxel for the Prevention of Endovascular Restenosis (COPPER-A) study-Below-the-Knee Cohort was a prospective, nonrandomized, multicenter, feasibility, and safety study that enrolled 35 patients at 11 participating sites. The safety endpoints at 1, 3, and 6 months were freedom from thrombosis, major amputation in the target limb and target limb related death. The efficacy endpoints were primary patency and freedom from clinically driven target lesion revascularization at 6 months. RESULTS: All patients tolerated the procedure well with no reports of adverse procedural events. Thirty-five patients were treated with a mean lesion length of 112 ± 81.2 mm with the lesion length range of 20-286 mm. At 6-month follow-up, primary patency was 89.3% and freedom from clinically driven target lesion revascularization was 96.4%. No patients demonstrated thrombosis, major amputation in the target limb and target limb related death at the 1-, 3- and 6-months follow-up intervals. CONCLUSIONS: The results of this multi-center study demonstrated that infrapopliteal arteries can be safely and effectively treated with liquid paclitaxel using the occlusion perfusion catheter.

Comparison of proximal and distal corticosteroid injections for carpal tunnel syndrome.

INTRODUCTION: Evidence for the efficacy of distal corticosteroid injection compared with proximal injection in carpal tunnel syndrome (CTS) is inadequate. METHODS: We conducted a randomized, double-blind noninferiority trial of 131 wrists with CTS. Forty milligrams of methylprednisolone was injected medial to the palmaris longus tendon 2 cm proximal to the wrist crease, or at the volar aspect, 2 to 3 cm distal to the wrist crease. Proximal & distal groups received a placebo. The primary outcome was difference in CTS Symptom Severity Scale (SSS) score at 1 month. Secondary outcome measures included the difference in SSS score at 3 months, Functional Status Scale (FSS) score at 1 and 3 months, and pain of injections. RESULTS: No significant differences were noted between groups in scores on the SSS and FSS. Pain was lower in the proximal group compared with the distal group. DISCUSSION: Corticosteroid injections for CTS distal to the wrist are not inferior to proximal injections, yet they are more painful.

Telemedicine in epilepsy: How can we improve care, teaching, and awareness?

Telemedicine (TM) is the use of telecommunications' technologies to provide medical information and services. Telehealth (TH) permits broader and psychosocial support for patients and their families. We aimed to highlight the importance of the use of TH for all aspects of epilepsy, either for the scientific aspects (e.g., research, education, care, management, etc.) or for the social matters (e.g., education, sensitization, association support, etc.). There is a deep gap in knowledge and use of TH in the developing and developed countries. Epilepsy is a condition responsible for 1% of the global burden of disease. More than 50 million people have epilepsy, and barriers to care include shortage of human resources, medical facilities, and resources. Eighty (80) percent of people with epilepsy (PWE) live in low- and middle-income countries. Telehealth has the potential of addressing limited resources and improving access to PWE across the globe.

Role of Ultrasound to Monitor Patients With Carpal Tunnel Syndrome Treated With a Local Corticosteroid.

OBJECTIVES: Carpal tunnel syndrome (CTS) is an entrapment neuropathy resulting from compression of the median nerve at the carpal tunnel (CT). We assessed the role of high-resolution ultrasound (US) in monitoring patients with CTS treated with corticosteroid injection. METHODS: We performed high-resolution US evaluations of the wrists of patients with CTS before and after treatment with local corticosteroid. Thirty-nine and 17 wrists were included for analysis at the end of 1 and 3 months, respectively. The cross-sectional area (CSA) and anteroposterior diameter (APD) of the median nerve at the CT and clinical and electrophysiologic data were recorded. We assessed whether changes in US measurements before and after the treatment correlated with clinical and electrophysiologic parameters. RESULTS: The Boston symptom severity scale (p < .01), Boston functional status scale (p < .01), median nerve motor latency (p = .017), median nerve sensory velocity (p = .003), and difference in motor latencies (p = 0.03) and difference in sensory latencies (p = .03) between median and ulnar nerves showed significant changes over 1 or/and 3 months compared to baseline values. Changes in the CSA and APD correlated with changes in some clinical and electrophysiologic parameters. However, measurements of the CSA and APD at 1 or 3 months were not significantly different from baseline values. CONCLUSIONS: High-resolution US parameters such as the APD and CSA of the median nerve at the CT inlet were not useful to monitor patients with CTS treated with corticosteroid injections.

New-onset interictal headache in Persons with epilepsy (PWE): A case-control study.

PURPOSE: In our personal experience, headache is a frequent complaint in Persons with epilepsy (PWE) receiving antiepileptic drugs (AEDs), carbamazepine (CBZ) in particular. There is hardly any systematic study on AEDs-associated headache. We assessed the association of new-onset interictal headache in PWE with CBZ compared with other AEDs and factors associated with it. METHODS: Two thousand PWE on AEDs were screened, and 165 persons having new-onset interictal headache were identified. Eight persons were excluded because of comorbid illnesses that could potentially contribute to a headache. Finally, 157 were recruited for the study. One hundred fifty-seven age- and sex-matched PWE on AEDs, without headache, were recruited as controls. Headache questionnaire based on the International Classification of Headache Disorders (ICHD-II) criteria was used. Demographic factors, seizure characteristics, type and dose of AEDs, findings on electroencephalogram (EEG), and magnetic resonance imaging (MRI)/computerized tomography (CT) were recorded. RESULTS: Among PWE with headache, the majority [88 (56.1%)] were on CBZ compared with other AEDs but not significantly different from controls. In 71 (45%) persons, the headache had migrainous character. In both univariate and multivariate analyses, lower seizure frequency and fewer EEG abnormalities were found to be independent predictors of headache. CONCLUSIONS: New-onset interictal headache is a significant issue in PWE; nonmigrainous headache is more common than the migrainous type. Carbamazepine was not found to have any predilection for new-onset interictal headache compared with other AEDs. A lower frequency of seizures and EEG abnormalities in PWE with headache may suggest that seizures contribute less to the development of headache and may further support the hypothesis that AEDs may be significant contributing factors for the headache.

Enhancing the antitumor efficacy of a cell-surface death ligand by covalent membrane display.

TNF superfamily death ligands are expressed on the surface of immune cells and can trigger apoptosis in susceptible cancer cells by engaging cognate death receptors. A recombinant soluble protein comprising the ectodomain of Apo2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) has shown remarkable preclinical anticancer activity but lacked broad efficacy in patients, possibly owing to insufficient exposure or potency. We observed that antibody cross-linking substantially enhanced cytotoxicity of soluble Apo2L/TRAIL against diverse cancer cell lines. Presentation of the ligand on glass-supported lipid bilayers enhanced its ability to drive receptor microclustering and apoptotic signaling. Furthermore, covalent surface attachment of Apo2L/TRAIL onto liposomes--synthetic lipid-bilayer nanospheres--similarly augmented activity. In vivo, liposome-displayed Apo2L/TRAIL achieved markedly better exposure and antitumor activity. Thus, covalent synthetic-membrane attachment of a cell-surface ligand enhances efficacy, increasing therapeutic potential. These findings have translational implications for liposomal approaches as well as for Apo2L/TRAIL and other clinically relevant TNF ligands.

Is 'burned-out hippocampus' syndrome a distinct electro-clinical variant of MTLE-HS syndrome?

AIM: To study the clinical, electrophysiological and imaging characteristics of patients with unilateral mesial temporal lobe epilepsy (MTLE) with contralateral ictal onset on scalp EEG, viz. 'burned-out hippocampus' syndrome (MTLE-BHS). METHODS: MTLE-BHS was defined as TLE with unilateral hippocampal sclerosis (HS) without any dual pathology on MRI and contralateral ictal onset on scalp EEG, unlike in classical hippocampal sclerosis (HS). Consecutive "MTLE-BHS" patients evaluated at our Centre for Comprehensive Epilepsy Care from January 2005 to July 2014 were studied. Twenty-five cases of classic MTLE-HS operated during the same period were also analyzed for comparison. RESULTS: Seventeen patients were diagnosed to have MTLE-BHS. Mean age of seizure onset was 9.5±7.7years and the mean duration of epilepsy was18.2±7.3years. Epigastric aura was more common in MTLE-HS and fear, secondary generalized seizures and temporal polar changes on MRI were more prevalent in the MTLE-BHS subgroup. In the latter group, five (29%) exhibited seizure semiology and 2 (12%) had interictal discharges discordant to the side of MTS. Eight (47%) patients in the MTLE-BHS sub-group had normal medial temporal volume on Scheltens scale. Eight patients among MTLE-BHS underwent surgery (4 following intracranial monitoring that localized to the side of HS) with Engel class I outcome at 1year follow-up in 6 and Engel class II outcome in 2. CONCLUSION: Attenuation of ipsilateral fast ictal rhythms on scalp EEG as well as neocortical changes are likely to be deterministic factors for MTLE-BHS as opposed to the severity of hippocampal atrophy. Considering good post-operative outcomes, intracranial monitoring for surgical selection is not mandatory in MTLE-BHS despite discordant semiology and ictal onset, in the presence of inter-ictal, functional imaging and neuropsychology data concordant to the side of HS.